Clinical trial NCT02864394
Conditions: Carcinoma, Non-Small-Cell Lung
Keywords: Programmed Cell Death-1 (PD1, PD-1) Programmed Death-Ligand 1 (PDL1, PD-L1)
Sponsor: Merck Sharp & Dohme LLC
Start date: 2016-09-07; Completion date: 2022-10-14
Enrollment: 425 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the efficacy of pembrolizumab (MK-3475) versus docetaxel in participants with non-small cell lung cancer (NSCLC) with programmed cell death ligand 1 (PD-L1) positive tumors who have experienced disease progression after platinum-containing systemic therapy. The primary hypotheses of this study are that pembrolizumab (MK-3475) prolongs overall survival (OS) and that pembrolizumab prolongs progression-free survival (PFS), compared to docetaxel in participants with PD-L1 positive tumors.

Detailed description:

Arms: arm 1: Participants with NSCLC receive pembrolizumab 2 mg/kg intravenously (IV) over 30 minutes every 3 weeks (Q3W) for up to 35 doses (approximately 24 months). arm 2: Participants with NSCLC receive Docetaxel 75 mg/m\^2 IV over 1 hour Q3W until disease progression, toxicity, investigator's decision to discontinue, or consent withdrawal.
Interventions: intervention 1: Pembrolizumab intervention 2: Docetaxel
Intervention descriptions: intervention 1: Pembrolizumab administered IV at 2 mg/kg on Day 1 of each 21-day cycle for up to 35 doses (approximately 24 months). intervention 2: Docetaxel administered IV at 75 mg/m\^2 on Day 1 of each 21-day cycle as per the approved product label.

