A Phase II/III Randomized Trial of Two Doses of MK-3475 (SCH900475) Versus Docetaxel in Previously Treated Subjects With Non-Small Cell Lung Cancer
Phase: PHASE2
Conditions: Non Small Cell Lung Cancer (NSCLC)
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
Document Date: 
A Phase II/III Randomized Trial of Two Doses of MK-3475 
(SCH900475) versus Docetaxel in Previously Treated Subjects 
with Non-Small Cell Lung Cancer
9-Feb-2018
NCT01905657

Product:  MK-3475 (SCH 900475)
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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.
This protocol amendment is applicable only to Germany.
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.
TITLE:
A Phase II/III Randomized Trial of Two Doses of MK-3475 (SCH900475) versus Docetaxel 
in Previously Treated Subjects with Non-Small Cell Lung Cancer
IND NUMBER: 116833
EudraCT NUMBER:  2012-004391-19
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 11
1.0
TRIAL SUMMARY.................................................................................................. 17
2.0
TRIAL DESIGN........................................................................................................ 18
2.1
Trial Design ........................................................................................................... 18
2.2
Trial Diagram........................................................................................................ 20
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 22
3.1
Primary Objective(s) & Hypothesis(es) .............................................................. 22
3.2
Secondary Objective(s) & Hypothesis(es)........................................................... 22
3.3
Exploratory Objectives......................................................................................... 23
4.0
BACKGROUND & RATIONALE.......................................................................... 24
4.1
Background ........................................................................................................... 24
Pharmaceutical and Therapeutic Background .................................................... 24
4.1.1
Information on Other Trial-Related Therapy...................................................... 25
4.1.2
4.2
Rationale................................................................................................................ 26
Rationale for the Trial and Selected Subject Population .................................... 26
4.2.1
Rationale for Dose Selection/Regimen/Modification ......................................... 27
4.2.2
Rationale for Endpoints ...................................................................................... 28
4.2.3
4.2.3.1
Efficacy Endpoints....................................................................................... 28
4.2.3.1.1
Primary.................................................................................................. 28
4.2.3.1.2
Secondary.............................................................................................. 28
4.2.3.2
Patient Reported Outcomes.......................................................................... 28
4.2.3.2.1
eEORTC QLQ-C30 and EORTC QLQ-LC13...................................... 28
4.2.3.2.2
eEuroQol EQ-5D .................................................................................. 29
4.2.3.3
Future Biomedical Research........................................................................ 29
5.0
METHODOLOGY ................................................................................................... 30
5.1
Entry Criteria........................................................................................................ 30
Diagnosis/Condition for Entry into the Trial ...................................................... 30
5.1.1
Subject Inclusion Criteria.................................................................................... 30
5.1.2
Subject Exclusion Criteria .................................................................................. 34
5.1.3
 
 
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5.2
Trial Treatments................................................................................................... 36
Dose Selection/Modification .............................................................................. 37
5.2.1
5.2.1.1
Dose Selection ............................................................................................. 37
5.2.1.2
Dose Modification ....................................................................................... 37
Timing of Dose Administration .......................................................................... 42
5.2.2
5.2.2.1
MK-3475...................................................................................................... 43
5.2.2.2
Docetaxel ..................................................................................................... 43
Trial Blinding/Masking....................................................................................... 43
5.2.3
5.2.3.1
Treatment Trial Blinding ............................................................................. 43
5.2.3.2
Biomarker Trial Blinding............................................................................. 43
5.3
Randomization or Treatment Allocation............................................................ 43
5.4
Stratification.......................................................................................................... 44
5.5
Concomitant Medications (allowed & prohibited) ............................................ 44
Acceptable Concomitant Medications ................................................................ 44
5.5.1
Prohibited Concomitant Medications.................................................................. 44
5.5.2
5.6
Rescue Medications & Supportive Care............................................................. 45
Supportive Care Guidelines ................................................................................ 45
5.6.1
5.7
Diet/Activity/Other Considerations..................................................................... 46
Diet...................................................................................................................... 46
5.7.1
Contraception...................................................................................................... 46
5.7.2
Use in Pregnancy ................................................................................................ 48
5.7.3
Use in Nursing Women....................................................................................... 48
5.7.4
5.8
Subject Withdrawal/Discontinuation Criteria................................................... 48
5.9
Subject Replacement Strategy............................................................................. 50
5.10
Beginning and End of the Trial ........................................................................... 50
5.11
Clinical Criteria for Early Trial Termination ................................................... 50
5.12
Post MK-3475/Docetaxel Therapies.................................................................... 51
6.0
TRIAL FLOW CHART ........................................................................................... 52
6.1
Treatment Phase ................................................................................................... 52
MK-3475 2 and 10 mg/kg Q3W and Docetaxel Arms ....................................... 52
6.1.1
6.2
Post-Treatment Follow-up Phase ........................................................................ 56
6.3
Second Course Phase............................................................................................ 58
 