Protocol documents:
Prot_SAP_001.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Multinational, Multicenter, Phase III,
Randomized Open-label Trial of
Pembrolizumab versus Docetaxel in Previously
Treated Subjects with Non-Small Cell Lung
Cancer
NCT02864394
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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, NJ 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File
Binder (or equivalent).
TITLE:
A Multinational, Multicenter, Phase III, Randomized Open-label Trial of Pembrolizumab 
versus Docetaxel in Previously Treated Subjects with Non-Small Cell Lung Cancer
IND NUMBER:  [Not Applicable]
EudraCT NUMBER:  [Not Applicable]
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 10
SUMMARY OF CHANGES................................................................................................ 11
1.0
TRIAL SUMMARY.................................................................................................. 14
2.0
TRIAL DESIGN........................................................................................................ 15
Trial Design ........................................................................................................... 15
Trial Diagram........................................................................................................ 16
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 17
Primary Objective(s) & Hypothesis(es).............................................................. 17
Secondary Objective(s) & Hypothesis(es)........................................................... 17
Exploratory Objectives......................................................................................... 17
4.0
BACKGROUND & RATIONALE.......................................................................... 18
Background ........................................................................................................... 18
Pharmaceutical and Therapeutic Background .................................................... 18
Ongoing Clinical Trials....................................................................................... 19
Rationale................................................................................................................ 19
Rationale for the Trial and Selected Subject Population .................................... 19
Rationale for Dose Selection/Regimen/Modification......................................... 20
Rationale for Endpoints ...................................................................................... 21
4.2.3.1
Efficacy Endpoints....................................................................................... 21
4.2.3.2
Safety Endpoints.......................................................................................... 21
4.2.3.3
Immune-related RECIST ............................................................................. 21
4.2.3.4
Patient Reported Outcome........................................................................... 22
4.2.3.5
Future Biomedical Research........................................................................ 22
Benefit/Risk ........................................................................................................... 23
5.0
METHODOLOGY ................................................................................................... 24
Entry Criteria........................................................................................................ 24
Diagnosis/Condition for Entry into the Trial...................................................... 24
Subject Inclusion Criteria.................................................................................... 24
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Subject Exclusion Criteria .................................................................................. 26
Trial Treatment(s) ................................................................................................ 28
Dose Selection/Modification .............................................................................. 29
5.2.1.1
Dose Selection (Preparation) ....................................................................... 29
5.2.1.2
Dose Modification (Escalation/Titration/Other).......................................... 29
Timing of Dose Administration.......................................................................... 34
Trial Blinding/Masking....................................................................................... 34
Randomization or Treatment Allocation............................................................ 34
Stratification.......................................................................................................... 35
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 35
Acceptable Concomitant Medications ................................................................ 35
Prohibited Concomitant Medications.................................................................. 35
Rescue Medications & Supportive Care............................................................. 36
Supportive Care Guidelines ................................................................................ 36
Diet/Activity/Other Considerations..................................................................... 38
Diet...................................................................................................................... 38
Use in Pregnancy ................................................................................................ 38
Subject Withdrawal/Discontinuation Criteria................................................... 39
Subject Replacement Strategy............................................................................. 40
Beginning and End of the Trial ........................................................................... 40
Clinical Criteria for Early Trial Termination ................................................... 40
Post Pembrolizumab (MK-3475)/Docetaxel Therapies..................................... 41
6.0
TRIAL FLOW CHART ........................................................................................... 42
Treatment Phase ................................................................................................... 42
Post-Treatment Follow-Up Phase........................................................................ 46
Second Course Treatment and Follow-up Phase for Pembrolizumab Arm.... 48
7.0
TRIAL PROCEDURES ........................................................................................... 52
Trial Procedures ................................................................................................... 52
Administrative Procedures.................................................................................. 52
7.1.1.1
Informed Consent......................................................................................... 52
7.1.1.1.1
General Informed Consent.................................................................... 52
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7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 52
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 53
7.1.1.3
Subject Identification Card .......................................................................... 53
7.1.1.4
Medical History ........................................................................................... 53
7.1.1.5
Prior and Concomitant Medications Review............................................... 53
7.1.1.5.1
Prior Medications.................................................................................. 53
7.1.1.5.2
Concomitant Medications..................................................................... 53
7.1.1.6
Non-small cell lung cancer (NSCLC) Disease Details and Treatments ...... 53
7.1.1.6.1
Disease Details...................................................................................... 53
7.1.1.6.2
Prior Treatment..................................................................................... 54
7.1.1.6.3
Subsequent Antineoplastic Therapy Status........................................... 54
7.1.1.7
Assignment of Screening Number............................................................... 54
7.1.1.8
Assignment of Treatment/Randomization Number..................................... 54
7.1.1.9
Trial Compliance (Medication/Diet/Activity/Other)................................... 54
Clinical Procedures/Assessments........................................................................ 55
7.1.2.1
Adverse Event (AE) Monitoring.................................................................. 55
7.1.2.2
Physical Exam.............................................................................................. 55
7.1.2.2.1
Full Physical Exam ............................................................................... 55
7.1.2.2.2
Directed Physical Exam........................................................................ 55
7.1.2.3
Vital Signs.................................................................................................... 55
7.1.2.4
12-Lead Electrocardiogram (ECG).............................................................. 55
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale ........... 56
7.1.2.6
Tumor Imaging and Assessment of Disease................................................ 56
7.1.2.6.1
Initial Tumor Imaging........................................................................... 56
7.1.2.6.2
Tumor Imaging During Trial ................................................................ 57
7.1.2.6.3
Assessment of Disease.......................................................................... 57
irRECIST Assessment of Disease.................................................. 58
Laboratory Procedures/Assessments .................................................................. 62
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 62
7.1.3.2
Molecular Testing ........................................................................................ 63
7.1.3.3
Future Biomedical Research........................................................................ 64
Other Procedures................................................................................................. 64
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7.1.4.1
Withdrawal/Discontinuation........................................................................ 64
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 64
7.1.4.2
Blinding/Unblinding .................................................................................... 64
7.1.4.3
Patient Reported Outcomes (PROs)............................................................. 64
7.1.4.4
Tumor Tissue Collection.............................................................................. 65
7.1.4.5
Calibration of Critical Equipment................................................................ 65
Visit Requirements.............................................................................................. 66
7.1.5.1
Screening...................................................................................................... 66
7.1.5.2
Treatment Phase........................................................................................... 66
7.1.5.3
Post-Treatment Follow-up Phase................................................................. 66
7.1.5.3.1
Safety Follow-up Visit.......................................................................... 67
7.1.5.3.2
Follow-up Visits ................................................................................... 67
7.1.5.3.3
Survival Follow-up ............................................................................... 67
7.1.5.4
Second Course Phase................................................................................... 67
7.1.5.5
Survival Status ............................................................................................. 68
Assessing and Recording Adverse Events .......................................................... 68
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 69
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 70
Immediate Reporting of Adverse Events to the Sponsor.................................... 70
7.2.3.1
Serious Adverse Events ............................................................................... 70
7.2.3.2
Events of Clinical Interest............................................................................ 71
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 72
Evaluating Adverse Events................................................................................. 72
Sponsor Responsibility for Reporting Adverse Events ...................................... 75
TRIAL GOVERNANCE AND OVERSIGHT................................................... 75
Executive Oversight Committee......................................................................... 75
Data Monitoring Committee............................................................................... 75
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 75
Statistical Analysis Plan Summary ..................................................................... 76
Responsibility for Analyses/In-House Blinding ................................................. 77
Hypotheses/Estimation......................................................................................... 77
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Analysis Endpoints ............................................................................................... 78
Efficacy Endpoints.............................................................................................. 78
Safety Endpoints ................................................................................................. 78
Analysis Populations............................................................................................. 79
Efficacy Analysis Populations ............................................................................ 79
Safety Analysis Populations ............................................................................... 79
Statistical Methods................................................................................................ 79
Statistical Methods for Efficacy Analyses.......................................................... 79
8.6.1.1
Overall Survival (OS) .................................................................................. 79
8.6.1.2
Progression-Free Survival (PFS) ................................................................. 80
8.6.1.3
Objective Response Rate (ORR) ................................................................. 82
8.6.1.4
Duration of Response (DOR)....................................................................... 82
Statistical Methods for Safety Analyses ............................................................. 84
Summaries of Demographic and Baseline Characteristics ................................. 86
Interim Analyses ................................................................................................... 86
Multiplicity ............................................................................................................ 87
Sample Size and Power Calculations .................................................................. 88
Subgroup Analyses and Effect of Baseline Factors ........................................... 88
Compliance (Medication Adherence).................................................................. 89
Extent of Exposure................................................................................................ 89
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 89
Investigational Product ........................................................................................ 89
Packaging and Labeling Information ................................................................. 90
Clinical Supplies Disclosure................................................................................. 90
Storage and Handling Requirements.................................................................. 90
Discard/Destruction/Returns and Reconciliation .............................................. 90
Standard Policies................................................................................................... 90
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 91
Confidentiality....................................................................................................... 91
Confidentiality of Data ....................................................................................... 91
Confidentiality of Subject Records..................................................................... 91
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Confidentiality of Investigator Information........................................................ 91
Confidentiality of IRB/IEC Information............................................................. 92
Compliance with Financial Disclosure Requirements....................................... 92
Compliance with Law, Audit and Debarment ................................................... 92
Compliance with Trial Registration and Results Posting Requirements........ 94
Quality Management System............................................................................... 94
Data Management................................................................................................. 95
Publications ........................................................................................................... 95
11.0
LIST OF REFERENCES......................................................................................... 96
12.0
APPENDICES........................................................................................................... 99
Merck Code of Conduct for Clinical Trials........................................................ 99
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 101
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 107
ECOG Performance Status................................................................................ 118
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............. 119
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors .............................................................. 120
Strong Inhibitors of CYP3A4 ............................................................................ 121
Contraceptive Guidance..................................................................................... 122
Definitions......................................................................................................... 122
Contraception Requirements............................................................................. 123
13.0
SIGNATURES......................................................................................................... 124
Sponsor's Representative ................................................................................... 124
Investigator.......................................................................................................... 124
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values................................................... 25
Table 2
Trial Treatment .................................................................................................. 28
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-
related AEs Associated with Pembrolizumab.................................................... 30
Table 4
Pembrolizumab (MK-3475) Infusion Reaction Dose Modification and 
Treatment Guidelines......................................................................................... 37
Table 5
Imaging and Treatment After 1st Radiologic Evidence of PD.......................... 60
Table 6
Laboratory Tests ................................................................................................ 63
Table 7
Evaluating Adverse Events................................................................................ 73
Table 8
Censoring rules for Primary and Sensitivity Analyses of PFS.......................... 81
Table 9
Censoring Rules for DOR.................................................................................. 82
Table 10
Analysis Strategy for Key Efficacy Endpoints.................................................. 83
Table 11
Analysis Strategy for Safety Parameters ........................................................... 85
Table 12
Summary of Timing, Sample Size and Decision Guidance of Interim 
Analyses and Final Analyses............................................................................. 87
Table 13
Product Descriptions.......................................................................................... 89
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LIST OF FIGURES
Figure 1
Trial Design ....................................................................................................... 16
Figure 2
Imaging and Treatment for Clinically Stable Subjects after First Radiologic 
Evidence of PD Assessed by the Site ................................................................ 61
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 05
14-JUL-2021
To add standard extension study language, update contraception language, and updated 
the dose modification table.
Amendment 04
1-OCT-2018
Amendment
Amendment 03
19-DEC-2017
Amendment
Amendment 02
15-MAR-2017
Amendment
Amendment 01
30-AUG-2016
Amendment
Original Protocol
15-APR-2016
Original Protocol
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
1.0
Trial Summary/Duration of 
Participation
Added: 
Once the subject has achieved the study 
objective or the study has ended, the 
subject is discontinued from the study 
and may be enrolled in an extension 
study to continue protocol defined
assessments and treatment.
To include the extension study.
2.2 
Trial Diagram
Added: 
Study Completion and Pembrolizumab
Extension Study
To include the extension study.
5.1.2
Subject Inclusion Criteria
Updated Inclusion Criterion #15 to 
reflect no contraceptive requirement for 
pembrolizumab and 90 days for 
docetaxel for males.
In Inclusion Criteria #14 and #15, cross-
references to the contraception guidance 
redirected to Section 12.8.
To reflect current contraceptive 
requirements. 
5.1.3
Subject Exclusion Criteria
Removed Exclusion Criterion #19.
Redundant with language 
available elsewhere in the 
protocol.
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Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
5.7.2
Contraception
Deleted.
Not in the updated template. 
Redundant with language 
available elsewhere in the 
protocol.
5.7.4
Use in Nursing Mothers
Deleted.
Not in the updated template. 
Redundant with language 
available elsewhere in the 
protocol.
5.10
Beginning and End of the 
Trial
Added: Upon study completion, subjects
are discontinued and may be enrolled in 
a pembrolizumab extension study, if 
available.
To include the extension study.
5.2.1.2
Dose Modification 
(Escalation/Titration/Other)
In table of dose modification and 
toxicity management guidelines for 
immune-related AEs associated with 
pembrolizumab: 
Added dose modification and toxicity 
management guidelines for neurological 
toxicities and exfoliative dermatologic 
conditions.
Modified guidelines for pneumonitis,
diarrhea/colitis, myocarditis, and other 
immune-related AEs.
To be aligned with current 
pembrolizumab package insert.
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Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
5.6.1
Supportive Care Guidelines
Added guidance for the use of 
epinephrine in table for pembrolizumab 
(MK-3475) infusion reaction dose 
modification and treatment guidelines.
To be aligned with current 
pembrolizumab package insert.
12.8
Contraception Guidance
Added.
To reflect current guidance.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
No additional changes.
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1.0 TRIAL SUMMARY
Abbreviated Title
Pembrolizumab versus Docetaxel in second line NSCLC
Trial Phase
Phase III
Clinical Indication
The treatment of subjects with non-small cell lung cancer (NSCLC) whose 
tumors are positive for PD-L1 expression who have experienced disease 
progression after a platinum-containing systemic therapy
Trial Type
Interventional
Type of control
Active Control without Placebo
Route of 
administration
Intravenous
Trial Blinding
Unblinded Open-label
Treatment Groups
Pembrolizumab (MK-3475): 2 mg/kg every three weeks (Q3W)
Docetaxel: 75 mg/m2 Q3W
Number of trial 
subjects
Approximately 400 subjects will be enrolled.
Estimated duration of 
trial
The sponsor estimates that the trial will require approximately 4 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 (ICF) through the final contact. After a screening 
phase of up to 42 days, eligible subjects will receive assigned treatment on 
Day 1 of each 3-week dosing cycle. Treatment with pembrolizumab (MK-
3475) will continue until two years of delivery of pembrolizumab (MK-
3475) every 3 weeks and no documented progression of disease, or 35 
administrations of study medication, whichever is later, documented disease 
progression, unacceptable adverse event(s), intercurrent illness that prevents 
further administration of treatment, investigator’s decision to withdraw the 
subject, subject withdraws consent, pregnancy of the subject, noncompliance 
with trial treatment or procedure requirements, or administrative reasons. 
Pembrolizumab (MK-3475) treated subjects who attain complete response 
(CR) per Immune-Related Response Criteria (irRECIST) may be considered 
for stopping trial treatment. These subjects, as well as those subjects 
assigned to the pembrolizumab arm that stop trial therapy after 35 treatment 
administrations for reasons other than disease progression or intolerability, 
may be eligible for re-treatment with pembrolizumab for up to 17 
administrations (12 months) in the Second Course Phase after they have
experienced radiographic disease progression at the discretion of the
investigator according to the criteria in Section 7.1.5.4.
After the end of treatment, each subject will be followed for a minimum of 
30 days for adverse event monitoring (serious adverse events will be 
collected for up to 90 days after the end of treatment unless the subject starts 
a new anticancer therapy between days 31 and 90). Subjects who have 
discontinued study treatment without confirmed disease progression will 
have post-treatment follow-up for disease status until initiating a non-study 
cancer treatment, experiencing disease progression, death, withdrawing 
consent, or becoming lost to follow-up whichever occurs first.
Once the subject has achieved the study objective or the study has ended, the 
subject is discontinued from the study and may be enrolled in an extension 
study to continue protocol-defined assessments and treatment.
Randomization Ratio
1: 1
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2.0 TRIAL DESIGN
Trial Design
This is a multi-country, multi-center, randomized, open-label, Phase III trial of intravenous 
(IV) pembrolizumab (MK-3475) versus docetaxel in subjects with NSCLC with programmed 
cell death ligand 1 (PD-L1) positive tumors who have experienced disease progression after 
platinum-containing systemic therapy. Approximately 400 PD-L1 positive subjects (defined 
as tumor proportion score (TPS) ≥1%) will be enrolled in this trial to examine the efficacy of 
pembrolizumab (MK-3475) compared to docetaxel in a population enriched for PD-L1 
positive expression. The enrollment will continue until approximately 216 subjects with TPS 
≥50% are randomized into pembrolizumab (MK-3475) arm and docetaxel arm. Subjects will 
be randomized in a 1:1 ratio to receive pembrolizumab (MK-3475) 2 mg/kg Q3W or 
docetaxel at 75 mg/m2 every 3 weeks (Q3W) (Figure 1). Randomization to pembrolizumab 
(MK-3475) or docetaxel will be unblinded, that is, the investigator and subjects will know 
the treatment administered. Subjects will be stratified by extent of tumoral PD-L1 expression 
(TPS 1-49% vs. TPS ≥50%).  
Subjects will be evaluated every 9 weeks (63 ± 7 days) with radiographic imaging to assess 
response to treatment. Investigators will make all treatment-based decisions using Immune-
Related Response Criteria (irRECIST) for subject receive pembrolizumab. Images will be 
assessed using Response Evaluation Criteria In Solid Tumors 1.1 (RECIST 1.1) for 
determination of objective response rate (ORR) and Progression-Free Survival (PFS). 
Adverse events (AEs) will be monitored throughout the trial and graded in severity according 
to the guidelines outlined in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0. Treatment with pembrolizumab (MK-3475) will continue until two 
years of delivery of pembrolizumab (MK-3475) every 3 weeks and no documented 
progression of disease, or 35 administrations of study medication, whichever is later, 
documented disease progression, unacceptable adverse event(s), intercurrent illness that 
prevents further administration of treatment, investigator’s decision to withdraw the subject, 
subject withdraws consent, pregnancy of the subject, noncompliance with trial treatment or 
procedure requirements, or administrative reasons. Pembrolizumab (MK-3475) treated 
subjects who attain an investigator-determined confirmed complete response (CR) per 
Immune-Related Response Criteria in Solid Tumor (irRECIST) may consider stopping trial 
treatment. These subjects, as well as those subjects assigned to the pembrolizumab arm that 
stop trial therapy after 35 treatment administrations for reasons other than disease 
progression or intolerability, may be eligible for re-treatment with open-label pembrolizumab 
monotherapy after they have experienced radiographic disease progression at the discretion 
of the investigator according to defined criteria in Section 7.1.5.4. This re-treatment will be 
the Second Course Phase. Response or progression in the Second Course Phase will not 
count towards the ORR and PFS endpoints in this trial.
After the end of treatment, each subject will be followed for a minimum of 30 days for 
adverse event monitoring (serious adverse events will be collected for up to 90 days after the 
end of treatment unless the subject starts a new anticancer therapy between days 31 and 90). 
Subjects who have discontinued study treatment without confirmed disease progression will 
have post-treatment follow-up for disease status until initiating a non-study cancer treatment, 
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experiencing disease progression, death, withdrawing consent, or becoming lost to follow-up
whichever occurs first. In these subjects, the imaging evaluation will continue as scheduled. 
Patients in the docetaxel group will not be allowed to cross over to MK-3475. Subjects in the 
Docetaxel arm may switch to another anti PD-1 treatment following the verification of 
progressive disease by blinded central radiologists’ review.
The primary objectives of the trial are provided in Section 3.1. Refer to Section 7.1.4.4 for 
the requirement of tissue collection.
This trial will use an independent, external Data Monitoring Committee (eDMC) to monitor 
safety and efficacy. Detail of eDMC is provided in Section 7.3.2.
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.
Trial Diagram
The trial design is depicted in Figure 1.
Figure 1
Trial Design
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
In subjects with NSCLC whose tumors are positive (TPS ≥1%) for PD-L1 expression and 
have experienced disease progression after at least one platinum-containing systemic therapy.
(1) Objective: To evaluate OS in the TPS ≥50% stratum treated with pembrolizumab (MK-
3475) compared to docetaxel.
Hypothesis: Pembrolizumab (MK-3475) prolongs OS in TPS ≥50% stratum compared to 
docetaxel.
(2) Objective: To evaluate OS in the TPS ≥1% population treated with pembrolizumab 
(MK-3475) compared to docetaxel.
Hypothesis: Pembrolizumab (MK-3475) prolongs OS in TPS ≥1% population compared 
to docetaxel.
(3) Objective: To evaluate PFS per RECIST 1.1 by blinded central radiologists’ review in 
the TPS ≥50% stratum treated with pembrolizumab (MK-3475) compared to docetaxel.
Hypothesis: Pembrolizumab (MK-3475) prolongs PFS per RECIST 1.1 by blinded 
central radiologists’ review in the TPS ≥50% stratum compared to docetaxel. 
(4) Objective: To evaluate PFS per RECIST 1.1 by blinded central radiologists’ review in 
the TPS ≥1% population treated with pembrolizumab (MK-3475) compared to docetaxel.
Hypothesis: Pembrolizumab (MK-3475) prolongs PFS per RECIST 1.1 by blinded 
central radiologists’ review in the TPS ≥1% population compared to docetaxel.
The study is considered to have met its primary objective if pembrolizumab (MK-3475) is 
superior to docetaxel in OS at the interim or final analysis in the TPS ≥50% stratum.
Secondary Objective(s) & Hypothesis(es)
In subjects with NSCLC whose tumors are positive (TPS ≥1%) for PD-L1 expression and 
have experienced disease progression after at least one platinum-containing systemic therapy.
(1) Objective: To evaluate safety and tolerability profile of pembrolizumab (MK-3475) in 
subjects whose tumors are TPS ≥1%.
(2) Objective: To evaluate ORR and Duration of Response (DOR) per RECIST 1.1 by 
blinded central radiologists’ review in the TPS ≥50% stratum and in the TPS ≥1% 
population treated with pembrolizumab (MK-3475) compared to docetaxel.
Exploratory Objectives
In subjects with NSCLC whose tumors are positive (TPS ≥1%) for PD-L1 expression and 
have experienced disease progression after at least one platinum-containing systemic therapy.
(1) Objective: To evaluate PFS, ORR and DOR per irRECIST by blinded central 
radiologists’ review in subjects whose tumors have TPS ≥50% treated with 
pembrolizumab (MK-3475) compared to docetaxel.
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(2) Objective: To evaluate changes in health-related quality-of-life assessments from 
baseline in subjects in the TPS ≥50% stratum treated with pembrolizumab (MK-3475) 
compared to docetaxel using the EORTC QLQ C-30 and EORTC QLQ LC-13.
(3) Objective: To characterize utilities in subjects in the TPS ≥50% stratum treated with 
pembrolizumab (MK-3475) compared to docetaxel using the EuroQoL EQ-5D.
4.0 BACKGROUND & RATIONALE
Background
Refer to the Investigator’s Brochure (IB) for detailed background information on 
pembrolizumab (MK-3475).
Pharmaceutical and Therapeutic Background
The programmed cell death 1 (PD-1) pathway represents a major immune control switch 
which may be engaged by tumor cells to overcome active T-cell immune surveillance. The 
normal function of PD-1, expressed on the cell surface of activated T cells, under healthy 
conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions [1-4]. PD-1 is an immunoglobulin (Ig) superfamily member which has 
been shown to negatively regulate antigen receptor signaling upon engagement of its ligands 
(PD-L1 and/or PD-L2) [5; 6]. PD-L1 and PD-L2 are constitutively expressed at low levels in 
healthy organs, or can be induced in various tumors. High levels of expression of PD-L1 on 
tumor cells (and to a lesser extent of PD-L2) has been found to correlate with poor prognosis 
and poor survival in various cancer types, including renal cell carcinoma (RCC) [7], 
pancreatic carcinoma [8], hepatocellular carcinoma [9], ovarian carcinoma [10] and NSCLC.
The observed correlation of clinical prognosis with PD-L1 expression in multiple cancers 
suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and 
should be considered as an attractive target for therapeutic intervention. Therapeutic studies 
in mouse models have shown that administration of antibodies blocking PD-1/PD-L1 
interaction enhances infiltration of tumor-specific CD8+ T-cells and leads ultimately to 
tumor rejection, either as a mono-therapy or in combination with other treatment modalities 
[8; 11-15]. Monoclonal antibodies (mAb) against PD-1 such as Nivolumab [16] (BMS-
936558, MDX-1106) have been tested in multiple human solid tumors and promising clinical 
activity was noted in melanoma, renal cell carcinoma (RCC), and NSCLC at multiple doses 
up to 10 mg/kg Q2W. Nivolumab was also well tolerated up to the dose of 20 mg/kg in a 
phase I study in Japanese subjects with advanced solid tumors, and showed anti-tumor 
activities in melanoma, colorectal cancer (CRC), and thyroid carcinoma.
Pembrolizumab (MK-3475) is a potent and highly selective humanized monoclonal anti-PD-
1 mAb of the IgG4/kappa isotype designed to directly block the interaction between PD-1 
and its ligands PD-L1 and PD-L2. This blockade enhances functional activity of the target 
lymphocytes to facilitate tumor regression and ultimately immune rejection. The detailed 
information on pembrolizumab (MK-3475) is described in the IB. 
Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer death 
worldwide including China. NSCLC accounts for approximately 85% of all lung cancers. 
The mortality of NSCLC is much higher in China than in US and Europe. In China, age-
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standardized incidence rate is 33.5 per 100,000 persons, with an estimated number of 
522,050 patients per year. The age-standardized mortality rate is 28.7 per 100,000 persons, 
with an estimated number of 452,813 patients per year. Males have remarkably higher 
incidence and mortality than females. Lung cancer happens more frequently among people 
older than 45 year old, particularly in males. The incidence and mortality of lung cancer in 
China is expected to gradually increase in the next 20 years, attributed to cigarette smoking 
and air pollution [17; 18]. 
Per the National Comprehensive Cancer Network (NCCN) guideline, a systemic treatment 
for advanced or metastatic NSCLC is based on the histologic type, biomarker expression, 
performance status (PS) and previous treatment. Patients with advanced or metastatic 
NSCLC with EGFR wild type and no echinoderm microtubule-associated protein-like 4
(EML4) gene is fused to the muted lymphoma kinase (ALK) gene (EML4-ALK) translocation 
are often treated with platinum-containing doublet chemotherapy as 1st line therapy. NSCLC 
with EGFR mutation or EML4-ALK positive are usually treated with tyrosine kinase 
inhibitors (TKIs) or Crizotinib. However, disease progression usually happens after the first 
line treatment and most of the patients require second line therapy. Median overall survival 
for patients treated with second-line chemotherapy is around 7.5 months [19-21]. So 
advances in the treatment of patients with NSCLC requiring second-line therapy are badly 
needed.
Ongoing Clinical Trials
Ongoing clinical trials are being conducted in advanced melanoma, non-small cell lung 
cancer, a number of advanced solid tumor indications and hematologic malignancies. In
KN010, of the 2222 patients whose tumor samples were assessable for PD-L1 expression, 
1475 (66%) had PD-L1 expression on at least 1% of tumor cells, including 633 (28%) with 
PD-L1 expression on at least 50% of tumor cells. For study details please refer to the IB.
Rationale
Rationale for the Trial and Selected Subject Population
Four second line chemotherapy products (docetaxel, pemetrexed, erlotinib, and gefitinib) 
have been approved for treatment of NSCLC in China. Pemetrexed’s approved indication is 
limited to patients with NSCLC with non-squamous histology. Erlotinib and Gefitinib are 
inappropriate second-line therapy for patients with a good performance status who do not 
have an EGFR mutation. Docetaxel is a widely used and accepted second-line standard of 
care for patients with various histologic types of NSCLC, however the objective response 
rate is only about 5-10%, median progression-free survival is about 3 months, and the median 
overall survival is about 7.5 months [8; 19]. Improvements in OS are desirable since no one 
with progressive NSCLC is cured. 
Proof of concept by targeting PD-1 pathway as a promising therapy for NSCLC has been 
achieved with two different anti-PD1 antibodies. The Phase I trial of anti-PD-1 antibody 
Nivolumab demonstrated that subjects with tumors expressing PD-L1 were more likely to 
respond to anti-PD-1 therapy than subjects with tumors that did not express PD-L1 [22]. 
Preliminary data from pembrolizumab (MK-3475) PN001 Part C also suggested that NSCLC 
subjects with high level of PD-L1 expression on their tumor are more likely to respond. The 
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activity of pembrolizumab (MK-3475) against NSCLC in patients from China and other 
countries will be confirmed in this proposed study.
Therefore, this study will compare monotherapy pembrolizumab (MK-3475) with standard of 
care docetaxel in subjects with NSCLC whose tumors exhibit PD-L1 expression. The 
patient’s tumor will be classified as TPS ≥50% and TPS 1-49% based on PD-L1 scoring. OS 
and PFS in the TPS ≥50% and TPS≥1% subpopulation are the primary endpoints of this trial.
Rationale for Dose Selection/Regimen/Modification
An open-label Phase I trial (KEYNOTE 001) is being conducted to evaluate the safety and 
clinical activity of single agent pembrolizumab (MK-3475). The dose escalation portion of 
this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 
weeks (Q2W) in subjects with advanced solid tumors. All three dose levels were well 
tolerated and no dose-limiting toxicities were observed. This first in human study of 
pembrolizumab (MK-3475) showed evidence of target engagement and objective evidence of 
tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W). No MTD has 
been identified.
In KEYNOTE 001, two randomized cohort evaluations of melanoma subjects receiving 
pembrolizumab (MK-3475) at a dose of 2 mg/kg versus 10 mg/kg Q3W have been 
completed, and one randomized cohort evaluating of 10 mg/kg Q3W versus 10 mg/kg Q2W 
has also been completed. The clinical efficacy and safety data demonstrate a lack of 
clinically important differences in efficacy response or safety profile at these doses. For 
example, in Cohort B2, advanced melanoma subjects who had received prior ipilimumab 
therapy were randomized to receive pembrolizumab (MK-3475) at 2 mg/kg versus 10 mg/kg 
Q3W. The ORR was 26% (21/81) in the 2mg/kg group and 26% (20/76) in the 10 mg/kg 
group (FAS). The proportion of subjects with drug-related AE, grade 3-5 drug-related AE, 
serious drug-related AE, death or discontinuation due to an AE was comparable between 
groups or lower in the 10 mg/kg group. In Cohort B3, advanced melanoma subjects 
(irrespective of prior ipilimumab therapy) were randomized to receive pembrolizumab (MK-
3475) at 10 mg/kg Q2W versus 10 mg/kg Q3W. The ORR was 30.9% (38/123) in the 
10mg/kg Q2W group and 24.8% (30/121) in the 10 mg/kg Q3W group (APaT). The 
proportion of subjects with drug-related AE, grade 3-5 drug-related AE, serious drug-related 
AE, death or discontinuation due to an AE was comparable between groups.
PK data analysis of pembrolizumab (MK-3475) administered Q2W and Q3W showed slow 
systemic clearance, limited volume of distribution, and a long half-life (refer to IB). 
Pharmacodynamic data (Interleukin 2 (IL-2) release assay) suggested that peripheral target 
engagement is durable (>21 days). This early PK and pharmacodynamic data provides 
scientific rationale for testing a Q3W dosing schedule. In addition to the pharmacodynamics 
data, Q3W dosing is more convenient for patients. Accordingly, Q3W dosing will be further 
studied.
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab 
(MK-3475) in solid tumors is based on the following: 1) similar efficacy and safety of 
pembrolizumab (MK-3475) when dosed at either 2 mg/kg or 10 mg/kg Q3W in melanoma 
patients, 2) the flat exposure-response relationships of pembrolizumab (MK-3475) for both 
efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W, 3) the lack of 
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effect of tumor burden or indication on distribution behavior of pembrolizumab (MK-3475) 
(as assessed by the population PK model) and 4) the assumption that the dynamics of 
pembrolizumab (MK-3475) target engagement will not vary meaningfully with tumor type.
Rationale for Endpoints
4.2.3.1
Efficacy Endpoints
OS and PFS are the primary endpoints of the trial. PFS is an acceptable scientific endpoint 
for a randomized Phase III trial to demonstrate superiority of a new antineoplastic therapy, 
especially if it is believed that the median time to OS with the new therapy may be 
significantly longer than that seen with standard of care. OS is the gold standard endpoint to 
demonstrate superiority of antineoplastic therapy, but it is potentially impacted by other 
follow-up therapies such as cross-over for treatment failure. RECIST 1.1 will be used to 
determine progression as this methodology is accepted by regulatory authorities. Because the 
treatment assignment is unblinded regarding pembrolizumab (MK-3475) vs. docetaxel, 
images used for efficacy assessment will be read by independent radiologists blinded to 
treatment assignment to minimize bias in the response assessments. In addition, final 
determination of radiologic progression will be based on the central assessment of 
progression, rather than site assessment. Real-time determination of radiologic progression as 
determined by central review (verification of progressive disease (PD)) will be 
communicated to the site.
4.2.3.2
Safety Endpoints
The acceptable safety and tolerability of pembrolizumab (MK-3475) have been characterized 
in previous clinical studies among various solid tumors including NSCLC. This study will 
confirm the safety and tolerability of pembrolizumab (MK-3475) in previously-treated 
subjects with NSCLC in Asians with majority of subjects from China.
4.2.3.3
Immune-related RECIST
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
with treatment of pembrolizumab (MK-3475). Immunotherapeutic agents such as 
pembrolizumab (MK-3475) may produce antitumor effects by potentiating endogenous 
cancer-specific immune responses. The response patterns seen with such an approach may 
extend beyond the typical time course of responses seen with cytotoxic agents, and can 
manifest a clinical response after an initial increase in tumor burden or even the appearance 
of new lesions. Such response patterns are referred to as pseudoprogression of the tumor.  
Standard RECIST 1.1 may, thus, not provide an accurate response assessment of 
immunotherapeutic agents such as pembrolizumab (MK-3475). 
Based on an analysis of patients with melanoma enrolled in Keynote-001, 7 % of evaluable 
patients experienced delayed or early tumor pseudoprogression. Of note, patients who had 
progressive disease by RECIST 1.1 but not by immune related Response Criteria had longer 
OS than patients with progressive disease by both criteria. This data suggest that RECIST 1.1 
may underestimate the benefit of pembrolizumab (MK-3475) in approximately 15% of 
patients. These findings support the need to apply a modification to RECIST 1.1 that takes 
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into account the unique patterns of atypical response in immunotherapy and enable treatment 
beyond initial radiographic progression. 
Immune-related RECIST (irRECIST) is RECIST 1.1 adapted to account for the unique tumor 
response seen with immuno-therapeutics as described in Nishino et al., CCR 2013. The 
assessment of unidimensional target lesions and response categories per irRECIST are 
identical to RECIST 1.1. However, Merck has implemented an adaptation related to new 
lesions, non-target and tumor burden assessment in order to confirm radiographic 
progression. irRECIST will be used by local site investigators to assess tumor response and 
progression, and to make treatment decisions, as well as by the central imaging vendor in 
support of PFS as exploratory endpoint.
4.2.3.4
Patient Reported Outcome
EORTC QLQ-C30 and EORTC QLQ-LC13
The EORTC QLQ-C30 is the most widely used cancer specific Health-Related Quality of 
Life (HRQOL) instrument, which contains 30 items and measures five functional dimensions 
(physical, role, emotional,
cognitive, and social), three symptom items (fatigue, 
nausea/vomiting, and pain), six single items (dyspnea, sleep disturbance, appetite loss, 
constipation, diarrhea, and financial impact), and a global health and quality of life scale 
[23]. This instrument is translated and validated into more than 80 languages. In addition to 
EORTC QLQ-C30, the EORTC QLQ-LC13 measures lung cancer associated symptoms 
(cough, hemoptysis, dyspnea, and site-specific pain), and treatment related symptoms (sore 
mouth, dysphagia, peripheral neuropathy, and alopecia) [24]. The EORTC QLQ-C30 and 
QLQ-LC13 are the most frequently utilized and reported patient reported outcome measures 
in lung cancer clinical trials [25; 26]. The reliability, validity and practicality of these 
instruments have been reported [24; 27].
EuroQol EQ-5D
The EuroQol-5D (EQ-5D) is a standardized instrument for use as a measure of health 
outcome. The EQ-5D will provide data for use in economic models and analyses including 
developing health utilities or quality-adjusted life-years (QALYs). The five health state 
dimensions in this instrument include the following: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension is rated on a three point scale from 
1 (extreme problem) to 3 (no problem). The EQ-5D also includes a graded (0 to 100) vertical 
visual analog scale on which the patient rates his or her general state of health at the time of 
the assessment. The EQ-5D will always be completed by patients first before completing the 
EORTC QLQ C-30 and EORTC LC-13.
4.2.3.5
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens collected for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
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Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. For instance, exploratory 
pharmacogenetic 
(PGt) 
studies 
may 
be 
performed 
if 
significant 
Pharmacokinetic/Pharmacodynamic (PK/PD) relationships are observed or adverse events 
are identified.  Genomic markers of disease may also be investigated.  Such retrospective 
pharmacogenetic studies will be conducted with appropriate biostatistical design and analysis 
and compared to PK/PD results or clinical outcomes. Any significant PGt relationships to 
outcome would require validation in future clinical trials. The overarching goal is to use such 
information to develop safer, more effective drugs/vaccines, and/or to ensure that subjects 
receive the correct dose of the correct drug/vaccine at the correct time.  The details of this 
Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
Benefit/Risk
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
Specific benefits to patients participating in the trial, (assuming that pembrolizumab (MK-
3475)’s clinical activity in patients with previously-treated NSCLC is confirmed with this 
study), a patient has a 50% likelihood of being assigned Pembrolizumab (MK-3475). Patients 
in the TPS ≥50% subset who receive pembrolizumab (MK-3475) may be likely to experience 
a decrease in the size of their tumor burden, a longer time to progression of disease, and a 
longer survival relative to those who receive docetaxel. Risks to patients in this study relative 
to most others include the risk of pneumothorax, bleeding, and, rarely, death from a new 
tumor biopsy. Patients assigned to pembrolizumab (MK-3475) may be less likely to 
experience drug-related grade 3-4 toxicity, relative to docetaxel, but the development of 
autoimmune –mediated adverse events, including colitis, hyperthyroidism, hypothyroidism, 
and pneumonitis are possible.
While these autoimmune –mediated adverse events usually are manageable with hormone 
replacement and glucocorticoids, some cases may involve challenging management. Many 
thoracic oncologists are learning how to manage toxicities that may evolve from an activated
immune system and most are not as comfortable managing adverse events from 
Pembrolizumab (MK-3475) as they might be from docetaxel. Considering all the factors, the 
benefit:risk profile for the study favors conducting the trial.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying Investigators Brochure (IB) and Informed 
Consent documents.
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5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male/Female subjects with NSCLC whose tumors are positive (TPS ≥1%) for PD-L1 
expression and have experienced disease progression after at least one platinum-containing 
systemic therapy will be enrolled in this trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent for the trial.
Note: Subject may also provide consent for Future Biomedical Research. However, the 
subject may participate in the main trial without participating in Future Biomedical 
Research.
2. Be ≥18 years of age on day of signing informed consent.
3. Chinese subject must be born, raised and reside within China.
4. Have a life expectancy of at least 3 months.
5. Have a histologically or cytologically confirmed diagnosis of stage IIIB/IV or recurrent 
NSCLC and have at least one measurable lesion as defined by RECIST 1.1.
6. Have investigator determined progression of disease per RECIST 1.1 after treatment with 
at least two cycles of a platinum-containing doublet, assessed from at least 2 dates of pre-
trial images with diagnostic quality. 
Note: A platinum-containing doublet is defined as a platinum-based cytotoxic systemic 
agent administered in the same cycle as another cytotoxic systemic chemotherapeutic 
agent. Completion of treatment with a platinum-containing doublet as adjuvant therapy 
within one year of signing informed consent will satisfy the prior treatment requirement.
7. Site must be able to provide documentation of EGRF mutation and ALK translocation 
status. If the site is unable to provide this source documentation, then the Sponsor will 
offer this molecular testing of the tumor. Subjects will not be randomized until EGFR 
mutation and ALK translocation status is available in source documentation at the site
with the exceptions noted in sub-bullet c and d below:
a.
Subjects with an EGFR sensitizing mutation tumor will be excluded.
b. Subjects with an ALK translocation must be able to demonstrate progression of 
disease on both platinum-containing doublet and ALK-directed tyrosine kinase 
inhibitor (examples: crizotinib, ceritinib, alectinib etc.). Radiographic images that 
demonstrate progression after initiation of the ALK-directed tyrosine kinase inhibitor
therapy and platinum-containing doublet or combination of ALK-directed tyrosine 
kinase inhibitor and platinum-containing doublet as first line therapy must be 
submitted prior to randomization. An exception is the subject who receives four 
cycles of a platinum doublet does not experience progression of disease, and begins 
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ALK-directed tyrosine kinase inhibitor as a maintenance therapy within 28 days of 
the last administration of the platinum doublet chemotherapy. For this subject, only 
one set of images demonstrating progression on the ALK-directed tyrosine kinase 
inhibitor is required for submission for the subject to be eligible.
c.
If a patient is known to have one molecular alteration (either sensitizing EGFR 
mutation or ALK translocation), then testing for the other alteration is not required.
d. For patients enrolled who are known to have a tumor with pure squamous histology, 
molecular testing for EGFR mutation and ALK translocation will not be required as 
this is not standard of care and is not part of current diagnostic guidelines. Patients 
with adenosquamous histology or any component of adenocarcinoma in mixed 
histology are required to have EGFR testing done.
8. Have a performance status of 0 or 1 on the ECOG Performance Scale as assessed within 
10 days prior to randomization.
9. Have adequate organ function as indicated in Table 1 below:
Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500 /mcL
Platelets
≥100,000 / mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L without transfusion for 4 weeks 
Renal
Serum creatinine OR
Measured or calculateda creatinine clearance 
(GFR can also be used in place of creatinine or 
CrCl)
≤1.5xULN OR
≥60 mL/min for subject with creatinine levels >1.5x 
institutional ULN
Hepatic
Serum total bilirubin
≤1.5xULN OR
Direct bilirubin ≤ULN for subjects with total bilirubin 
levels >1.5xULN
AST (SGOT) and ALT (SGPT)
≤1.5xULN 
Alkaline Phosphatase
≤ 2.5 X ULN
Endocrine
Thyroid stimulating hormone (TSH)b
Within normal limits
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
Activated Partial Thromboplastin Time (aPTT)
≤1.5xULN unless subject is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants
≤1.5xULN unless subject is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants
a Creatinine clearance should be calculated per institutional standard. If no local guideline is available, 
Creatinine Clearance should be calculated using the Cockcroft-Gault Method: CrCl = [(140-age) * weight 
(kg) * (0.85 for females only)] / (72 * serum creatinine)
b If TSH is not within normal limits at baseline, the subject may still be eligible if T3/FT3 and free T4 are 
within the normal limits.
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10. Have provided archival tumor tissue sample or newly obtained formalin fixed tumor 
tissue from a recent biopsy of a tumor lesion not previously irradiated.  
Note: The investigator may submit an archival formalin-fixed, paraffin embedded tumor 
specimen for PD-L1 analysis. The tissue sample must be received and evaluated by the 
central vendor prior to randomization. Fine needle aspirates are not acceptable. Core 
needle or excisional biopsies, or resected tissue is required. 
11. Have a PD-L1 positive tumor as determined by immunohistochemistry (IHC) at a central 
laboratory.
Note: Only PD-L1 positive patients will be randomized. If a patient’s initial tumor 
specimen is not classified as PD-L1 positive by the central laboratory, a newly obtained 
specimen (different from the sample previously submitted) may be submitted for testing. 
If the newer specimen is classified as PD-L1 positive by the central laboratory, the 
patient meets this eligibility criterion.
12. Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 or 
less (except alopecia). If subject received major surgery or radiation therapy of > 30 Gy, 
they must have recovered from the toxicity and/or complications from the intervention. 
13. Female subjects of childbearing potential must have a negative urine or serum pregnancy 
test within 72 hours prior to receiving the first dose of study medication. If the urine test 
is positive or cannot be confirmed as negative, a serum pregnancy test will be required.  
14. Female subjects of childbearing potential (Section 12.8) must be willing to use an 
adequate method of contraception as outlined in Section 12.8 – Contraceptive Guidance, 
for the course of the study through 120 days after the last dose of pembrolizumab (MK-
3475) or 180 days after the last dose of docetaxel.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject.
15. Male subjects of childbearing potential must agree to use an adequate method of 
contraception as outlined in Section 12.8- Contraceptive Guidance, starting with the first 
dose of study therapy through 90 days after the last dose of docetaxel.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject.
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Has received prior therapy with docetaxel for NSCLC.
2. Is currently participating or has participated in a study of an investigational agent or has 
used an investigational device within 4 weeks prior to the first dose of trial treatment.
Note: Subjects who have entered the follow-up phase of an investigational trial may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
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3. Is receiving systemic steroid therapy within three days prior to the first dose of trial 
treatment or receiving any other form of immunosuppressive medication (corticosteroid 
use on study for management of ECIs or as a pre-medication for docetaxel is allowed).
4. Is expected to require any other form of systemic or localized antineoplastic therapy 
while on trial (including maintenance therapy with another agent for NSCLC or radiation 
therapy).
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed 
after consultation with Sponsor.
5. Has received prior systemic cytotoxic chemotherapy, antineoplastic biological therapy 
(e.g., cetuximab), any other agents used as systemic treatment for cancer, or major 
surgery within 3 weeks of the first dose of trial treatment; received thoracic radiation 
therapy of > 30 Gy within 6 months of the first dose of trial treatment; received prior 
ALK-directed tyrosine kinase inhibitor therapy or completed palliative radiotherapy of 30
Gy or less within 7 days of the first dose of trial treatment. 
6. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, with an agent 
directed to an agonist or antagonist T-cell check point receptor (i.e., CTLA-4, OX-40, 
CD137), or has previously participated in Merck sponsored clinical trials evaluating
pembrolizumab (MK-3475).
7. 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.
8. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by MRI for at least four weeks prior to 
the first dose of trial treatment and any neurologic symptoms have returned to baseline), 
have no evidence of new or enlarging brain metastases, and are using no steroids for at 
least three days prior to study medication.  
9. Has active autoimmune disease that has required systemic treatment in past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.
10. Has had an allogeneic tissue/solid organ transplant.
11. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis.
12. Has received or will receive a live vaccine within 30 days prior to the first administration 
of study medication. Seasonal flu vaccines that do not contain live virus are permitted.
13. Has an active infection requiring intravenous systemic therapy.
14. Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
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15. Has known active Hepatitis B or C. Active Hepatitis B is defined as a known positive 
HBsAg result. Active Hepatitis C is defined by a known positive Hep C Ab result and 
known quantitative HCV RNA results greater than the lower limits of detection of the 
assay.
16. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.
17. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial.
18. Is, at the time of signing informed consent, a regular user (including “recreational use”) 
of any illicit drugs or had a recent history (within the last year) of substance abuse 
(including alcohol).
19. Removed.
20. Require treatment with a strong inhibitor of CYP3A4 will be excluded. Subject may be 
included if there is an alternate treatment available (not a strong CYP3A4 inhibitor) and 
they are willing to switch prior to randomization. If a subject opts to change from a 
strong CYP 3A4 inhibitor to a weaker CYP 3A4 inhibitor, the subject must stop the 
strong CYP 3A4 inhibitor 7 days before study drug administration. Please refer to Section 
5.5.2 for Prohibited Concomitant Medications.
Trial Treatment(s)
The treatments to be used in this trial are outlined below in Table 2.
Trial treatment should begin on the day of randomization or as close as possible to the date 
on which treatment is allocated/assigned.
Table 2
Trial Treatment
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment 
Period
Use
Pembrolizumab 
(MK-3475)
2 mg/kg
Q3W
IV infusion
Day 1 of each 
cycle
Experimental
Docetaxel 
75 mg/m2
Q3W
IV infusion
Day 1 of each 
cycle
Experimental
All supplies indicated in Table 2 will be provided centrally by the Sponsor or locally by the 
trial site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
The trial site will be responsible for recording the lot number, manufacturer and expiry date 
of any locally purchased product.
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The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
5.2.1.1
Dose Selection (Preparation)
The rationale for selection of doses to be used in this trial is provided in Section 4.0
Background & Rationale.
The dose amount required to prepare the pembrolizumab (MK-3475) infusion solution will 
be based on the subject’s weight in kilograms (kg). The details will be described in the 
Pharmacy Manual.
Docetaxel will be prepared and administered as per the approved product label.
5.2.1.2
Dose Modification (Escalation/Titration/Other)
Docetaxel
Refer to approved product label for subjects receiving docetaxel.
Pembrolizumab (MK-3475)
Adverse events associated with pembrolizumab exposure may represent an immune-related 
response. These irAEs may occur shortly after the first dose or several months after the last 
dose of pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation. Dose modification and toxicity management guidelines for 
irAEs associated with pembrolizumab are provided in Table 3 below. See Section 5.6.1 for 
supportive care guidelines, including use of corticosteroids.
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Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids.
2.
Study intervention must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of the 
last study intervention treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If study intervention has been withheld, study intervention may resume after the irAE decreased to ≤Grade 1 after corticosteroid taper.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
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