 
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Second Course Phase for MK-3475 200 mg Q3W Arms ................................... 58
6.3.1
6.4
Second Course Post-Treatment Follow-up Phase.............................................. 60
6.5
Crossover Phase .................................................................................................... 62
7.0
TRIAL PROCEDURES ........................................................................................... 64
7.1
Trial Procedures ................................................................................................... 64
Administrative Procedures.................................................................................. 64
7.1.1
7.1.1.1
Informed Consent......................................................................................... 64
7.1.1.1.1
General Informed Consent.................................................................... 64
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 65
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 65
7.1.1.3
Subject Identification Card .......................................................................... 65
7.1.1.4
Medical History ........................................................................................... 65
7.1.1.5
Prior and Concomitant Medications Review ............................................... 65
7.1.1.5.1
Prior Medications.................................................................................. 65
7.1.1.5.2
Concomitant Medications..................................................................... 65
7.1.1.6
Non-small cell lung cancer (NSCLC) Disease Details and Treatments ...... 66
7.1.1.6.1
Disease Details...................................................................................... 66
7.1.1.6.2
Prior Treatment..................................................................................... 66
7.1.1.6.3
Subsequent Antineoplastic Therapy Status........................................... 66
7.1.1.7
Assignment of Screening Number............................................................... 66
7.1.1.8
Assignment of Randomization Number....................................................... 66
7.1.1.9
Trial Compliance (Medication/Diet/Activity/Other) ................................... 66
Clinical Procedures/Assessments........................................................................ 67
7.1.2
7.1.2.1
Adverse Event (AE) Monitoring.................................................................. 67
7.1.2.2
Physical Exam.............................................................................................. 67
7.1.2.2.1
Full Physical Exam ............................................................................... 67
7.1.2.2.2
Directed Physical Exam........................................................................ 67
7.1.2.3
Vital Signs.................................................................................................... 68
7.1.2.4
12-Lead Electrocardiogram (ECG).............................................................. 68
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale ........... 68
7.1.2.6
Pulmonary Function Tests ........................................................................... 68
 
 
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Laboratory Procedures/Assessments .................................................................. 68
7.1.3
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry, Urinalysis and 
Other)........................................................................................................... 69
7.1.3.2
Pharmacokinetic Evaluations....................................................................... 70
7.1.3.2.1
Blood Collection for Serum MK-3475 ................................................. 70
7.1.3.3
Anti-MK-3475 Antibodies........................................................................... 70
7.1.3.4
Molecular Testing ........................................................................................ 70
7.1.3.5
Future Biomedical Research........................................................................ 70
Other Procedures................................................................................................. 70
7.1.4
7.1.4.1
Tumor Imaging ............................................................................................ 70
7.1.4.2
Patient Reported Outcomes (PROs)............................................................. 72
7.1.4.3
Tumor Tissue Collection.............................................................................. 72
7.1.4.4
Withdrawal/Discontinuation........................................................................ 73
7.1.4.4.1
Withdrawal from Future Biomedical Research .................................... 73
7.1.4.5
Blinding/Unblinding .................................................................................... 73
Visit Requirements.............................................................................................. 73
7.1.5
7.1.5.1
Screening...................................................................................................... 73
7.1.5.2
Treatment Phase........................................................................................... 74
7.1.5.3
Post-Treatment Follow-up Phase................................................................. 74
7.1.5.3.1
Safety Follow-up Visit.......................................................................... 74
7.1.5.3.2
Follow-up Visits ................................................................................... 75
7.1.5.3.3
Survival Follow-up ............................................................................... 75
7.1.5.3.4
Survival Status ...................................................................................... 76
7.1.5.4
Second Course Phase ................................................................................... 76
7.1.5.5
Crossover for Subjects in the Docetaxel Arm to MK-3475 200 mg Arm ... 78
7.1.5.5.1
Inclusion Criteria for Optional Crossover from docetaxel to MK-
3475 200 mg arm .................................................................................. 78
7.1.5.5.2
Exclusion Criteria for Optional Crossover from docetaxel to MK-
3475 200 mg arm .................................................................................. 79
7.1.5.6
Crossover Assessments and Procedures ...................................................... 79
Post Final Analysis Activities............................................................................. 80
7.1.6
7.2
Assessing and Recording Adverse Events .......................................................... 80
 