Add prophylactic antibiotics for 
opportunistic infections

Monitor subjects for signs and symptoms of 
pneumonitis

Evaluate subjects with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment
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.
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
Corticosteroid and/or other 
therapies 
Monitor and follow-up 
AST / ALT 
elevation or 
Increased 
bilirubin
Grade 2a
Withhold

Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone 
or equivalent) followed by taper

Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable
Grade 3b or 4c
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withholdd

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 
thionamides as appropriate 

Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hypothyroidism
Grade 2, 3, or 4
Continue 

Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyronine) per standard of care

Monitor for signs and symptoms of thyroid 
disorders. 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
Corticosteroid and/or other 
therapies 
Monitor and follow-up 
Nephritis:
grading according 
to increased 
creatinine or acute 
kidney injury
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
Neurological 
Toxicities
Grade 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
Myocarditis
Grade 1 
Withhold

Based on severity of AE 
administer corticosteroids

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 2, 3, or 4
Permanently 
discontinue
Exfoliative 
Dermatologic 
Conditions
Suspected 
SJS, 
TEN, or DRESS
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
or exclude other causes
Confirmed 
SJS, 
TEN, or DRESS
Permanently 
discontinue
All other immune-
related AEs
persistent Grade 2
Withhold

Based on type and severity of AE 
administer corticosteroids 

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3
Withhold or 
discontinue based 
on the type of 
event.e
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
Corticosteroid and/or other 
therapies 
Monitor and follow-up 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 
1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
AST/ALT: >3.0 to 5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal.
b
AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline if 
baseline abnormal.
c
AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal.
d
The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or ≤Grade 2, 
pembrolizumab may be resumed.
e
Events that require discontinuation include but are not limited to encephalitis and other clinically important irAEs.
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Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient 
vacation, and/or holidays). Subjects should be placed back on study therapy within 3 weeks 
of the scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient's study record.
Timing of Dose Administration
Trial treatment should be administered on Day 1 of each cycle after all procedures/ 
assessments have been completed. Trial treatment may be administered up to 3 days after 
Day 1 of each cycle due to administrative reasons only.
Pembrolizumab (MK-3475) will be administered as a 30-minute IV infusion Q3W. Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible. 
However, given the variability of infusion pumps from site to site, a window of -5 minutes 
and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).
The Procedures Manual contains specific instructions for pembrolizumab (MK-3475) dose 
calculation, reconstitution, preparation of the infusion fluid, and administration.
Docetaxel 75 mg/m2 will be administered as an IV infusion over 1 hour every Q3W. All 
subjects should be pre-medicated with oral or injectable steroids according to the approved 
product label and/or standard practice. Additional pre-medications should be administered as 
per standard practice.
Investigators treating subjects, if clinically stable, assigned to docetaxel who experience
disease progression may elect to interrupt treatment by deferring the decision to
continue/discontinue treatment in the trial until confirmation of disease progression per 
irRECIST at least 28 days from the date of imaging demonstrating disease progression. 
Patients treated with docetaxel for whom disease progression is not confirmed on subsequent 
imaging may resume treatment with docetaxel.
Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Imaging data for the primary analysis will be centrally reviewed by independent 
radiologist(s) without knowledge of subject treatment assignment.
The sites will be notified the positive and negative PD_L1 results for enrollment but the 
details of PD_L1 score will not be shared with the sites and will be directly transferred to 
IVRS for stratification. The sites, the principal investigators, sub-investigators and their staff 
as well as Merck’s clinical research coordinators (CRAs) involved in on-site monitoring will 
remain blinded to the details of PD_L1 score.
Randomization or Treatment Allocation
Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS).
There are 2 treatment arms.  
Subjects will be assigned randomly in a 1:1 ratio to pembrolizumab (MK-3475) 2 mg/kg 
Q3W, or docetaxel 75 mg/m2 Q3W.
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Stratification
Treatment allocation/randomization will be stratified according to the following factor:

Extent of tumor PD-L1 expression (TPS ≥50% vs. TPS 1-49%)
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 standards of medical care. 
All concomitant medication will be recorded on the case report form (CRF) including all 
prescription, over-the-counter (OTC), herbal supplements, and IV medications and fluids. If 
changes occur during the trial period, documentation of drug dosage, frequency, route, and 
date will also be included on the CRF.
Specifically, subjects using bisphosphonates or anti-RANKL mAb who were receiving this
medication prior to study start, may continue receiving the medication during the study.
All concomitant medications received within 30 days before the first dose of trial treatment
through the Safety Follow-up Visit should be recorded. After the Safety Follow-up Visit
record all medications taken for SAEs and ECIs as defined in Section 7.2.
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening,
Treatment and Second Course Phases of this trial (unless otherwise noted below):

Antineoplastic systemic chemotherapy or biological therapy not specified in this
Protocol.

Immunotherapy not specified in this protocol.

Chemotherapy not specified in this protocol.

Investigational agents other than pembrolizumab (MK-3475).

Radiation therapy.
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed after consultation with Sponsor.
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
Live vaccines within 30 days prior to the first dose of trial treatment and while
participating in the trial. Examples of live vaccines include, but are not limited to, the
following: measles, mumps, rubella, chicken pox, yellow fever, seasonal flu, H1N1
flu, rabies, BCG, and typhoid vaccine. Seasonal flu vaccines that do not contain live 
viruses are permitted.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
immune-related adverse Event (as listed in Section 5.6) or for use as a pre-medication 
for chemotherapeutic agents specified in the protocol or as a pre-medication prior to a 
CT scan for subjects with contrast allergy or for use for COPD exacerbation requiring 
steroid for recovery. Replacement doses of steroids (for example, prednisone 10 mg 
daily) are permitted while on study.