 
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Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 81
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 81
7.2.2
Immediate Reporting of Adverse Events and Incidents to the Sponsor ............. 82
7.2.3
7.2.3.1
Serious Adverse Events ............................................................................... 82
7.2.3.2
Events of Clinical Interest............................................................................ 83
7.2.3.3
Protocol-Specific Exceptions to Serious Event Reporting .......................... 84
7.2.3.4
Device Events .............................................................................................. 84
Evaluating Adverse Events ................................................................................. 85
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 88
7.2.5
7.3
TRIAL GOVERNANCE AND OVERSIGHT ................................................... 88
Scientific Advisory Committee........................................................................... 88
7.3.1
Trial Steering Committee.................................................................................... 88
7.3.2
Executive Oversight Committee ......................................................................... 88
7.3.3
Data Monitoring Committee ............................................................................... 88
7.3.4
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 89
8.1
Statistical Analysis Plan Summary ..................................................................... 89
Efficacy Analyses ............................................................................................... 89
8.1.1
Safety Analyses................................................................................................... 90
8.1.2
Power and Sample Size....................................................................................... 91
8.1.3
Multiplicity Adjustment...................................................................................... 91
8.1.4
Interim Analyses ................................................................................................. 92
8.1.5
8.2
Statistical Analysis Plan ....................................................................................... 93
Responsibility for Analyses/In-House Blinding ................................................. 93
8.2.1
Hypotheses/Estimation ....................................................................................... 94
8.2.2
Analysis Endpoints ............................................................................................. 94
8.2.3
8.2.3.1
Efficacy/Immunogenicity Endpoints ........................................................... 94
8.2.3.2
Safety Endpoints.......................................................................................... 95
8.2.3.3
Patient Reported Outcomes analysis............................................................ 95
Analysis Populations........................................................................................... 95
8.2.4
8.2.4.1
Efficacy Analysis Populations ..................................................................... 95
8.2.4.2
Safety Analysis Populations ........................................................................ 95
 
 
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Statistical Methods.............................................................................................. 96
8.2.5
8.2.5.1
Statistical Methods for Efficacy Analyses ................................................... 96
8.2.5.1.1
Overall Survival (OS) ........................................................................... 96
8.2.5.1.2
Progression-free-survival (PFS) ........................................................... 97
8.2.5.1.3
Overall Response Rate (ORR).............................................................. 98
8.2.5.1.4
Response Duration................................................................................ 99
8.2.5.1.5
Exploratory Analyses............................................................................ 99
8.2.5.2
Statistical Methods for Safety Analyses ...................................................... 99
8.2.5.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses..................................................................................................... 102
Multiplicity ....................................................................................................... 102
8.2.6
Sample Size and Power Calculations................................................................ 103
8.2.7
Subgroup Analyses and Effect of Baseline Factors .......................................... 106
8.2.8
Interim Analyses ............................................................................................... 107
8.2.9
Compliance (Medication Adherence) ............................................................... 111
8.2.10
Extent of Exposure............................................................................................ 111
8.2.11
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 111
9.1
Investigational Product ...................................................................................... 111
9.2
Packaging and Labeling Information ............................................................... 112
9.3
Clinical Supplies Disclosure............................................................................... 112
9.4
Storage and Handling Requirements................................................................ 112
9.5
Returns and Reconciliation................................................................................ 112
9.6
Standard Policies................................................................................................. 112
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 112
10.1
Confidentiality..................................................................................................... 112
Confidentiality of Data ..................................................................................... 112
10.1.1
Confidentiality of Subject Records ................................................................... 113
10.1.2
Confidentiality of Investigator Information...................................................... 113
10.1.3
10.2
Compliance with Financial Disclosure Requirements..................................... 114
10.3
Compliance with Law, Audit and Debarment ................................................. 114
10.4
Compliance with Trial Registration and Results Posting Requirements ...... 116
 
 
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10.5
Quality Management System............................................................................. 116
10.6
Data Management............................................................................................... 116
10.7
Publications ......................................................................................................... 117
11.0
LIST OF REFERENCES....................................................................................... 119
12.0
APPENDICES......................................................................................................... 123
12.1
Merck Code of Conduct for Clinical Trials...................................................... 123
12.2
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 125
12.3
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 131
12.4
ECOG Performance Status................................................................................ 142
12.5
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............. 143
12.6
Immune Related Response Criteria .................................................................. 144
12.7
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors .............................................................. 146
12.8
Strong Inhibitors of CYP3A4 ............................................................................ 147
13.0
SIGNATURES......................................................................................................... 148
13.1
Sponsor's Representative ................................................................................... 148
13.2
Investigator.......................................................................................................... 148
 
 
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values........................................................ 32
Table 2
Trial Treatments...................................................................................................... 37
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related 
AEs Associated with Pembrolizumab.................................................................... 38
Table 4
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines 41
Table 5
Laboratory Tests ..................................................................................................... 69
Table 6
Evaluating Adverse Events..................................................................................... 86
Table 7
Primary Analysis Strategy for Key Efficacy Endpoints in Strongly Positive PD-
L1 Stratum.............................................................................................................. 90
Table 8
Summary of Interim Analysis Strategy .................................................................. 92
Table 9
Censoring Rules for Primary and Sensitivity Analyses of PFS.............................. 98
Table 10 Analysis Strategy for Safety Parameters.............................................................. 101
Table 11 Operating Characteristics at IA1 for Futility Stopping (With 40 subjects/arm in 
the strongly positive PD-L1 stratum) ................................................................... 108
Table 12 Approximate empirical bars for a positive OS in the PD-L1 strongly positive 
stratum at the final analysis based on outcomes in PFS for the overall PD-L1 
positive population ............................................................................................... 110
Table 13 Approximate empirical bars for a positive OS in the overall PD-L1 positive 
population at the final analysis based on outcomes in PFS for the overall PD-L1 
positive population ............................................................................................... 110
Table 14 Product Description.............................................................................................. 111
 
 
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LIST OF FIGURES
Figure 1
Trial Design......................................................................................................... 21
Figure 2
Multiplicity Strategy.......................................................................................... 103
Figure 3
Power for OS Superiority in the PD-L1 Strongly Positive Stratum under 
Various Hazard Ratios using Hochberg Procedure at the Second Interim 
Analysis (IA2) and the Final Analysis (FA) ..................................................... 105
Figure 4
Power for OS Superiority in the Overall PD-L1 Positive Population under 
Various Hazard Ratios using Hochberg Procedure at the Final Analysis 
(378 deaths between two groups)...................................................................... 106
 
 
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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
2.1
2.2
2.3
4.2.2
5.8
6.3.1
7.1.5.4
7.1.5.5
Trial Summary
Trial Design
Trial Diagram
Crossover for Subjects in Docetaxel 
Arm to MK-3475 200 mg arm
Rationale 
for 
Dose 
Selection/ 
Regimen/ Modification
Subject Withdrawal/Discontinuation 
Criteria 
Second Course Phase for MK-3475 
200 mg Q3W Arm
Second Course Phase
Crossover 
for 
Subjects
in 
the 
Docetaxel Arm to MK-3475 200 mg 
Arm
Treatment 
Group 
added: 
200 mg every 3 weeks (Q3W) 
for retreatment and crossover 
subjects.
Pembrolizumab 
dose 
for 
Second Course (Retreatment) 
and Crossover was changed to a 
fixed dose of 200 mg Q3W.
Section 2.3 was deleted due to 
the change in dose for crossover 
subjects.
Adaptive trial design discussion 
was expanded to explain the 
transition to the 200 mg fixed 
dose.  Material from Section 
4.2.2 was moved up to Section 
2.1 for this reason.
The current approved standard of care 
for pembrolizumab treatment of non-
small cell lung cancer (NSCLC) in the 
US is the fixed dose of 200 mg Q3W. 
This dose will be used for all subjects in 
the study who are in crossover or 
second course of treatment.  The 
justification for using 200 mg Q3W 
fixed dose is provided in section 4.2.2.
 
 
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Section Number (s) Section Title(s)
Description of Change (s)
Rationale
2.1
6.1.1
6.3
6.4
7.1.4.1
7.1.5.3.2
Trial Design
MK-3475 2 and 10 mg/kg Q3W and 
Docetaxel Arms
Second Course Phase for MK-3475 
200 mg Q3W Arm
Second 
Course 
Post-Treatment 
Follow-up Phase
Tumor Imaging
Follow-up Visits
Radiographic 
imaging 
frequency during follow-up in 
the initial treatment phase was 
decreased after 54 week from 
every 9 weeks (63 ± 7 days) to 
every 12 weeks (84 ± 7 days) 
and in the Second Course Phase 
to every 12 weeks (84 ± 
7 days).
To 
align 
with 
current 
follow-up 
schedule for pembrolizumab NSCLC 
studies.
6.2
7.1.5.3.3
Post-Treatment Follow-up Phase
Survival Follow-up
Updated Survival Follow-up 
intervals from 2 months to 
12 Weeks
To 
align 
with 
current 
follow-up 
schedule for pembrolizumab studies.
 