Strong inhibitors of the CYP3A4 enzymes (a common list of such agents may be
found in Appendix 12.7).
Subjects who, in the assessment by 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. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
Rescue Medications & Supportive Care
Supportive Care Guidelines
Docetaxel
Pre-medication(s) for docetaxel will be given as per standard of care. Corticosteroid
Pretreatment and/or post treatment of docetaxel is acceptable in concordance with the local
label or standard of care.
Pembrolizumab (MK-3475)
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined in Table 3. Where appropriate, these 
guidelines include the use of oral or intravenous 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 (MK-3475). 
Note: if after the evaluation the event is determined not to be related, the investigator does
not need to follow the treatment guidance (as outlined below). Refer to Section 5.2.1.2 for 
dose modification.
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It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
Signs and symptoms of infusion reactions usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion of infusion. 
Table 4 shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475).
Table 4
Pembrolizumab (MK-3475) 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 infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, 
NSAIDS, 
narcotics, 
IV 
fluids); 
prophylactic 
medications 
indicated for < =24 hrs
Stop Infusion and monitor symptoms.
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 one hour of 
stopping drug infusion, the infusion may 
be restarted at 50% of the original 
infusion rate (e.g., from 100 mL/hr to 50 
mL/hr). Otherwise dosing will be held 
until symptoms resolve and the subject 
should be premedicated for the next 
scheduled dose.
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from 
further trial treatment administration.
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab 
(MK-3475) with:
Diphenhydramine 50 mg po 
(or 
equivalent 
dose 
of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic).
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly 
responsive 
to 
symptomatic 
medication 
and/or 
brief 
interruption 
of 
infusion); 
recurrence 
of 
symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (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 
trial 
treatment 
administration.
No subsequent dosing
h=hour; IV=intravenous; CTCAE=Common Terminology Criteria for Adverse Events; NCI=National Cancer 
Institute; NSAIDs= nonsteroidal anti-inflammatory drugs.
Note:  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
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.
Use in Pregnancy
If a female subject inadvertently becomes pregnant while on treatment with docetaxel or
pembrolizumab (MK-3475), 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 a serious adverse 
experience (e.g., death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn). The study investigator will make every effort to 
obtain permission to follow the outcome of the pregnancy and report the condition of the 
fetus or newborn to the Sponsor. If a male subject impregnates his female partner the study 
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personnel at the site must be informed immediately and the pregnancy reported to the 
Sponsor and followed as described above and in Section 7.2.2.
Subject Withdrawal/Discontinuation Criteria
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
A subject must be discontinued from the trial for any of the following reasons:
●
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.
A subject must be discontinued from treatment (but should continue to be monitored in the 
post-treatment follow up portion of the trial) for any of the following reasons:

Documented disease progression. 
Note: If a subject has confirmed progression of disease by irRECIST, the subject 
should not receive further trial treatment on study. If a subject has unconfirmed 
progression of disease and is clinically stable, it is at the discretion of the investigator 
to continue treating the subject with the assigned treatment per protocol until 
progression of disease is confirmed at least 28 days from the date of the scan 
suggesting progression of disease. Clinical Stability is defined as:
o
Absence of symptoms and signs indicating clinical significant progression of 
disease (including worsening of laboratory values) indicating disease progression.
o
No decline in ECOG performance status.
o
Absence of rapid progression of disease or progressive tumor at critical 
anatomical sites (e.g., cord compression) requiring urgent alternative medical 
intervention.

Unacceptable adverse experiences as described in Section 5.2.1.2.

Two years of delivery of pembrolizumab (MK-3475) every 3 weeks and no 
documented progression of disease, or 35 administrations of study medication, 
whichever is later. These patients may be eligible for re-treatment with open-label
pembrolizumab monotherapy after they have experienced radiographic disease
progression at the discretion of the investigator according to defined criteria in 
Section 7.1.5.4.

Intercurrent illness that prevents further administration of treatment.

Investigator’s decision to discontinue the subject from treatment.

The subject has a confirmed positive serum pregnancy test.
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14-Jul-2021
Confidential

Noncompliance with trial treatment or procedure requirements.

Administrative reasons.

If a pembrolizumab (MK-3475) treated subject attains an investigator-determined 
confirmed CR according to irRECIST, has been treated for at least six months with 
pembrolizumab (MK-3475), and has at least two treatments with pembrolizumab 
(MK-3475) beyond the date when the initial CR was declared, the subject and
investigator may consider stopping therapy with pembrolizumab (MK-3475). 
Subjects who discontinue pembrolizumab and then experience radiographic disease 
progression by local investigator’s assessment according to irRECIST may be eligible 
for re-treatment with pembrolizumab in the Second Course Phase at the discretion of 
the Investigator as described in Section 7.1.5.4.
The End of Treatment and Follow-up visit procedures are listed in Section 6 - Trial Flow
Chart and Section 7.1.5 - Visit Requirements. After the end of treatment, each subject will be 
followed for a minimum of 30 days for adverse event monitoring (serious adverse events will 
be collected for up to 90 days after the end of treatment as described in Section 7.2.3.1).
Subjects will have post-treatment follow-up for disease status until disease progression,
initiating a non-study cancer treatment, withdrawing consent, or becoming lost to follow-up
or entering the Second Course Phase.