 
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
1.0
2.1
Trial Summary
Trial Design
Added possible transition to an 
extension 
study 
following 
completion of KN010 treatment.
An extension study is planned, 
which may be available to 
subjects completing KN010.
1.0
Trial Summary –
Estimated 
duration of the trial
Updated to 60 months.
To account for second course of 
treatment.
4.2.2
Rationale for Dose Selection/ 
Regimen/ Modification
Updated section to reflect current 
regulatory 
status 
of 
pembrolizumab
Section 
contained 
outdated 
material regarding dose selection.
5.2.1.2
Dose Modification
The dose modification guidelines 
for pembrolizumab were updated 
to 
add 
guidance 
for 
dose 
modification in the event of 
immune-related myocarditis, and 
to adjust guidance for all other 
immune-related AEs.
Guidance 
for 
treatment 
of 
infusion 
reactions
associated 
with pembrolizumab was moved 
to this section from Section 5.6.1
To reflect the current reference 
safety information and to align 
with the pembrolizumab standard 
template.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.5.1
5.5.2 
Acceptable 
Concomitant 
Medications
Prohibited 
Concomitant 
Medications
Removed the prohibition of
bisphosphonate or anti-RANKL 
mAb
To 
align 
with 
recent
pembrolizumab NSCLC studies 
because this class of drug is 
commonly 
used 
to 
control 
symptoms of bone metastasis 
rather than tumor growth.
5.6.1
Supportive Care Guidelines
Section was updated to refer to 
Section 5.2.1.2 for guidance.
To 
align 
with 
the 
current 
pembrolizumab 
standard 
template.
5.6.3
Guidelines 
for 
Infusion 
Reaction
Moved to the Dose Modification 
Section
To 
align 
with 
the 
updated 
pembrolizumab 
standard 
template
5.7.2
Contraception
Updated 
to 
current 
pembrolizumab language
To 
align 
with 
the 
updated 
pembrolizumab 
standard 
template
5.7.3
Use in Pregnancy
Updated text to indicate that if a 
subject became pregnant, she 
would 
be 
removed 
from 
treatment rather than from the 
study.
To allow for safety follow-up.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.8
6.1.1
7.1.5.4
Appendix 12.6
Subject Withdrawal/ 
Discontinuation Criteria
Flow Chart for MK-3475 2 and 
10 mg/kg Q3W and Docetaxel 
Arms (Footnote 17)
Second Course Phase
Immune-related Response 
Criteria
Changed timing for confirmatory 
scans from “at least 4 weeks” to 
“the next scheduled visit (ie, 
every 63 ± 7 days)”.
Correction.
7.1.2.1
7.2.3.2
Adverse Event (AE) Monitoring
Events of Clinical Interest
Removed reference to separate 
guidance on ECIs and events 
listed as ECIs that are no longer 
included in this category for 
reporting purposes.
Guidance 
is 
outdated 
and 
superseded by labeling.
7.1.3.1
Laboratory Safety Evaluations 
(Hematology, 
Chemistry, 
Urinalysis and Other)
Testing for Carbon Dioxide (CO2
or bicarbonate) is no longer 
mandatory
Testing for Carbon Dioxide is 
not standard of care in all 
regions.
7.1.5.3
Post-Treatment 
Follow-up 
Phase
Removed 2 year limit of follow-
up period and added specific 
instances when follow-up would 
end 
Follow-up
will continue until 
start 
of 
new 
antineoplastic 
therapy, 
disease 
progression, 
death, or is lost to follow-up, and 
is not limited to 2 years.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
7.1.5.3.4
Survival Status
Updated text to indicate that 
contacts to determine survival 
may occur at more frequent 
intervals than scheduled.
To allow for obtaining current 
survival data and for such 
reasons as an updated analysis
7.1.5.4
Second Course Phase
Changed duration of treatment 
from “up to 12 months” to “up to 
17 
cycles 
(approximately 
1 
year)”
To 
align 
with 
standard 
pembrolizumab protocol.
7.1.5.4
Second Course Phase
Updated 
the 
inclusion 
and 
exclusion criteria section for the 
second course phase.
To facilitate determination of 
eligibility.
7.1.5.4
Second Course Phase
Updated the exclusion criterion 
for use of systemic steroids
To align with the pembrolizumab 
standard for lung cancer studies.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
MK-3475 vs. Docetaxel in Second-Line NSCLC
Trial Phase
Phase II/III
Clinical Indication
The treatment of subjects with non-small cell lung cancer (NSCLC) 
whose tumors are positive for PD-L1 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 
MK-3475 10 mg/kg every 3 weeks
MK-3475 2 mg/kg every 3 weeks
Docetaxel 75 mg/m2 every 3 weeks
Second Course and Crossover MK-3475 200 mg every 3 weeks
Number of trial subjects
Approximately 920 subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 60 months  
from the time the first subject signs the informed consent until the last 
subject’s last visit.
Duration of Participation
Each subject will participate in the trial from the time the subject signs the 
Informed Consent Form (ICF) through the final protocol-specified 
contact. After a screening phase of up to 42 days, eligible subjects will 
receive assigned treatment on Day 1 of each 3-week (Q3W) dosing cycle.  
Treatment with MK-3475 or docetaxel will continue for up to 35 cycles 
(approximately 2 years) of therapy have been administered, 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. MK-3475 treated subjects who attain a complete 
response may consider stopping trial treatment.  These subjects will be 
eligible for re-treatment for up to 17 cycles (approximately 1 year) with 
MK-3475 after experiencing disease progression at the discretion of the 
investigator if they meet the criteria for re-treatment; this will be 
designated the Second Course phase.  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). Subjects will have post-treatment follow-up 
for disease status, including initiating a non-study cancer treatment and 
experiencing disease progression, until death, withdrawing consent, or 
becoming lost to follow-up. Following demonstration of a survival 
benefit, eligible subjects who were allocated to docetaxel, who 
experienced disease progression, will be permitted to cross-over to 
MK-3475 200 mg Q3W.
Once the subject has achieved the study objective or the study has ended, 
the subject will be discontinued from this study and will be enrolled in an
extension study to continue protocol-defined assessments and treatment.
Crossover patients who have not transitioned to pembrolizumab will be 
considered for the extension study on a case-by-case basis. 
Randomization Ratio
1:1:1
 