After documented disease progression each subject will be followed for overall 
survival until death or withdrawal of consent.
Subject Replacement Strategy
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit,
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
Upon study completion, subjects are discontinued and may be enrolled in a pembrolizumab 
extension study, if available.
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. The trial will be stopped early for efficacy at the recommendation of the eDMC if the 
interim analysis results show pembrolizumab (MK-3475) is superior to docetaxel in 
OS.
2. The trial will be stopped early at the recommendation of the eDMC if the risk/benefit 
ratio to the trial population as a whole is unacceptable.
Enrollment will not be halted during the planned interim analyses. 
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Protocol/Amendment No.: 033-05 
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Confidential
Further recruitment in the trial or at (a) particular trial site(s) may be stopped due to 
insufficient compliance with the protocol, GCP and/or other applicable regulatory 
requirements, procedure-related problems or the number of discontinuations for 
administrative reasons is too high.
Post Pembrolizumab (MK-3475)/Docetaxel Therapies
After a subject stops the designated study treatment for one of the reasons described in 
Section 5.8, other than for an irCR, the subject may be interested in pursuing other therapies. 
If investigators assess that the subject is fit for subsequent therapy, it is encouraged. The 
exact subsequent treatment(s) used will be at the discretion of the investigator and 
determined by the interests of the subject.
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Protocol/Amendment No.: 033-05 
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Confidential
6.0 TRIAL FLOW CHART
Treatment Phase
Pembrolizumab (MK-3475) 2 mg/kg Q3W and Docetaxel 75 mg/m2 Q3W
Screening
(Visit 1)
Treatment Cycles1
End of Treatment
Treatment Cycle / Scheduled 
Time
-42 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13
14 and 
beyond
Discontinuation 
Visit
Scheduling Window (Days):2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Administrative Procedures
Informed Consent 3
X
Informed Consent for Future 
Biomedical Research 4 (optional)
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics 
and 
Medical 
History
X
Prior 
and 
Concomitant 
Medications5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
NSCLC Disease Details and Prior 
Treatment
X
Trial Treatment Administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assignment of Screening Number
X
Survival Status23
Clinical Procedures / Assessments
Review Adverse Events 6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Full Physical Examination18
X
X18
Directed Physical Examination18
X
X
X
X
X
X
X
X
X
X18
X
Vital Signs and Height 7
X7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Product:  MK-3475 
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Protocol/Amendment No.: 033-05 
MK-3475-033-05 Final Protocol
14-Jul-2021
Confidential
Screening
(Visit 1)
Treatment Cycles1
End of Treatment
Treatment Cycle / Scheduled 
Time
-42 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13
14 and 
beyond
Discontinuation 
Visit
Scheduling Window (Days):2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Laboratory Procedures / Assessments: analysis performed by local laboratory
Pregnancy Test - Urine or Serum 
β-HCG 8
X
PT/INR and aPTT 9
X 10
CBC with Differential11
X 10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Comprehensive Serum Chemistry 
Panel11,22
X 10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis11
X 10
X
X
X12
X
T3/FT3, FT4 and TSH 11, 12
X 10
X
X
X
X
X
X
X 12
X
ALK Translocation Testing19
X
EGFR Mutation Testing19
X
HBsAg
X22
Anti HCV
X22
Laboratory Procedures / Assessments: analysis performed by central laboratory
Blood for Future Biomedical 
Research13 (optional)
X
Tissue for PD-L1 status 
X
Efficacy Measurements
Tumor Imaging 14, 15
X
X
X
X
X
X14
X21
Patient 
Report 
Outcomes 
(PRO)
EuroQoL EQ-5D 20
X
X
X
X
X
X
X
X
EORTC QLQ-C30 20
X
X
X
X
X
X
X
X
EORTC QLQ-LC-13 20
X
X
X
X
X
X
X
X
Tumor Biopsies / Archival Tissue Collection
Tumor Tissue Collection 
X16
X17
X17
X17
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Product:  MK-3475 
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Protocol/Amendment No.: 033-05 
MK-3475-033-05 Final Protocol
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Confidential
Screening
(Visit 1)
Treatment Cycles1
End of Treatment
Treatment Cycle / Scheduled 
Time
-42 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13
14 and 
beyond
Discontinuation 
Visit
Scheduling Window (Days):2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
1.
In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of trial treatment for each cycle unless otherwise specified. Treatment cycles are 
3 weeks (21-days); however the pembrolizumab (MK-3475) treatment cycle interval may be increased due to toxicity according to the dose modification guidelines 
provided in Section 5.2.1. If treatment cycles are increased all procedures except imaging will be completed according to the Cycle number and not weeks on treatment, 
imaging will be performed every 9 weeks (± 7 days) from the date of randomization regardless of any treatment delays.
2.
In general, the window for each visit is ± 3 days unless otherwise specified.
3.
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 (e.g., within 42 days prior to the first dose of trial treatment). 
Assign Baseline number when the study informed consent is signed. 
4.
Signing the informed consent for future biomedical research (FBR) samples is optional. Informed consent for future biomedical research (FBR) must be obtained prior to
sample collection. Detailed instructions for the collection and management of specimens for FBR are provided in the procedures manual and full protocol.
5.
Prior medications - Record all medications taken within 30 days of start of treatment cycle 1 and all treatments for a prior cancer other than NSCLC even if taken greater 
than 30 days prior to first dose of trial treatment (prior treatments for NSCLC will be recorded separately). Concomitant Medications - Enter new medications started 
during the trial through the Safety Follow-up Visit. After the Safety Follow-up Visit record all medications taken for SAEs and ECIs as defined in full protocol.
6.
AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.0. All AEs, whether gradable by CTCAE or not, will also be evaluated for seriousness. 
7.
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure. Height will be measured at Visit 1 only.
8.
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. Pregnancy tests (serum and/or urine tests) should be repeated 
if required by local guidelines. Monthly pregnancy testing should be conducted as per local regulations where applicable.
9.
Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
10. Laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment.
11. After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point. Laboratory results must be known and acceptable prior to dosing. 
12. Urinalysis will be performed every 4 cycles after Cycle 13; perform thyroid testing every other cycle. Thyroid function tests will be performed by a central laboratory only 
if the local laboratory is unable to perform this service.
13. Informed consent for future biomedical research samples must be obtained before the DNA sample. DNA sample for analysis should be obtained predose, on Cycle 1 (or 
with the next scheduled blood draw), as the last sample drawn, on randomized subjects only, or at a later date as soon as the informed consent is obtained. Detailed 
instructions for the collection and management of specimens for FBR are provided in the Procedures manual and full protocol. 
14. The initial tumor imaging will be performed within 28 days prior to the date of randomization. Scans performed as part of routine clinical management are acceptable for 
use as the screening scan if they are of diagnostic quality and performed within 28 days prior to the first dose of trial treatment. Local reading (investigator assessment with 
site radiology reading) will be used to determine eligibility and for subject management. The Sponsor will collect radiological assessments for analysis by a central imaging 
vendor.  The processes for image collection and transmission to the central vendor are in the Site Imaging Manual. 
15. After the first documentation of progression (if the subject is clinically stable) or response per irRECIST repeat imaging for confirmation is required. Confirmatory imaging 
may be performed as early as 28 days later; alternately, the scan performed at the next scheduled time point (e.g. every 63 ±7 days) may be used as confirmation.
16. Tumor tissue for biomarker analysis (archival tumor tissue sample or newly obtained formalin fixed tumor tissue from a resent biopsy of a tumor lesion not previously 
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Product:  MK-3475 
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Protocol/Amendment No.: 033-05 
MK-3475-033-05 Final Protocol
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Confidential
Screening
(Visit 1)
Treatment Cycles1
End of Treatment
Treatment Cycle / Scheduled 
Time
-42 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13
14 and 
beyond
Discontinuation 
Visit
Scheduling Window (Days):2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
irradiated are required for PD-L1 determination) must be provided and received by the central vendor before randomization. For patients enrolled who are known to have a 
tumor with pure squamous histology, molecular testing for EGFR mutation and ALK translocation will not be required. Patients with adenosquamous histology or any 
component of adenocarcinoma in mixed histology are required to have EGFR testing done. Detailed instructions for tissue collection, processing and shipment are provided 
in the Procedures Manual. If the subject signs the Future Biomedical Research (FBR) consent, any leftover tissue biopsies that would ordinarily be discarded at the end of 
the main study will be retained for FBR.
17. Pembrolizumab (MK-3475) treated subjects in the Treatment Phase – Additional optional biopsies at approximately Week 6, Week 12 and Week 24 and at disease 
progression are highly desired when feasible; these biopsies will only be performed in non-target lesions after disease progression has been confirmed. Detailed 
instructions for tissue collection, processing and shipment are provided in the Procedures Manual. THESE SAMPLES ARE TO BE COLLECTED ONLY FROM 
NON-TARGET LESIONS, TO AVOID ANY IMPACT ON irRECIST OUTCOMES.  Additional biopsy samples at disease progression can be obtained from the 
target lesion, but only after confirmation of disease progression by the Central Imaging Vendor.
18. Perform a full physical examination at baseline and end of treatment and perform directed PE at other visits. 
19. Site must be able to provide documentation of the subject’s tumor EGFR mutation and ALK translocation status. If the site is unable to provide this source documentation,  
then the Sponsor will offer this molecular testing of the tumor.
20. Patient Reported Outcomes (PROs) are to be administered by trained site personnel and completed by subjects. It is strongly recommended that PROs are administered 
prior to drug administration, adverse event evaluation and disease status notification starting with the EQ-5D, followed by EORTC QLQ-C30, and EORTC LC-13; an 
exception to this recommendation may occur at the treatment discontinuation visit where patients may have already been notified of their disease status or an AE evaluation 
is known prior to them arriving to the clinic. All PROs are to be performed at Cycle 1, Cycle 2, Cycle 3, Cycle 4, and every 3 cycles (9 weeks) thereafter (e.g., Cycle 7, 
Cycle 10, Cycle 13, etc.) up to a year or End of Treatment, whichever comes first. If the subject does not complete the PROs, the MISS_MODE form must be completed to 
capture the reason the assessment was not performed.
21. In subjects who discontinue study therapy without centrally verified disease progression, a radiologic evaluation should be performed at the time of treatment 
discontinuation (i.e., date of discontinue ± 4 week window). If a previous scan was obtained within 4 weeks prior to the date of discontinuation, then a scan at treatment 
discontinuation isn’t mandatory.
22. Tests will be performed by a central laboratory only if the local laboratory is unable to perform this service. The need for additional testing due to positive test results will 
be at the discretion of the Investigator.
23. After documented local site assessed disease progression, or the start of new anticancer treatment; contacts are approximately every 2 months by telephone. Updated 
survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will not have a scheduled 
study visit or study contact during the Sponsor-defined time period will be contacted for their survival status (excluding subjects who have a death event previously 
recorded).
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Protocol/Amendment No.: 033-05 
MK-3475-033-05 Final Protocol
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Confidential
Post-Treatment Follow-Up Phase
Trial Phase
Safety Follow-up 1
Follow-up 2
Survival 
Follow-up3
Time from Last Dose of Trial Treatment
30 Days
3 Months
6 Months
Every 9 weeks (63 
days) after Month 6
Approx. Every 2 Months
Visit
Safety Follow-up Visit
Follow-up Visit 1
Follow-up Visit 2
Follow-up Visit 3 and 
beyond
Survival Follow-up Visit 1 
and beyond
Scheduling Window
+ 7 days
± 7 days
± 7 days
± 7 days
14 days
Administrative Procedures
Review Medications
X
Subsequent antineoplastic therapy Status
X
X
X
X
X
Survival Status 3
X
Clinical Procedures/Assessments
Review Adverse Events 4
X
X
X
X
X
ECOG Performance Status
X
X
X
Directed Physical Examination
X
X
X
Vital Signs 5
X
X
X
Efficacy Measurement
Tumor Imaging 6
X7
X7
X7
X7
Laboratory Procedures/Assessments: analysis performed by local laboratory
CBC with Differential 8
X
Comprehensive Serum Chemistry Panel 8
X
T3/FT3, FT4 and TSH 9
X
Patient Report Outcomes (PRO)
EuroQoL EQ-5D 10
X
EORTC QLQ-C30 10
X
EORTC QLQ-LC-13 10
X
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Product:  MK-3475 
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Protocol/Amendment No.: 033-05 
MK-3475-033-05 Final Protocol
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Confidential
Trial Phase
Safety Follow-up 1
Follow-up 2
Survival 
Follow-up3
Time from Last Dose of Trial Treatment
30 Days
3 Months
6 Months
Every 9 weeks (63 
days) after Month 6
Approx. Every 2 Months
Visit
Safety Follow-up Visit
Follow-up Visit 1
Follow-up Visit 2
Follow-up Visit 3 and 
beyond
Survival Follow-up Visit 1 
and beyond
Scheduling Window
+ 7 days
± 7 days
± 7 days
± 7 days
14 days
1.
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. 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.
2.
Subjects who discontinue trial treatment for a reason other than disease progression will move into the Follow-up Phase and should be assessed every 9 weeks (63 ± 7 
days) by radiologic imaging to monitor disease status. Follow-up Visit 1 should be scheduled 3 months after the last dose of trial treatment. Follow-up Visit 2 should occur 
6 months after the last dose of trial treatment. After Follow-up Visit 2 subjects only need to be assessed every 9 weeks (63 ± 7 days) by radiologic imaging to monitor 
disease status, development of drug related SAEs and ECIs, and initiation of new antineoplastic therapy. Unless otherwise noted in the flow chart, every effort should be 
made to collect subject information until the start of new antineoplastic therapy, disease progression, or death, whichever occurs first. 
3.
Once a subject experiences disease progression or starts a new antineoplastic therapy, the subject moves into the Survival Follow-up Phase and should be contacted by 
telephone approximately every 2 months to assess for survival status and start of new antineoplastic therapy if applicable.  Updated survival status may be requested by the 
Sponsor at any time during the course of the study.  Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or study contact during the 
Sponsor-defined time period will be contacted for their survival status (excluding subjects who have a death event previously recorded).
4.
Record all AEs occurring within 30 days after the last dose of trial treatment regardless of initiation of new therapy. Report all SAEs (related and unrelated to trial 
treatment), occurring within 90 days of the last dose of trial treatment or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever 
comes first. After this time, report only SAEs that are considered related to trial treatment.
5.
Vital signs to include temperature, pulse, respiratory rate, blood pressure and weight. 
6.
The same imaging technique should be used in a subject as was used earlier in the trial. Imaging should continue until the start of a new antineoplastic therapy, documented 
disease progression, or death, whichever occurs first.
7.
Subjects who discontinue trial treatment due to reasons other than disease progression should continue to be assessed every 9 weeks (63 ± 7 days) by radiologic imaging 
calculated from the date of randomization until initiation of a new cancer treatment or death.
8.
Will be provided in full protocol for list of laboratory tests.
9.
Analysis will be performed by a central laboratory only if the local laboratory is unable to perform this service.
10. Patient reported outcomes (PROs) are to be administered by trained site personnel and completed by subjects. It is strongly recommended that PROs are administered prior 
to adverse event evaluation and disease status notification starting with the EQ-5D, followed by EORTC QLQ-C30, and EORTC LC-13. All PROs are to be performed at 
the 30-day post-treatment discontinuation follow-up visit. If the subject does not complete the PROs, the MISS_MODE form must be completed to capture the reason the 
assessment was not performed.
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Protocol/Amendment No.: 033-05 
MK-3475-033-05 Final Protocol
14-Jul-2021
Confidential
Second Course Treatment and Follow-up Phase for Pembrolizumab Arm
Second Course Treatment Cycles1
End of Second Course 
Treatment
Follow-up16
Survival 
Follow-up11
1
2
Every 3 
Months after 
Visit 2
Approx. 
Every 2 
Months
Treatment Cycle/ 
Scheduled Time
1
2
3
4
5
6
7
8
9
10
11
12
13 and 
beyond
Discontinuation 
Visit
Safety 
Follow-
up 
Visit15
Follow-up 
Visit 1
Follow-up 
Visit 2
Follow-up 
Visit 3 and 
Beyond
Survival 
Follow-up 
Visit 1 and 
Beyond
Scheduling 
Window (Days) 2:
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At study drug 
discontinuation
±3
30 days 
from last 
dose
±3
±7 
̉±7 
±7 
±14 
Administrative Procedures
Eligibility Criteria
X
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subsequent 
Antineoplastic 
Therapy Status
X
X
X
X
X
X
Survival Status11
X
Study Drug Administration
Pembrolizumab13
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Procedures/Assessments
Review Adverse 
Events12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Full Physical 
Examination
X
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs17
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG 
Performance 
Status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Product:  MK-3475 
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Protocol/Amendment No.: 033-05 
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Confidential
Second Course Treatment Cycles1
End of Second Course 
Treatment
Follow-up16
Survival 
Follow-up11
1
2
Every 3 
Months after 
Visit 2
Approx. 
Every 2 
Months
Treatment Cycle/ 
Scheduled Time
1
2
3
4
5
6
7
8
9
10
11
12
13 and 
beyond
Discontinuation 
Visit
Safety 
Follow-
up 
Visit15
Follow-up 
Visit 1
Follow-up 
Visit 2
Follow-up 
Visit 3 and 
Beyond
Survival 
Follow-up 
Visit 1 and 
Beyond
Scheduling 
Window (Days) 2:
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At study drug 
discontinuation
±3
30 days 
from last 
dose
±3
±7 
̉±7 
±7 
±14 
Laboratory Procedures/Assessments: Analysis Performed by Local Laboratory5
Pregnancy Test -
Urine or Serum 
β-HCG3
X
PT/INR and 
aPTT4
X
CBC with 
Differential6, 9
X
X
X
X
X
X
X
X
X
X
X9
X
X18
X18
X18
Comprehensive 
Chemistry Panel6, 9
X
X
X
X
X
X
X
X
X
X
X9
X
X18
X18
X18
Urinalysis10
X
X
X
X10
X
X
T3/FTE3, FT4 and 
TSH6, 7
X
X
X
X
X
X
X7
X
X18
X18
X18
Efficacy Measurements
Tumor Imaging8, 14
X
X
X
X
X8
X
X14
X
X
X
1.
In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of trial treatment for each cycle unless otherwise specified. Treatment cycles are 3 
weeks (21 days). If treatment cycles are adjusted, all procedures except imaging will be completed according to the cycle number and not weeks on treatment; imaging will 
be performed every 9 weeks (63 ± 7 days) from the date of randomization regardless of any treatment delays.
2.
In general, the window for each visit is 3 days unless otherwise specified.
3.
For women of childbearing potential (WOCBP), a urine pregnancy test will be performed within 72 hours prior to the first Second Course dose. If urine pregnancy results 
cannot be confirmed as negative, a serum pregnancy test, performed by the local study site laboratory, will be required. Pregnancy tests (serum and/or urine tests) should be 
repeated if required by local guidelines.
4.
Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
5.
Laboratory tests for determining eligibility for Second Course Phase are to be performed within 10 days prior to the first dose of pembrolizumab. See Section 7.1.3 for details 
regarding laboratory tests.
6.
After the first dose, lab samples can be collected up to 3 days prior to the scheduled time point. Laboratory results must be known and acceptable prior to dosing. See Section 
7.1.3 for details regarding laboratory tests.
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Product:  MK-3475 
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Protocol/Amendment No.: 033-05 
MK-3475-033-05 Final Protocol
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Second Course Treatment Cycles1
End of Second Course 
Treatment
Follow-up16
Survival 
Follow-up11
1
2
Every 3 
Months after 
Visit 2
Approx. 
Every 2 
Months
Treatment Cycle/ 
Scheduled Time
1
2
3
4
5
6
7
8
9
10
11
12
13 and 
beyond
Discontinuation 
Visit
Safety 
Follow-
up 
Visit15
Follow-up 
Visit 1
Follow-up 
Visit 2
Follow-up 
Visit 3 and 
Beyond
Survival 
Follow-up 
Visit 1 and 
Beyond
Scheduling 
Window (Days) 2:
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At study drug 
discontinuation
±3
30 days 
from last 
dose
±3
±7 
̉±7 
±7 
±14 
7.
Thyroid function tests will be performed by a central laboratory only if the local laboratory is unable to perform this service. Thyroid function tests should be performed 
every other cycle. 
8.
Sponsor will collect radiological assessments for analysis by a central vendor. If the subject enters the Second Course Phase, Cycle 1 scan may be performed up to 30 days 
prior to the first dose of trial treatment in the Second Course Phase. Imaging will be performed every 9 weeks (63 7 days) after the first dose of Second Course Phase trial 
treatment up until Cycle 13 and every 12 weeks (84 ± 7 days) thereafter. The timing of imaging should follow calendar days and should not be adjusted for delays in cycle 
starts or extension of pembrolizumab cycle frequencies. The same imaging technique should be used in a subject throughout the trial.
9.
CBC with differentials and chemistry will be performed every cycle up to Cycle 10, then every other cycle thereafter.
10. Perform every 4 cycles.
11. Once a subject experiences disease progression or starts a new antineoplastic therapy, the subject moves into the Survival Follow-up Phase and should be contacted by 
telephone approximately every 2 months to assess for survival status and start of new antineoplastic therapy if applicable.  Updated survival status may be requested by the 
Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or study contact during the 
Sponsor defined time period will be contacted for their survival status (excluding subjects who have a death event previously recorded).
12. Record all AEs occurring within 30 days after the last dose of trial treatment. Report all SAEs (related and unrelated to trial treatment) occurring within 90 days following 
cessation of treatment or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier. After this time, report only SAEs that 
are considered related to trial treatment.
13. Pembrolizumab can be administered up to 17 trial treatment in Second Course Phase.
14. Subjects who discontinue trial treatment due to reasons other than disease progression should continue to be assessed every 9 weeks (63 ± 7 days) by radiologic imaging until 
the start of a new antineoplastic therapy, documented disease progression, or death, whichever occurs first. If trial treatment is discontinued after Cycle 13, tumor imaging 
should be performed every 12 weeks (84 days ± 7 days). Continued imaging is not needed for subjects who start another antineoplastic treatment. The same imaging 
technique should be used in a subject throughout the trial.
15. 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. 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. Subjects who are eligible for treatment with pembrolizumab during the Second Course Phase may have up to two Safety 
Follow-up Visits, one after the Treatment Phase and the second after the Second Course Phase.
16. Subjects who discontinue trial treatment for a reason other than disease progression will move into the Follow-up Phase and should be assessed every 9 weeks (63 ± 7 days) 
by radiologic imaging to monitor disease status. Follow-up Visit 1 should be scheduled 3 months after the last dose of trial treatment. Follow-up Visit 2 should occur 6 
months after the last dose of trial treatment. After Follow-up Visit 2 subjects only need to be assessed every 9 weeks (63 ± 7 days) by radiologic imaging to monitor disease 
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Second Course Treatment Cycles1
End of Second Course 
Treatment
Follow-up16
Survival 
Follow-up11
1
2
Every 3 
Months after 
Visit 2
Approx. 
Every 2 
Months
Treatment Cycle/ 
Scheduled Time
1
2
3
4
5
6
7
8
9
10
11
12
13 and 
beyond
Discontinuation 
Visit
Safety 
Follow-
up 
Visit15
Follow-up 
Visit 1
Follow-up 
Visit 2
Follow-up 
Visit 3 and 
Beyond
Survival 
Follow-up 
Visit 1 and 
Beyond
Scheduling 
Window (Days) 2:
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At study drug 
discontinuation
±3
30 days 
from last 
dose
±3
±7 
̉±7 
±7 
±14 
status, development of drug-related SAEs, and initiation of new antineoplastic therapy. Unless otherwise noted in the flow chart, every effort should be made to collect 
subject information until the start of new antineoplastic therapy, disease progression or death, whichever occurs first.
17. Vital signs to include temperature, pulse, respiratory rate, blood pressure, and weight.
18. Every effort should be made to collect blood samples at the Safety Follow-up Visit, Follow-up Visit 1, and Follow-up Visit 2 until the start of new antineoplastic therapy, 
disease progression or death, whichever comes first.
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7.0 TRIAL PROCEDURES
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
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performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator. In addition, record any prior 
cancer other than NCSLC even if diagnosed greater than 10 years prior to Visit 1. NSCLC 
history will be recorded separately and not listed as Medical History. Medical history will 
also include an assessment of smoking history.
7.1.1.5
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 30 days before first dose of trial treatment. In addition, record all treatments for a prior 
cancer other than NSCLC even if taken greater than 30 days prior to first dose of trial 
treatment. Prior treatments for NSCLC will be recorded separately and not listed as a prior 
medication.
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 30-day Safety Follow-up Visit. After the Safety Follow-up Visit 
record all medications related to reportable SAEs and ECIs as defined in Section 7.2.
7.1.1.6
Non-small cell lung cancer (NSCLC) Disease Details and Treatments
7.1.1.6.1 Disease Details
The investigator or qualified designee will obtain prior and current NSCLC disease details.
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7.1.1.6.2 Prior Treatment
The investigator or qualified designee will review all prior treatments for NSCLC including
systemic treatments, radiation and surgeries.
7.1.1.6.3 Subsequent Antineoplastic Therapy Status
The investigator or qualified designee will review all new antineoplastic therapy initiated 
after the last dose of trial treatment. If a subject initiates a new antineoplastic therapy within 
30 days after the last dose of trial treatment, the “30-day Safety Follow-up visit” must occur 
before the first dose of the new therapy. Once new antineoplastic therapy has been initiated 
the subject will move into survival follow-up.
7.1.1.7
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization 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.
7.1.1.8
Assignment of Treatment/Randomization Number
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number. The treatment/randomization number identifies the subject for all procedures 
occurring after treatment allocation/randomization. Once a treatment/randomization number 
is assigned to a subject, it can never be re-assigned to another subject. IVRS/IWRS will be 
used in this study to randomize subjects and assign treatment/randomization number. 
A single subject cannot be assigned more than 1 treatment/randomization number.
7.1.1.9
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment plan for greater than 12 weeks between 
pembrolizumab (MK-3475) doses due to toxicity will require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
subject management.
Administration of trial medication will be witnessed by the investigator and/or trial staff. The 
total volume of trial treatment infused will be compared to the total volume prepared to 
determine compliance with each dose administered.
The instructions for preparing and administering pembrolizumab (MK-3475) will be 
provided in the Procedures Manual.
Docetaxel will be prepared and administered as per the approved product label.
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Clinical Procedures/Assessments
7.1.2.1
Adverse Event (AE) Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically
indicated. Adverse experiences will be graded and recorded throughout the study and during
the follow-up period according to NCI CTCAE Version 4.0 (see Section 12.5). Toxicities
will be characterized in terms including seriousness, causality, toxicity grading, and action
taken with regard to trial treatment.
An immune related adverse event (irAE) may be defined as an adverse event of unknown
etiology, associated with drug exposure and is consistent with an immune phenomenon.
Efforts should be made to rule out neoplastic, infectious, metabolic, toxin or other etiologic
causes prior to labeling an adverse event immune related. Immunological, serological and
histological (biopsy) data should be used to support the diagnosis of an immune–related
toxicity. 
Please refer to Section 7.2 for detailed information regarding the assessment and recording of
AEs.
7.1.2.2
Physical Exam
7.1.2.2.1 Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the 
screening period and the end of treatment visit. Clinically significant abnormal findings 
should be recorded as medical history. After the first dose of trial treatment new clinically 
significant abnormal findings should be recorded as AEs.
7.1.2.2.2 Directed Physical Exam
For cycles that do not required a full physical exam per the Trial Flow Chart, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to 
trial treatment administration. New clinically significant abnormal findings should be 
recorded as AEs/SAEs.
7.1.2.3
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of trial treatment and during the Follow-up period as specified in the Trial 
Flow Chart. Vital signs include temperature, pulse, respiratory rate, weight and blood 
pressure. Height will be measured at Visit 1 only.
7.1.2.4
12-Lead Electrocardiogram (ECG)
A standard 12-lead ECG will be performed using local standard procedures once at 
screening. Clinically significant abnormal findings should be recorded as medical history.
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7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (see Section 12.4) at 
screening, prior to the administration of each dose of trial treatment and during the Follow-up 
period as specified in the Trial Flow Chart.
7.1.2.6
Tumor Imaging and Assessment of Disease
All imaging obtained on study will be submitted for blinded central radiologists’ review. The 
process for image collection and transmission to the central vendor can be found in the Site 
Imaging Manual (SIM). Tumor imaging should be acquired by computed tomography (CT, 
strongly preferred). Magnetic resonance imaging (MRI) should be used when CT is 
contraindicated or for imaging the brain. The same imaging technique regarding modality 
and use of contrast should be used in a subject throughout the trial to optimize the 
visualization of existing and new tumor burden. 
Imaging includes the chest, abdomen and pelvis.
Local site investigator/radiology assessment based on RECIST 1.1 will be used to determine 
subject eligibility. Although RECIST 1.1 references to maximum of 5 target lesions in total 
and 2 per organ, Merck allows maximum of 10 target lesions in total and 5 per organ. All 
scheduled images for all study subjects from the sites will be submitted to the central 
imaging vendor. In addition, additional imaging (including other modalities) that are 
obtained at unscheduled time points to determine disease progression, as well as imaging 
obtained for other reasons but captures radiologic progression, should be submitted to the 
central imaging vendor.
The central imaging vendor will verify PD following the first radiologic evidence of PD 
(based on local Investigator assessment). Expedited verification of radiologic PD by the 
central imaging vendor will be communicated to the trial site and Sponsor (See 
Section 7.1.2.6.3).
7.1.2.6.1 Initial Tumor Imaging
Initial tumor imaging must be performed within 28 days prior to the date of randomization. 
The site study team must review screening images to confirm the subject has measurable 
disease per RECIST 1.1.
Scans performed as part of routine clinical management are acceptable for use as the 
screening scan if they are of diagnostic quality and performed within 28 days prior to the date 
of randomization and can be assessed by the central imaging vendor.  
Subjects with previously treated brain metastases may participate provided they have stable 
brain metastases, i.e., without evidence of progression by imaging during screening;
(confirmed by magnetic resonance imaging (MRI) if MRI was used at prior imaging, or 
confirmed by computed tomography (CT) imaging if CT used at prior imaging) for at least 4 
weeks prior to the first dose of trial treatment. Any neurologic symptoms must have returned 
to baseline and subjects must have no clinical evidence of new or enlarging brain metastases, 
and have not used steroids for brain metastases for at least 3 days prior to trial initiation as 
per local site assessment. This exception does not include carcinomatous meningitis, as 
subjects with carcinomatous meningitis are excluded regardless of clinical stability.  
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7.1.2.6.2 Tumor Imaging During Trial
The first imaging assessment should be performed at 9 weeks (63 days ±7 days) from the 
date of randomization. Subsequent imaging should be performed every 9 weeks (63 days ±7 
days) or more frequently if clinically indicated. Imaging timing should follow calendar days 
and should not be delayed for delays in cycle starts or extension of pembrolizumab (MK-
3475) cycle intervals. Imaging should continue to be performed until disease progression 
verified by the central imaging vendor (unless site PI elects to continue treatment and follow 
irRECIST), the start of new anti-cancer treatment, withdrawal of consent, or death, 
whichever occurs first. All supplemental imaging must be submitted to the central imaging 
vendor.
Per RECIST 1.1, partial or complete response should be confirmed by a repeat radiographic 
assessment not less than 4 weeks from the date the response was first documented. The tumor 
imaging for confirmation of response may be performed at the earliest 4 weeks after the first 
indication of response, or at the next scheduled scan (i.e., 9 weeks later), whichever is 
clinically indicated. Subjects will then return to regular scheduled imaging, starting with the 
next scheduled imaging time point. Subjects who obtain a confirmation scan do not need to 
undergo the next scheduled tumor imaging if it is < 4 weeks later; tumor imaging may 
resume at the subsequent scheduled imaging time point.
Continue to perform imaging until whichever of the following occurs first: 

Initial site-assessed disease progression is verified by the central imaging vendor

The start of new anti-cancer treatment

Withdrawal of consent

Death 

The end of the study
It is the discretion of the PI to continue to treat and image the subject at least 4 weeks after 
the first scan indicating progressive disease. irRECIST would then be followed by the site to 
determine if the follow-up scan confirms progressive disease (see Procedure Manual).
Subjects who have unconfirmed disease progression may continue on treatment and follow 
the regular imaging schedule intervals until progression is confirmed provided they have met 
the conditions detailed in Section 7.1.2.6.3.
Subjects who move into the Second Course Phase will continue to have scans performed 
every 9 weeks (63 ± 7 days) up to Cycle 13 and then every 12 weeks (84 ± 7 days).
7.1.2.6.3 Assessment of Disease 
RECIST 1.1 will be applied by the central imaging vendor as the primary measure for 
assessment of tumor response, date of disease progression, and as a basis for all protocol 
guidelines related to disease status (e.g., discontinuation of study therapy). Initial tumor 
imaging showing site-assessed PD should be submitted to the central imaging vendor 
immediately. The site will be notified if the central imaging vendor verifies PD using 
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RECIST 1.1. Figure 2 illustrates the imaging flow involving verification of PD for clinically 
stable subjects.
irRECIST Assessment of Disease 
irRECIST is RECIST 1.1 adapted as described below to account for the unique tumor 
response seen
with immunotherapeutic
drugs. irRECIST will be used by site 
investigator/local radiology review to assess tumor response and progression, and make 
treatment decisions. This data will be collected in the clinical database. Treatment
efficacy based on irRECIST as assessed by central imaging vendor review will be evaluated 
retrospectively.
As noted above, per irRECIST,  if tumor imaging shows initial PD, tumor assessment 
should be repeated ≥4 weeks later in order to confirm PD with the option of continuing 
treatment while awaiting radiologic confirmation of progression. Subjects who obtain a 
confirmation scan do not need to undergo scheduled tumor imaging if it is < 4 weeks later 
and may wait until the next scheduled imaging time point if clinically stable (see Section 
4.2.3.2 and Table 5). 
When feasible subjects should not be discontinued until progression is confirmed by the local
site investigator/radiology assessment. This allowance to continue treatment despite initial
radiologic progressive disease (PD) takes into account the observation that some subjects 
can have a transient tumor flare in the first few months after the start of immunotherapy, and
then experience subsequent disease response. Subjects that are deemed clinically unstable
are not required to have repeat tumor imaging for confirmation of PD. Tumor flare
includes any of the following scenarios:

Worsening of existing target lesion(s)

Worsening of existing non-target lesion(s)

Development of new lesions(s)
In subjects who have initial evidence of radiological PD by RECIST 1.1 as verified by 
central imaging vendor, it is at the discretion of the PI whether to continue a subject on study 
treatment until repeat imaging is obtained (using irRECIST for subject management; see 
Table 5). This clinical judgment decision by the site 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:

Absence of symptoms and signs indicating clinically significant progression of
disease, including worsening of laboratory values

No decline in ECOG performance status

Absence of rapid progression of disease

Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention
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Any subject deemed clinically unstable should be discontinued from trial treatment at
central verification of site- assessed first radiologic evidence of PD and is not required to
have repeat imaging for PD confirmation.
In determining whether or not the tumor burden has increased or decreased per
irRECIST, the local site investigator should consider all target and non-target lesions as well 
as any incremental new lesion(s).
Scenarios where PD is not confirmed at repeat imaging if ALL of the following occur by 
irRECIST:

Target lesion sum of diameters is <20% or <5 mm absolute increase compared to 
Nadir

Non-target disease resulting in initial PD is stable or qualitatively improved

New lesion resulting in initial PD is stable or qualitatively improved

No incremental new lesion(s) since last evaluation

No incremental new non-target lesion progression since last evaluation
If repeat imaging does not confirm PD per irRECIST as assessed by the local site 
investigator and the subject continues to be clinically stable, study treatment and tumor 
imaging may continue per study schedule.
Scenarios where PD is confirmed at repeat imaging if ANY of the following occur by 
irRECIST:

Target lesion sum of diameters remains ≥20 % and at least 5 mm absolute increase 
compared to nadir

Non-target disease resulting in initial PD is qualitatively worse

New lesion resulting in initial PD is qualitatively worse

Additional new lesion(s) since last evaluation

Additional new non-target lesion progression since last evaluation
If repeat imaging confirms PD due to any of the scenarios listed above, subject will be 
discontinued from study therapy.
NOTE: If a subject has confirmed radiographic progression (i.e. 2 scans at least 4 weeks 
apart demonstrating progressive disease) per irRECIST, but the subject is achieving a 
clinically meaningful benefit, and there is no further increase in the tumor burden at the 
confirmatory tumor imaging, an exception to continue treatment may be considered 
following consultation with the Sponsor. In this case, if treatment is continued, tumor 
imaging should continue to be performed following the intervals as outlined in sections 6.0 
Study Flowchart and be submitted to the central imaging vendor.
Additional details about irRECIST are referenced in Merck TIP Sheet for RECIST 1.1 and 
irRECIST.
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Table 5
Imaging and Treatment After 1st Radiologic Evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic
evidence of PD
Repeat imaging at > 
4weeks at site to 
confirm PD
May continue study
treatment at the 
Investigator’s discretion 
while awaiting 
confirmatory scan by 
site by irRECIST
Repeat imaging at > 
4 weeks to confirm 
PD per investigator
discretion only
Discontinue 
treatment
Repeat scan 
confirms PD by 
irRECIST at the 
local site
No additional 
imaging Required*
Discontinue treatment
(exception is possible 
upon consultation with 
Sponsor)
No additional 
imaging required
N/A
Repeat scan shows
SD, PR or CR by 
irRECIST at the 
local site
Continue regularly
scheduled imaging 
assessments
Continue study
treatment at the 
Investigator’s discretion
Continue regularly
scheduled imaging 
assessments
May restart study
treatment if 
condition has 
improved and/or 
clinically stable per 
Investigator’s 
discretion. Next 
tumor image should 
occur according to 
the regular imaging 
schedule
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Figure 2
Imaging and Treatment for Clinically Stable Subjects after First Radiologic 
Evidence of PD Assessed by the Site
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
In determining whether or not the tumor burden has increased or decreased, 
investigators should consider all target lesions as well as non-target lesions (please refer 
to the Imaging Tip Sheet). Subjects that are deemed clinically unstable are not required 
to have repeat imaging for confirmation. If radiologic progression is confirmed by 
subsequent scan then the subject will be discontinued from trial treatment. If radiologic 
progression is not confirmed, then the subject should resume or continue trial treatment 
and have their next scan according to the protocol schedule of every 9 weeks (63 ± 7 
days).  
NOTE: If a subject has confirmed radiographic progression (i.e., 2 scans at least 4 
weeks apart demonstrating progressive disease) per irRECIST, but the patient is 
achieving a clinically meaningful benefit, an exception to continue treatment may be 
considered following consultation with the Sponsor (see Procedure Manual).
irRECIST data will be collected in the clinical database.
In subjects who discontinue trial treatment, tumor imaging should be performed at the time 
of treatment discontinuation (± 4 week window). If a previous scan was obtained within 4 
weeks prior to the date of discontinuation, then a scan at treatment discontinuation isn’t 
mandatory. In subjects who discontinue trial treatment due to documented disease 
progression, this is the final required tumor imaging.
In subjects who discontinue trial treatment without documented disease progression, every 
effort should be made to continue monitoring their disease status by radiologic imaging 
every9 weeks (63 days ± 7 days) until (1) the start of new anti -cancer treatment, (2) disease 
progression, (3) death, or (4) the end of the study, whichever occurs first.
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the Procedures 
Manual.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 6.
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Table 6
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
PT (INR)
Hemoglobin
Alkaline phosphatase
Glucose
aPTT
Platelet count
Alanine aminotransferase (ALT)
Protein
Triiodothyronine or Free 
Triiodothyronine (T3 or 
FT3)
WBC (total and 
differential)
Aspartate aminotransferase 
(AST)
Specific gravity 
Free thyroxine (FT4)
Red Blood Cell
Count
Lactate dehydrogenase (LDH)
Microscopic exam, if 
abnormal results are 
noted
Thyroid stimulating 
hormone (TSH)
Absolute 
Neutrophil Count
Carbon Dioxide (CO2 or 
bicarbonate)
Urine pregnancy test* 
Serum β-human chorionic
gonadotropin (β-hCG)*
Absolute
Lymphocyte Count
Creatinine or calculated
creatinine clearance (CrCl)
Blood for FBR (if 
applicable )
Uric acid 
GFR
Calcium 
HBsAg
Chloride 
Anti HCV
Glucose
Phosphorus
Potassium
Sodium
Magnesium
Total Bilirubin
Direct and indirect Bilirubin
Total protein
Blood Urea Nitrogen**
Urea
Total Cholesterol
Triglycerides
*
Perform on women of child bearing potential only. If urine pregnancy results cannot be confirmed as negative, a
serum pregnancy test will be required.
** Blood Urea Nitrogen is preferred, if not available urea may be test.
Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 10 days prior to the first dose of trial treatment. After Cycle 1, pre-dose laboratory 
procedures can be conducted up to 72 hours prior to dosing.
Results must be reviewed by the investigator or qualified designee and found to be 
acceptable prior to each dose of trial treatment.
7.1.3.2
Molecular Testing
Site must be able to provide documentation of subject’s tumor EGFR mutation and ALK 
translocation status. If the site is unable to provide this source documentation, then the 
Sponsor will offer this molecular testing of the tumor. Detailed instructions for tissue 
collection, processing and shipment are provided in the Procedures Manual.
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7.1.3.3
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:

Blood for genomics use

Leftover Fresh Tumor Biopsy and/or Archival Tumor Tissue from the main study
Other Procedures
7.1.4.1
Withdrawal/Discontinuation
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.
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
7.1.4.2
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
7.1.4.3
Patient Reported Outcomes (PROs)
The EuroQol EQ-5D, EORTC QLQ C-30 and EORTC QLQ LC-13 questionnaires will be 
administered by trained site personal and completed by subjects. It is strongly recommended 
that the PROs are completed by the patient prior to drug administration, adverse event 
evaluation and disease status notification; an exception to this recommendation may occur at 
the treatment discontinuation visit. PROs will be administrated in the following order: 
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EuroQol EQ-5D first, then EORTC QLQ-C30, and lastly the EORTC LC-13 at the time 
points specified in the Trial Flow Chart.
7.1.4.4
Tumor Tissue Collection
Participation in this trial will be dependent upon supplying tumor tissue for PD-L1 testing
from locations not radiated prior to biopsy; formalin-fixed specimens after the subject has
been diagnosed with metastatic disease will be preferred for determination of PD -L1 status
prior to randomization. Biopsies obtained prior to receipt of adjuvant/neoadjuvant therapy 
will be permitted if recent biopsy is not feasible. Only subjects whose tumors demonstrate 
evidence of PD-L1 expression (on the neoplastic cells) are eligible for enrollment. If the PD-
L1 status is considered indeterminate for a submitted specimen, the subject will be excluded. 
Patients will be stratified between TPS ≥50% and TPS 1-49% before randomization. A fine 
needle aspirate or cytological specimen is not adequate for both archival and new tissue 
samples. Core needle or excisional biopsies, or resected tissue is required. 
If the subject signs the Future Biomedical Research (FBR) consent, any leftover tissue 
biopsies that would ordinarily be discarded at the end of the main study will be retained for 
FBR, again providing the patient has signed the FBR consent.
Additional optional biopsies at approximately Week 6, Week 12 and Week 24 and at disease 
progression are highly desired when feasible, especially for those with an initial response to 
pembrolizumab (MK-3475).   THESE SAMPLES ARE TO BE COLLECTED ONLY 
FROM NON-TARGET LESIONS, TO AVOID ANY IMPACT ON irRECIST 
OUTCOMES.  Additional biopsy samples at disease progression can be obtained from the 
target lesion, but only after confirmation of disease progression by the Central Imaging 
Vendor.
Detailed instructions for tissue collection, processing and shipment are provided in the 
Procedures Manual. Older biopsy material or surgical specimens may be used to assess 
EGFR mutation status and ALK translocation status, if not already known when the patient 
signs informed consent.
7.1.4.5
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:
Imaging equipment – as required for study objectives.
See protocol-specified guidance in the Administrative Binder, Procedures Manu al and Site
Imaging Manual.
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Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.1
Screening
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
Approximately 42 days prior to randomization, potential subjects will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.1. Screening 
procedures may be repeated after consultation with the Sponsor.
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 42 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.

For WOCBP, 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.
Urine pregnancy isn’t required at subsequent visits, but pregnancy tests (serum and/or 
urine tests) should be repeated if required by local guidelines. Monthly pregnancy 
testing should be conducted as per local regulations where applicable.

Tumor imaging must be performed within 28 days prior to the first dose of trial 
treatment.
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments performed during the initial screening period are acceptable in lieu 
of a repeating a screening test if performed within the specified time frame and the results 
meet the inclusion/exclusion criteria.
7.1.5.2
Treatment Phase
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.3
Post-Treatment Follow-up Phase
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. Patients will be followed for up 
to 2 years in Follow-up. If the subject experienced a CR, PR, or SD during the Treatment 
Phase on pembrolizumab, and then experiences PD at any time during the 2-year follow-up 
period, he/she will be eligible to receive up to 12 months of therapy with pembrolizumab in 
the Second Course Phase according to the criteria in Section 7.1.5.4.
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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. 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. Subjects who are eligible per the requirements in Section 7.1.5.4 for 
treatment with pembrolizumab during the Second Course Phase may have up to two safety
follow-up visits, one after the Treatment Phase and the second after the Second Course Phase.
7.1.5.3.2 Follow-up Visits
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-up Phase and should continue to be assessed every 9 weeks (63 ± 7 
days) by radiologic imaging to monitor disease status. Follow-up Visit 1 should be scheduled 
3 months after the last dose of trial treatment. Assessment for drug-related immune-related 
adverse events should occur at Follow-up Visit 1. Follow-up Visit 2 should occur 6 months 
after the last dose of trial treatment. After Follow-up Visit 2 subjects should continue to be 
assessed every 9 weeks (63 ± 7 days) by radiologic imaging to monitor disease status and 
initiation of new antineoplastic therapy. Unless otherwise noted in the flow chart, every 
effort should be made to collect subject information on the start of new antineoplastic therapy, 
until disease progression and or death.
7.1.5.3.3 Survival Follow-up
Once a subject stops receiving study medication, they will be followed for survival. Initially 
these data will be collected at the Safety Follow-up visit, the 3-month and 6-month Follow up 
visits, and any subsequent visits for imaging that may occur every 9 weeks until PD is 
identified. Once the subject stops the imaging assessments for this protocol every 9 weeks 
(e.g. 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 2 months to 
assess for survival status. Post-study treatments and the subject’s response to them will also 
be collected.
The Sponsor may request survival status data more frequently than every 9 weeks at specific 
time points during the study. For example, survival status may be requested prior to an 
external Data Monitoring Committee (eDMC) safety review, efficacy interim analyses and 
final analysis. All subjects who are in the Survival Follow-Up Phase and not known to have 
died prior to the request for these additional survival status time points will be contacted at 
that time.
7.1.5.4
Second Course Phase
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.
Specific procedure-related details are provided above in Section 7.1 - Trial Procedures.
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Subjects who were randomized to receive pembrolizumab may be eligible to receive
pembrolizumab in the Second Course Phase of this study for up to 17 treatments (12 months) 
if the subject:

Stopped their initial treatment with pembrolizumab/placebo after attaining a
confirmed CR by central review, were treated for at least eight cycles with
pembrolizumab/placebo, 
and 
received 
at 
least 
two 
treatments 
with
pembrolizumab/placebo beyond the date when the initial CR was declared.
OR

Had SD, PR or CR and stopped pembrolizumab treatment after 35 treatments for
reasons other than disease progression or intolerability.
AND

Experienced an investigator-determined confirmed radiographic disease progression
according to irRECIST after stopping their initial treatment with pembrolizumab due
to achievement of a confirmed CR.

Did not receive any other systemic anti-cancer treatment since the last dose of
pembrolizumab. (Local treatment such as radiation or surgery as anti-cancer therapy
is allowed; Sponsor consultation must be obtained and subjects should have
recovered completely from side effects of local procedures. In patients with brain
metastases, 
neurological 
stability 
must 
be 
documented 
before 
initiating
pembrolizumab.)

Continues to meet inclusion criteria 8, 9, 13, 14 and 15.

Does not meet exclusion criteria 2-16 and/or 17.
An objective response or progression of disease that occurs during the Second Course Phase
for a subject will not be counted as an event for the primary analysis of either endpoint in this
trial.
7.1.5.5
Survival Status
To ensure current and complete survival data are available at the time of database locks, 
updated survival data may be requested during the course of the trial by the Sponsor.  For 
example, updated survival status may be requested prior to but not limited to an eDMC 
review, interim, and/or final analysis.  Upon Sponsor notification, all subjects who do 
not/will not have a scheduled study visit or study contact during the Sponsor-defined time 
period will be contacted for their survival status (excluding subjects who have a previously 
recorded death event in the collection tool).
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
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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 to be an adverse event.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 30 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
Section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any 
protocol-specified procedure or intervention.  If the subject requires a blood draw, fresh 
tumor biopsy etc., the subject is first required to provide consent to the main study and AEs 
will be captured according to guidelines for standard AE reporting.
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
For this trial, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater. No specific information is available on the treatment of overdose of pembrolizumab.
In the event of overdose, the subject should be observed closely for signs of toxicity.
Appropriate supportive treatment should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
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If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them), including the pregnancy of a male subject's female partner 
that occurs during the trial.
Pregnancies and lactations of subjects and female partners of male subjects from the time 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 of subjects 
and female partners of male subjects that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product or 180 
days after the last dose of docetaxel, or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, whichever is earlier, must be reported. All reported 
pregnancies must be followed to the completion/termination of the pregnancy. Pregnancy 
outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted 
ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as serious 
events (Important Medical Events). If the pregnancy continues to term, the outcome (health 
of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
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Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to Table 7 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study (reference 
Section 7.2.3.3 for additional details), that occurs to any subject must be reported within 24 
hours to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or follow up 
to a serious adverse event, including death due to any cause other than progression of the 
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 reporting procedures can be found in the EDC data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor.  
All subjects with serious adverse events must be followed up for outcome.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
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 
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the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 7.2.3. - Immediate Reporting of Adverse Events to the Sponsor.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor 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 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
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Table 7
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor’s 
Product
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor’s 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology 
or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an 
associated AE.)
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Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
TRIAL GOVERNANCE AND OVERSIGHT
Executive Oversight Committee
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior
Management. The EOC will receive and decide upon any recommendations made by the
external Data Monitoring Committee (eDMC) regarding the trial.
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (eDMC) will monitor the interim data from this trial. The voting 
members of the committee are external to the Sponsor. The members of the eDMC 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 eDMC will make recommendations to the EOC regarding steps to ensure both subject 
safety and the continued ethical integrity of the trial. Also, the eDMC will review interim 
trial results, consider the overall risk and benefit to trial participants and recommend to the 
EOC if the trial should continue in accordance with the protocol.
Specific details regarding 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 eDMC 
reports, minutes, and recommendations will be described in a separate charter that is 
reviewed and approved by the eDMC. The eDMC will monitor the trial at an appropriate 
frequency, as described in the detailed eDMC charter. The eDMC will also make 
recommendations to the Sponsor protocol team regarding steps to ensure both subject safety 
and the continued ethical integrity of the trial.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, changes made to primary and/or key secondary hypotheses, or the statistical 
methods related to those hypotheses, then the protocol will be amended (consistent with ICH 
Guideline E-9). Changes to exploratory or other non-confirmatory analyses made after the 
protocol has been finalized, but prior to the conduct of any analysis, will be documented in a 
supplemental SAP (sSAP) and referenced in the Clinical Study Report (CSR) for the study.
Post hoc exploratory analyses will be clearly identified in the CSR.
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Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below. The comprehensive plan 
is provided in Sections 8.2 through 8.12.
Study Design Overview
A Multinational, Multicenter, Phase III, Randomized Open-label Trial 
of Pembrolizumab versus Docetaxel in Previously Treated Subjects with 
Non-Small Cell Lung Cancer
Treatment Assignment
Subjects will be randomized in a 1:1 ratio to receive pembrolizumab 
(MK-3475) or docetaxel. This is an open-label study. 
Analysis Populations
Efficacy: Intention to Treat (ITT)
Safety: All Subjects as Treated (ASaT) 
Primary Endpoint(s)
1. Overall survival (OS) in the TPS ≥50% stratum
2. Overall survival (OS) in the TPS ≥1% population
3. Progression free survival (PFS) per RECIST 1.1 assessed by blinded 
central radiologists’ review in the TPS ≥50% stratum
4. PFS per RECIST 1.1 assessed by blinded central radiologists’ review
s in the TPS ≥1% population. 
Statistical Methods for 
Key Efficacy Analyses
The primary hypotheses will be evaluated by comparing pembrolizumab 
(MK-3475) to the control on OS and PFS using a Log-rank test. 
Estimation of the hazard ratio will be done using a Cox proportional 
hazard 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. Tier 2 
parameters will be assessed via point estimates with 95% confidence 
intervals provided for between-group comparisons; only point estimates 
by treatment group are provided for Tier 3 safety parameters. There are 
no Tier 1 events in this trial. The between- treatment difference will be 
analyzed using the Miettinen and Nurminen method. 
Interim Analyses
One interim analysis will be performed in this study. Details are 
provided in Section 8.7.
1) Timing: About 30 months after study starts.
2) Purpose: 
• Demonstrate superiority of pembrolizumab (MK-3475) in OS in 
TPS ≥50% stratum first, if achieved, and then sequentially demonstrate 
superiority of pembrolizumab (MK-3475) in OS in TPS ≥1% 
population. 
• If the OS superiority is demonstrated in the TPS ≥50% stratum and 
TPS ≥1% population in the interim analysis (IA) or final analysis, then 
demonstrate superiority of pembrolizumab (MK-3475) in PFS in TPS 
≥50% stratum and TPS ≥1% population sequentially.
Multiplicity
The overall type I error is strongly controlled at 2.5% (one-sided). See 
Section 8.8 Multiplicity for the Type I error control strategy.
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Sample Size and Power 
The study will randomize approximately 216 subjects with TPS ≥50% 
in a 1:1 ratio into pembrolizumab (MK-3475) arm and docetaxel arm. 
The overall sample size for this study is projected to be approximately 
400. The number of subjects randomized in the TPS ≥50% stratum 
drives the end of enrollment.  
The study is calendar time and final analysis is planned approximately 
36 months after the first subject randomized, at which time 
approximately 150 deaths will have been observed among two arms 
from the TPS ≥50% stratum. For primary endpoint OS in the TPS ≥50% 
stratum, the trial has ~87% power to demonstrate that pembrolizumab 
(MK-3475) is superior to docetaxel at a one-sided 2.5% alpha-level, if 
the underlying hazard ratio of OS is 0.6. The power will increase to 
approximately 90% if the underlying hazard ratio of OS is 0.58[34]. For 
OS in the TPS ≥1% population, the trial has ~90% power to demonstrate 
that pembrolizumab (MK-3475) is superior to docetaxel at a one-sided 
2.5% alpha-level, if the underlying hazard ratio of OS is 0.68 at 
approximate 280 events..   
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 IVRS vendor/Sponsor will generate the randomized allocation schedule(s) for study 
treatment assignment for this protocol, and the randomization will be implemented in IVRS.
Although the trial is open-label, analyses or summaries generated by randomized treatment 
assignment and actual treatment received will be limited and documented. In addition, the 
blinded central radiologist will perform the central imaging review without knowledge of 
treatment group assignment. The sites will be notified of the positive and negative PD_L1 
results for enrollment but the details of PD_L1 score will not be shared with the sites and will 
be directly transferred to IVRS for stratification. The sites, the principal investigators, sub-
investigators and their staff as well as Merck’s clinical research coordinators (CRAs) 
involved in on-site monitoring will remain blinded to details PD_L1 score.
The planned interim analysis is described in Section 8.7. The eDMC will serve as the 
primary reviewer of the unblinded results of the interim analyses and will make 
recommendations for discontinuation of the study or modification to an executive oversight 
committee of the SPONSOR. Depending on the recommendation of the eDMC, the Sponsor 
may prepare a regulatory submission. If the eDMC recommends modifications to the design 
of the protocol or discontinuation of the study, this executive oversight committee may be 
unblinded to results at the treatment level in order to act on these recommendations. 
Additional logistical details will be provided in the eDMC Charter. 
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0. 
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Analysis Endpoints
Efficacy Endpoints
Primary
Overall Survival (OS)
Overall Survival (OS) is defined as the time from randomization to death due to any cause. 
Subjects without documented death at the time of the final analysis will be censored at the 
date of the last follow-up.
Progression-free survival (PFS) – RECIST 1.1 by blinded central radiologists’ review
Progression-free-survival (PFS) is defined as the time from randomization to the first
documented disease progression per RECIST 1.1 based on blinded central radiologists’ 
review or death due to any cause, whichever occurs first. See Section 8.6.1 for the censoring 
rules.  
Secondary
Objective Response Rate (ORR) –RECIST 1.1 by blinded central radiologists’ review
Objective response rate is defined as the proportion of the subjects in the analysis population 
who have a complete response (CR) or partial response (PR).
Duration of Response (DOR) –RECIST 1.1 by blinded central radiologists’ review 
For subjects who demonstrated CR or PR, duration of response is defined as the time from 
first documented evidence of CR or PR until disease progression per RECIST 1.1 or death 
due to any cause, whichever occurs first. See Section 8.6.1 for the censoring rules. 
Safety Endpoints
Safety measurements are described in Section 4.2.3.2 Safety Endpoints and Section 7. 
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse events (AEs), laboratory tests, and vital signs. Furthermore, specific events will be 
collected and designated as events of clinical interest (ECIs) as described in Section 7.2.3. 
There are no “Tier 1” events in this trial. In addition, the broad clinical and laboratory AE 
categories consisting of the percentage of subjects with any AE, any drug related AE, any 
Grade 3-5 AE, any serious AE, any AE which is both drug-related and Grade 3-5, any AE 
which is both serious and drug-related, dose modification due to AE, and who discontinued 
due to an AE, and death will be considered Tier 2 endpoints. AEs (specific terms as well as 
system organ class terms) 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.
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Analysis Populations
Efficacy Analysis Populations
The Intention-to-Treat (ITT) population will serve as the population for primary efficacy 
analysis. All randomized subjects will be included in this population. Subjects will be 
included in the treatment group to which they are randomized.
Details on the approach to handling missing data are provided in Section 8.6 Statistical 
Methods.
Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study. The ASaT population consists of all randomized subjects who received at least 
one dose of study treatment. Subjects will be included in the treatment group corresponding 
to the study treatment they actually received for the analysis of safety data using the ASaT 
population. For most subjects this will be the treatment group to which they are randomized.
Subjects who take incorrect study treatment for the entire treatment period will be included in 
the treatment group corresponding to the study treatment actually received. Any subject who 
receives the incorrect study medication for one cycle but receives the correct treatment for all 
other cycles will be analyzed according to the correct treatment group and a narrative will be 
provided for any events that occur during the cycle for which the subject is incorrectly dosed. 
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in Section 
8.6 Statistical Methods.
Statistical Methods
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the supplemental 
SAP.
Statistical Methods for Efficacy Analyses
Efficacy results that will be deemed to be statistically significant after consideration of the 
Type I error control strategy are described in Section 8.8, Multiplicity. Nominal p-values will 
be computed for other efficacy analyses, but should be interpreted with caution due to 
potential issues of multiplicity.
8.6.1.1
Overall Survival (OS)
The non-parametric Kaplan-Meier method will be used to estimate the survival curves in 
each treatment group. The treatment difference in survival will be assessed by the log-rank 
test. A Cox proportional hazard model with Efron's method of tie handling will be used to 
assess the magnitude of the treatment difference (i.e., the hazard ratio). The hazard ratio and 
its 95% confidence interval from the Cox model with a single treatment covariate will be 
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reported. The stratification factor used for randomization (PD-L1 expression (TPS ≥50% vs. 
1-49% positive)) will be applied to both the stratified log-rank test and the stratified Cox 
model for analysis of TPS ≥1% subjects. Unstratified log-rank test and the unstratified Cox 
model will be used for the analysis of TPS ≥50% stratum.
Subjects in the Docetaxel arm may switch to another anti PD-1 treatment following the 
verification of progressive disease by blinded central radiologists’ review. As an exploratory 
analysis, the Rank Preserving Structural Failure Time (RPSFT) model proposed by Robins 
and Tsiatis (1989) [32] may be used to adjust for the effect of crossover to other PD-1 
therapies on OS. 
Further details of sensitivity analyses will be described in supplemental SAP.
8.6.1.2
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 log-rank test. A Cox 
proportional hazard model with Efron's method of tie handling will be used to assess the 
magnitude of the treatment difference (i.e., hazard ratio) between the treatment arms. The 
hazard ratio and its 95% confidence interval from the Cox model with Efron's method of tie 
handling and with a single treatment covariate will be reported. The stratification factor used 
for randomization (PD-L1 expression (TPS ≥50% vs. 1-49% positive)) will be applied to 
both the stratified log-rank test and the stratified Cox model for analysis of TPS ≥1% 
subjects. Unstratified log-rank test and the unstratified Cox model will be used for the 
analysis of TPS ≥50% stratum.  
Since disease progression is assessed periodically, progressive disease (PD) can occur 
anytime in the time interval between the last assessment where PD was not documented and 
the assessment when PD is documented. For the primary analysis, for the subjects who have 
PD, the true date of disease progression will be approximated by the date of the first 
assessment at which PD is objectively documented per RECIST 1.1 by blinded central 
radiologists’ review. Death is always considered as a confirmed PD event. Subjects without 
documented PD/death will be censored at the last disease assessment date.
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 by blinded central 
radiologists’ review, we will perform one primary and two sensitivity analyses with a 
different set of censoring rules. For the primary analysis, if the events (PD or death) are 
immediately after more than one missed disease assessment, the data are censored at the last 
disease assessment prior to missing visits. Also data after new anti-cancer therapy are 
censored at the last disease assessment prior to the initiation of new anti-cancer therapy. The 
first sensitivity analysis follows the intention-to-treat principle. That is, PDs/deaths are 
counted as events regardless of missed study visits or initiation of new anti-cancer therapy.
The second sensitivity analysis considers initiation of new anticancer treatment or 
discontinuation of treatment due to reasons other than complete response (whichever is 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 8. In case there is an imbalance 
between the treatment groups on disease assessment schedules or censoring patterns, a 
likelihood based score test for interval censored data, which modifies the Cox proportional 
hazard model for interval censored data [28], may be used as a supportive analysis for the 
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PFS endpoint. The interval will be constructed so that the left endpoint is the date of the last 
disease assessment without documented PD and the right endpoint is the date of documented 
PD or death, whichever occurs earlier.  
Table 8
Censoring rules for Primary and Sensitivity Analyses of PFS
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
PD or death 
documented after ≤ 1 
missed disease 
assessment, and 
before new anti-
cancer therapy, if any
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or 
death
PD or death 
documented 
immediately after ≥ 2 
consecutive missed 
disease assessments 
or after new anti-
cancer therapy, if any
Censored at last 
disease assessment 
prior to the earlier 
date of  ≥ 2 
consecutive missed 
disease assessment 
and new anti-cancer 
therapy, if any
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or 
death
No PD and no death; 
and new anticancer 
treatment is not 
initiated
Censored at last 
disease assessment 
Censored at last 
disease assessment 
Progressed at 
treatment 
discontinuation due to 
reasons other than 
complete response; 
otherwise censored at 
last disease 
assessment if still on 
study treatment or 
completed study 
treatment.
No PD and no death; 
new anticancer 
treatment is initiated
Censored at last 
disease assessment 
before new anticancer 
treatment 
Censored at last 
disease assessment
Progressed at date of 
new anticancer 
treatment
The proportional hazards assumption on PFS will be examined using both graphical and 
analytical methods if warranted. The log[-log] of the survival function vs. time for PFS will 
be plotted for the comparison between pembrolizumab (MK-3475) and the docetaxel arm. If 
the curves are not parallel, indicating that hazards are not proportional, supportive analyses 
may be conducted to account for the possible non-proportional hazards effect associated with 
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immunotherapies: for example, using Restricted Mean Survival Time (RMST) method [29], 
parametric method [30], etc.
Further details of sensitivity analyses will be described in supplemental SAP.
8.6.1.3
Objective Response Rate (ORR)
Miettinen and Nurminen’s method will be used for the comparison of the ORR between two 
treatment groups in the analysis for TPS ≥50% stratum and TPS ≥1% subjects respectively.
The difference in ORR and its 95% confidence interval from the Miettinen and Nurminen’s 
method will be reported respectively. Stratified Miettinen and Nurminen’s method with the 
stratification factor PD-L1 expression (TPS ≥50% vs. 1-49% positive) (See Section 5.4) will 
be applied to the analysis for TPS ≥1% subjects with strata weighting by sample size.
Unstratified Miettinen and Nurminen’s method will be applied to the analysis for TPS ≥50% 
subjects.
8.6.1.4
Duration of Response (DOR)
For subjects who demonstrate CR or PR, duration of response is defined as the time from 
first documented evidence of CR or PR until disease progression or death due to any cause,
whichever occurs first.  
Subjects who are alive, have not progressed, have not initiated new anti-cancer treatment, 
and have not been determined to be lost to follow-up are considered ongoing responders at 
the time of analysis. Censoring rules for DOR are summarized in Table 9. 
Table 9
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 immediately 
after ≥2 consecutive missed disease 
assessments or after new anti-cancer 
therapy, if any
Earlier date of last adequate disease 
assessment prior to ≥2 missed 
adequate disease assessments and 
new anti-cancer therapy, if any
Censor
(non-event)
Death or progression after ≤1 
missed disease assessments and 
before new anti-cancer therapy, if 
any
PD or death
End of response
(Event)
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for 
evaluation of response.  
Table 10 summarizes the primary analysis approach for primary and secondary efficacy 
endpoints. Sensitivity analysis methods are described above for each endpoint.
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The strategy to address multiplicity issues with regard to multiple efficacy endpoints, 
multiple populations, and interim analyses is described in Section 8.7 Interim Analyses and 
Final Analyses and in Section 8.8 Multiplicity.
Table 10
Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
(Description, Time Point)
Statistical Method†
Analysis Population
Missing Data Approach
Primary Hypothesis #1
OS in TPS ≥50% stratum 
Test: Unstratified Log-
rank test 
Estimation: 
Unstratified 
Cox 
model with Efron’s tie 
handling method 
ITT in TPS ≥50% stratum
Censored at last known 
alive date 
Primary Hypothesis #2
OS in TPS ≥1% 
population
Test: Stratified Log-
rank test 
Estimation: Stratified 
Cox 
model 
with 
Efron’s tie handling 
method 
ITT 
Censored at last known 
alive date 
Primary Hypothesis #3
PFS per RECIST 1.1 
blinded 
central 
radiologists’ review in 
TPS ≥50% stratum 
Test: Unstratified Log-
rank test 
Estimation: 
Unstratified 
Cox 
model with Efron’s tie 
handling method
ITT in TPS ≥50% stratum

Primary censoring 
rule 

Sensitivity analysis 
1

Sensitivity analysis 
2
(More details are in
Table 8)
Primary Hypothesis#4
PFS per RECIST 1.1 by 
blinded 
central 
radiologists’ review in 
TPS ≥1% population 
Test: Stratified Log-
rank test 
Estimation: Stratified 
Cox 
model 
with 
Efron’s tie handling 
method
ITT 

Primary censoring 
rule 

Sensitivity analysis 
1

Sensitivity analysis 
2
(More details are in 
Table 8)
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Endpoint/Variable
(Description, Time Point)
Statistical Method†
Analysis Population
Missing Data Approach
Secondary Endpoints
ORR
per RECIST 
1.1 
by 
blinded 
central 
radiologists’ 
review   
M & N method‡
ITT
Subjects with missing 
data 
are 
considered 
non-responders
Duration 
of 
Response 
per RECIST 
1.1 
by 
blinded 
central 
radiologists’ 
review    
Summary 
statistics 
using 
Kaplan-Meier 
method
All responders in ITT
Censored 
at 
last 
assessment 
date 
if 
responding at the time 
of analysis
† Statistical models are described in further detail in the text. For stratified analyses, the stratification factor used for 
randomization (PD-L1 expression (TPS ≥50% vs. 1-49% Positive)) will be applied to the analysis.
‡ Miettinen and Nurminen method.  
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, vital signs, and ECG measurements.
The analysis of safety results will follow a tiered approach (Table 11). The tiers differ with 
respect to the analyses that will be performed. AEs (specific terms as well as system organ 
class terms) and events that meet predefined limits of change in laboratory, vital signs, and 
ECG parameters are either prespecified as “Tier 1” endpoints or will be classified as 
belonging to “Tier 2” or “Tier 3” based on observed proportions of participants with an 
event.
Tier 1 Events
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. AEs 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. Finally, there are no known 
AEs associated with participants with NSCLC for which determination of a p value is 
expected to impact the safety assessment. Therefore, there are no Tier 1 events for this 
protocol.
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events using the Miettinen and Nurminen method, an 
unconditional, asymptotic method.
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Membership in Tier 2 requires that at least 10% of participants in any treatment group exhibit 
the event; all other AEs and predefined limits of change will belong to Tier 3. The threshold 
of at least 10% of participants was chosen for Tier 2 events because the population enrolled 
in this study are in critical conditions and usually experience various AEs of similar types 
regardless of treatment; events reported less frequently than 10% of participants would 
obscure the assessment of the overall safety profile and add little to the interpretation of 
potentially meaningful treatment differences. In addition, Grade 3 to 5 AEs (≥5% of 
participants in one of the treatment groups) and SAEs (≥5% of participants in one of the 
treatment groups) will be considered Tier 2 endpoints. Because many 95% CIs may be 
provided without adjustment for multiplicity, the CIs should be regarded as a helpful 
descriptive measure to be used in safety review, not a formal method for assessing the 
statistical significance of the between-group differences.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment group are provided for Tier 3 safety parameters.
Continuous Safety Measures
For continuous measures such as changes from baseline in laboratory, vital signs, and ECG 
parameters, summary statistics for baseline, on-treatment, and change from baseline values 
will be provided by treatment group in table format.
Table 11
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE (≥ 10% of participants in one of the treatment 
groups)
X
X
Any Grade 3 to 5 AE (≥ 5% of participants in one of the 
treatment groups)
X
X
Any serious AE (≥ 5% of participants in one of the 
treatment groups)
X
X
Tier 3
Any AE
X
Change from baseline results (laboratory test toxicity 
grade)
X
AE = adverse event; CI = confidence interval; X = results will be provided.
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Summaries of Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs. No statistical hypothesis tests will be performed on these 
characteristics. The number and percentage of subjects 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.
Interim Analyses
There is one planned interim analysis in this trial.
The interim analysis will be performed about 30 months after first subject randomized. By
then, about 125 deaths are projected to occur in the subjects with TPS≥50%. The actual HR 
boundary for interim analysis will be determined from the number of OS events observed at 
the time of the interim analysis using the alpha spending function.
The primary objective of this interim analysis is to demonstrate that pembrolizumab (MK-
3475) arm is superior to the docetaxel arm in OS in TPS ≥50% stratum at the 1.41% 
significance level, regardless of the actual number of deaths observed at the IA. A p-value of 
1.41% (one-sided) for OS approximately corresponds to an empirical hazard ratio of 0.6737. 
A positive finding on OS may lead to regulatory filing for drug approval upon discussion 
with regulatory agencies. PFS analysis using the interim data will be the final analysis for the 
PFS hypotheses. 
Table 12 summarizes the timing, sample size and decision guidance of the interim analysis 
and final analysis in the hypothetical scenario where the numbers of deaths at IA and FA are 
assumed to be the same as the projected (i.e., 125 for IA and 150 for FA in the subjects with 
TPS>50%). The IA p-value boundary will be fixed. The IA HR boundary will be re-
calculated if the actual number of IA death events is altered from the expected. The FA p-
value and HR boundaries will be re-calculated if the actual number of IA or FA death events 
is altered from the expected; the actual FA boundaries will be based on the observed number 
of death events at IA and FA.
Superiority of OS in both TPS ≥50% stratum and ≥1% population needs to be demonstrated 
in order for the eDMC to recommend stopping the trial due to efficacy. All details will be 
described in the eDMC Charter.   
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Table 12
Summary of Timing, Sample Size and Decision Guidance of Interim Analyses 
and Final Analyses
Analysis
Criteria for Conduct of Analysis
Value
Efficacy
Interim Analysis 
~ 30 months after trial starts2
(~125 OS events have been observed in 
TPS≥50% stratum)
p-value (1-sided) at 
boundary
~ HR at boundary
<=0.0141
0.6737
Final Analyses
~ 36 months after trial starts2
(~150 OS events have been observed in 
TPS≥50% stratum)
p-value (1-sided) at 
boundary
~ HR at boundary
<=0.0210
0.7160
1 In this hypothetical scenario, the numbers of deaths at IA and FA are assumed to be the same as the projected. The IA 
HR boundary will be re-calculated if the actual number of IA death events is altered from the expected. The FA p-value 
and HR boundaries will be re-calculated if the actual number of IA or FA death events are altered from the expected; the 
actual FA boundaries will be based on the observed number of death events at IA and FA
2 Trial start is defined as the date when the first subject was randomized.
Multiplicity
The multiplicity strategy specified in this section will be applied to the TPS ≥50% stratum 
and the TPS ≥1% population for the testing of the OS hypotheses and the PFS hypotheses. 
The overall type I error is strongly controlled at 2.5% (one-sided). The following hypotheses 
will be tested sequentially at the type I error rate of 2.5% (one-sided) in the following order: 

Superiority of pembrolizumab (MK-3475) in OS in the TPS ≥50% stratum;

Superiority of pembrolizumab (MK-3475) in OS in the overall TPS ≥1% population;

Superiority of pembrolizumab (MK-3475) in PFS in the TPS ≥50% stratum;

Superiority of pembrolizumab (MK-3475) in PFS in the overall TPS ≥1% population. 
Testing will stop with the first of these tests failing to reach statistical significance and all 
subsequent tests would not be considered for statistical significance. The sequential 
hypothesis testing for OS can continue across the interim and final analyses.
The type I error rates for the interim analysis and final analysis which will allow tight control 
of the overall type I error for testing the OS hypothesis in the TPS ≥50% stratum will be 
derived using the alpha-spending function approach. The OS efficacy boundary will be set 
using the O’Brien-Fleming approach with the total alpha 2.5% (one-sided) and specified 
calendar time fraction (0.83 for interim analysis and 1.00 for final analysis, respectively). No 
futility boundary will be set.
Both IA and FA will be conducted based on calendar time. Specifically, IA and FA will 
occur about 30 months and about 36 months after the date when the first subject was 
randomized. The cumulative alpha (one-sided) spending at the planned time of IA and FA
becomes 1.41% and 2.5%, regardless of the actual number of deaths observed at the IA and 
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FA. The actual HR boundary at IA will be calculated based on the cumulative alpha spent 
and actual number of deaths observed at IA; the actual p value boundary and HR boundary at 
FA will then be calculated based on the cumulative alpha spent and actual number of deaths 
observed at IA and FA.
If the pembrolizumab (MK-3475) arm demonstrates superior OS in the TPS ≥50% stratum at 
the interim analysis, the OS hypothesis in the TPS ≥1% population will be tested based on a 
group sequential approach with the cumulative alpha spent up to the IA as the same as the 
alpha spent for testing the OS hypothesis in the TPS ≥50% stratum up to that IA.  
The primary testing of the PFS hypothesis will only be conducted on the interim analysis
data, and only if OS superiority is demonstrated in both of the TPS≥50% stratum and the 
TPS ≥ 1% population. Since the time of the interim analysis is the only analysis for PFS, the 
p-values for PFS primary hypothesis tests will be sequentially compared to 2.5% (one-sided).
Sample Size and Power Calculations
The study will randomize approximately 216 subjects with TPS ≥50% in a 1:1 ratio into 
pembrolizumab (MK-3475) arm and docetaxel arm. The overall sample size for this study is 
projected to be approximately 400. The number of subjects randomized in the TPS ≥50% 
stratum drives the end of enrollment.  
The study is calendar time driven and will complete after approximately 36 months after the 
first subject randomized, at which time approximately 150 deaths will have been observed 
between the two arms in the TPS ≥50% stratum. With 150 deaths, the study has 
approximately 87% power to detect a 0.6 hazard ratio on OS at alpha=2.50% (one-sided) in 
the TPS ≥50% stratum. The power will increase to approximately 90% if the underlying 
hazard ratio of OS is 0.58 [34]. By the time when 150 deaths are observed in the TPS ≥50%
stratum, the expected number of deaths is about 280 in the TPS ≥1% population. With 280
deaths, the study has approximately 90% power to detect a 0.68 hazard ratio on OS at 
alpha=2.5% (one-sided) in the overall TPS ≥1% population. Details on the nominal alpha and 
the approximate efficacy boundary at each interim analysis are summarized in Section 8.7.
The power calculation is based on the following assumptions for subjects in the TPS ≥50% 
stratum and TPS ≥1% population: 1) OS follows an exponential distribution with a median of 
10 months in the docetaxel arm; 2) An enrollment period of 24 months; 3) A yearly drop-out 
rate of 2%.
Subgroup Analyses and Effect of Baseline Factors
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the primary 
endpoints will be estimated and plotted within each category of the following classification 
variables. These subgroup analyses would be carried out in TPS ≥50% stratum and TPS ≥
1% population as applicable: 

Age category (≤65 vs. >65 years)

Sex (Female vs. Male)

ECOG Performance Scale (0 vs. 1)
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
Disease Status (Locally advanced vs. Metastatic)

PD-L1 expression (TPS 1-49% vs. TPS ≥50%)
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 
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 13.
Table 13
Product Descriptions
Product Name & Potency
Dosage Form
Pembrolizumab (MK-3475) 100 mg/ 4 mL
Solution for Infusion
Docetaxel 80 mg/ 4 mL 
Solution for Infusion
Docetaxel 20 mg/ 0.5 mL
Solution for Infusion
All other supplies not indicated in Table 13 above will be provided centrally by the Sponsor 
or locally by the trial site, subsidiary or designee, depending on local country operational or 
regulatory requirements.
For any commercially available product that is provided by the trial site, subsidiary or 
designee every attempt will be made to source these supplies from a single lot/batch number.
The trial site is responsible for record the lot number, manufacturer and expiry date of any 
locally purchased product as per local guidelines unless otherwise instructed by the Sponsor.
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Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
All supplies will be provided open label. pembrolizumab (MK-3475) and docetaxel will be 
provided as a kitted supply
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.   Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Standard Policies
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
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10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
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investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor or through a secure password-protected electronic portal provided by the 
Sponsor.  The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
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The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
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The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Merck, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements.  Merck entries are not limited to FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.    
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
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functional area standard operating procedures (SOPs) to ensure that trials are conducted and
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
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investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
11.0 LIST OF REFERENCES
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Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema H, et
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Suzuki H, Chikazawa N, Tasaka T, Wada J, Yamasaki A, Kitaura Y, et al. Intratumoral
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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 
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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 
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Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Ann Rev Immunol
2005;23:515-48.
16.
Homsi J, Kashani-Sabet M, Messina JL, Daud A. Cutaneous melanoma: prognostic
factors. Cancer Control 2005;12(4):223-9.
17.
GLOBOCAN 2012. http://globocan.iarc.fr
18.
She J, Yang P, Hong Q, et al. Lung Cancer in China-Challenges and Interventions. 
Chest 2013; 143(4):1117–1126
19.
Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, et al. 
Randomized Phase III Trial of Docetaxel Versus Vinorelbine or Ifosfamide in Patients 
With Advanced Non–Small-Cell Lung Cancer Previously Treated With Platinum-
Containing Chemotherapy Regimens. J Clin Oncol 2000;18:2354-2362.
20.
Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O’Rourke M, et al.
Prospective Randomized Trial of Docetaxel Versus Best Supportive Care in Patients
With Non–Small-Cell Lung Cancer Previously Treated With Platinum-Based
Chemotherapy. J Clin Oncol 2000;18:2095-2103.
21.
Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, et al. Randomized 
Phase III Trial of Pemetrexed Versus Docetaxel in Patients With Non–Small-Cell Lung 
Cancer Previously Treated With Chemotherapy. J Clin Oncol 2004;22:1589-1597.
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22.
Gettinger S, Horn L, Antonia SJ, Spigel DR, Gandhi L, Sequist LV, et al. Clinical
activity and safety of anti-programmed death-1 (PD-1) (BMS-936558/MDX-
1106/ONO-4538) in patients (PTS) with advanced non-small cell lung cancer (NSCLC)
[Abstract 1237PD]. European Society for Medical Oncology 2012 Annual Meeting;
2012 Sep 28-2012 Oct 2. Vienna, Austria, 2012.
23.
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The
European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-
life instrument for use in international clinical trials in oncology. J Natl Cancer Inst
1993;85(5):365-76.
24.
Bergman B, Aaronson NK, Ahmedzai S, Kaasa S, Sullivan M. The EORTC QLQ-
LC13: a modular supplement to the EORTC Core Quality of Life Questionnaire (QLQ-
C30) for use in lung cancer clinical trials. EORTC Study Group on Quality of Life. Eur 
J Cancer 1994;30A(5):635-42.
25.
Fallowfield LJ, Harper P. Health-related quality of life in patients undergoing drug
therapy for advanced non-small-cell lung cancer. Lung Cancer 2005;48(3):365-77.
26.
EuroQol--a new facility for the measurement of health-related quality of life. The
EuroQol Group. Health Policy 1990;16(3):199-208.
27.
Bottomley A, Efficace F, Thomas R, Vanvoorden V, Ahmedzai SH. Health-related
quality of life in non-small-cell lung cancer: methodologic issues in randomized
controlled trials. J Clin Oncol 2003;21(15):2982-92.
28.
Finkelstein DM (1986). A proportional hazards model for interval-censored failure time 
data. Biometrics 42, 845-54.
29.
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.
30.
Odell P.M., Anderson K.M., Kannel B.W. New models for predicting cardiovascular 
events. Journal of Clinical Epidemiology 1994; 47(6): 583-592.
31.
Mehrotra D., Su S.C., Li X.  An efficient alternative to the stratified Cox model 
analysis. Statist. Med. 2012, 31 1849–1856.
32.
Robins JM, Tsiatis AT. Correcting For Non-Compliance in Randomized Trials Using 
Rank Preserving Structural Failure Time Models.  Comm. Stat. Theory Meth., 
1991;20(8):2609-2631
33.
Maurer W, Bretz F. Multiple Testing in Group Sequential Trials using Graphical 
Approaches. Statistics in Biopharmaceutical Research 2013; 5(4): 311-320.
34.
Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously 
treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a 
randomised controlled trial. Lancet. 2016 Apr 9;387(10027):1540-50.
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV.Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
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Collection and Management of Specimens for Future Biomedical Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens collected in this trial as outlined in Section 7.1.3.3 – Future Biomedical 
Research will be used to study various causes for how subjects may respond to a 
drug/vaccine.  Future biomedical research specimen(s) will be stored to provide a 
resource for future trials conducted by Merck focused on the study of biomarkers 
responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects of 
disease.  The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by Merck or designees and research 
will be monitored and reviewed by a committee of our scientists and clinicians.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  Information contained on the consent form alone cannot be traced 
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to any specimens, test results, or medical information once the specimens have been 
rendered de-identified
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.  Each consent will be assessed for 
appropriate specimen permissions.  
Each informed consent approved by an ethics committee is assigned a unique tracking 
number.  The tracking number on this document will be used to assign specimen 
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of both consent and acquisition of Future Biomedical Research 
specimens will be captured in the electronic Case Report Forms (eCRFs).  
Reconciliation of both forms will be performed to assure that only appropriately-
consented specimens are used for this sub-trial's research purposes. Any specimens 
for which such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Blood specimens for DNA or RNA isolation will usually be obtained at a time when 
the subject is having blood drawn for other trial purposes. Specimens like tissue and 
bone marrow will usually be obtained at a time when the subject is having such a 
procedure for clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where 
they will be processed (e.g., DNA or RNA extraction, etc) following the Merck 
approved policies and procedures for specimen handling and preparation.
If specimens are collected for a specific genotype or expression analysis as an 
objective to the main trial, this analysis is detailed in the main body of this protocol 
(Section 8.0 – Statistical Analysis Plan).  These specimens will be processed, 
analyzed, and the remainder of the specimen will be destroyed.  The results of these 
analyses will be reported along with the other trial results.  A separate specimen will 
be obtained from properly-consented subjects in this protocol for storage in the 
biorepository for Future Biomedical Research.
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, Merck has developed secure policies and procedures.  All 
specimens will be de-identified as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
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does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
This first code will be replaced with a second code at a Merck designated storage/lab 
facility.  The second code is linked to the first code via a second key. The specimen is 
now double coded.  Specimens with the second code are sometimes referred to as de-
identified specimens. The use of the second code provides additional confidentiality and 
privacy protection for subjects over the use of a single code.  Access to both keys would 
be needed to link any data or specimens back to the subject's identification.
The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the second 
code to the first code to allow clinical information collected during the course of the trial 
to be associated with the specimen.  This second key will be transferred under secure 
procedures by the Merck designated facility to an Entrusted Keyholder at Merck.  The 
second code will be logged into the primary biorepository database at Merck and, in this 
database, this identifier will not have identifying demographic data or identifying clinical 
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen 
will be stored in a designated biorepository site with secure policies and procedures for 
specimen storage and usage.
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by 
the Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would 
be directly linked to the full clinical data set would be those situations mandated by 
regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly 
transferred to the regulatory authority.
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the 
highly validated conditions usually associated with regulatory approval of diagnostics.  
The scope of research performed on these specimens is limited to the investigation of the 
variability in biomarkers that may correlate with a clinical phenotype in subjects.
Analyses utilizing the Future Biomedical Research specimens may be performed by 
Merck, or an additional third party (e.g., a university investigator) designated by Merck.  
The investigator conducting the analysis will be provided with double coded specimens.  
Re-association of analysis results with corresponding clinical data will only be conducted 
by the Merck Entrusted Keyholder.  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 the specific analysis is performed will be 
returned to the sponsor or destroyed and documentation of destruction will be reported to 
Merck.
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6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main 
trial are still available, the investigator will contact Merck using the designated mailbox 
(clinical.specimen.management@merck.com) and a form will be provided by Merck to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. A letter 
will be sent from Merck to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from acquisition.  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 Merck 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 Merck policies and procedures and 
this destruction will be documented in the biorepository database.
8. Data Security
Separate databases for specimen information and for results from the Future Biomedical 
Research sub-trial will be maintained by Merck.  This is done to separate the future 
exploratory test results (which include genetic data) from the clinical trial database 
thereby maintaining a separation of subject number and these results.  The separate 
databases are accessible only to the authorized Sponsor 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 in 
international standards (e.g., ISO17799) to protect against unauthorized access.  The 
Merck Entrusted Keyholder maintains control over access to all specimen data.  These 
data are collected for future biomedical research purposes only as specified in this sub-
trial will not be used for any other purpose.
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9. Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
the trial participant.  Some guidelines advocate a proactive return of data in certain 
instances.  No information obtained from exploratory laboratory studies will be reported 
to the subject or family, and this information will not be entered into the clinical database 
maintained by Merck on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation and absence of good clinical practice standards in 
exploratory research typically used for diagnostic testing.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information as 
to how to offer clinical diagnostic  testing (paid for by Merck) to subjects enrolled and 
will be advised that counseling should be made available for all who choose to participate 
in this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, Merck will publish the results without revealing specific 
subject information, inform all trial sites who participated in the Merck clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for 
public access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
10. Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on Merck clinical 
trials for future biomedical research.  When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens 
from subjects and controls to represent the ethnic and gender population representative of 
the disease under current investigation.
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. 
Merck 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.
It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, 
age, toxicities, etc.) to be re-associated to double coded specimens at the time of data 
analysis.  These subject data will be kept in a separate, secure Merck database, and all 
specimens will be stripped of subject identifiers.  No information concerning results 
obtained from future biomedical research will be entered into clinical records, nor will it 
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be released to outside persons or agencies, in any way that could be tied to an individual 
subject.
12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.
13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
14. 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
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff
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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;5:649-55. Eastern Cooperative Oncology Group, Robert Comis MD, Group Chair.
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Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html)
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Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors
RECIST version 1.1* will be used in this study for assessment of tumor response. While 
either CT or MRI may be used utilized, as per RECIST 1.1, CT is the preferred imaging 
technique in this study.  
* As published in the European Journal of Cancer:
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, S. 
Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij. New 
response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009 
Jan; 45(2):228-47.
In addition, volumetric analysis will be used for response assessment (so-called enhanced 
RECIST).
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Strong Inhibitors of CYP3A4
Strong inhibitors of CYP3A4 include:

Clarithromycin

Indinavir

Itraconazole

Ketoconazole

Nefazodone

Nelfinavir

Ritonavir

Saquinavir
This appendix is not intended to be a comprehensive list of strong CYP3A4 inhibitors, but to 
provide a practical list of commonly prescribed medications that should be avoided in 
subjects participating in this study. Additional guidance for investigators on potential strong 
CYP3A4 
inhibitors 
of 
clinical 
significance 
may 
be 
found 
at 
http://medicine.iupui.edu/flockhart/.
The web-based resources are intended as guidance for the investigators and not necessarily as 
a list of prohibited medications.
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Contraceptive Guidance
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:

Premenarchal

Premenopausal female with 1 of the following:
Documented hysterectomy
Documented bilateral salpingectomy
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.

Postmenopausal female
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.

A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
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Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.

Progestogen-only subdermal contraceptive implantb,c

Intrauterine hormone-releasing system (IUS)c

Non-hormonal IUD

Bilateral tubal occlusion

Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview.
Sexual Abstinence

Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant.
a
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c
IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
- Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
- Male condom with cap, diaphragm, or sponge with spermicide.
- Male and female condom should not be used together (due to risk of failure with friction).
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13.0 SIGNATURES
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – Assessing and Recording Adverse Events.  I also agree to handle 
all clinical supplies provided by the Sponsor and collect and handle all clinical specimens in 
accordance with the protocol.  I understand that information that identifies me will be used 
and disclosed as described in the protocol, and that such information may be transferred to 
countries that do not have laws protecting such information.  Since the information in this 
protocol and the referenced Investigator’s Brochure is confidential, I understand that its 
disclosure to any third parties, other than those involved in approval, supervision, or conduct 
of the trial is prohibited.  I will ensure that the necessary precautions are taken to protect such 
information from loss, inadvertent disclosure or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
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