 
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2.0 TRIAL DESIGN
2.1
Trial Design
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
This is a multi-center, worldwide, randomized, adaptively designed Phase II/III trial of 
intravenous (IV) MK-3475 at two dosing schedules versus docetaxel in subjects with non-
small cell lung cancer (NSCLC) with PD-L1 positive tumors who have experienced disease 
progression after platinum-containing systemic therapy.  Approximately 520-920 subjects 
will be enrolled in this trial to examine the efficacy compared to docetaxel in an enriched 
population.  Subjects will be randomized in a 1:1:1 ratio to receive MK-3475 at 10 mg/kg 
every 3 weeks (Q3W), 2 mg/kg Q3W, or docetaxel at 75 mg/m2 Q3W (Figure 1).  Because 
this is an adaptively designed trial, the total number of patients randomized will depend upon
demonstration of sufficient objective responses at interim analysis 1 in an MK-3475 arm in 
the stratum of subjects whose tumors test strongly positive for PD-L1.  Assignment to MK-
3475 or docetaxel will be unblinded.  Subjects will be stratified by extent of tumoral PD-L1 
expression (strongly positive vs. weakly positive), Eastern Cooperative Oncology Group 
(ECOG) Performance Scale (0 vs. 1), and geographic region of the enrolling site (East Asia 
vs. non-East Asia) prior to randomization.  
Subjects will be evaluated with radiographic imaging to assess response to treatment every 
9 weeks (63 ± 7 days) through Week 54, and every 12 weeks (84± 7 days) thereafter.  
Investigators will make all treatment-based decisions using the Immune-Related Response 
Criteria (irRC).  All imaging obtained on study will be submitted for independent 
radiologists’ review; they will assess the images using Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 for determination of overall response rate (ORR) and progression-free 
survival (PFS).  Adverse events will be monitored throughout the trial and graded in severity 
according to the guidelines outlined in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0.  Treatment with MK-3475 or docetaxel will continue for up to 
35 cycles (approximately 2 years) of therapy have been administered, 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.  MK-3475 treated subjects who attain an 
investigator-determined confirmed complete response (CR) per irRC may consider stopping 
trial treatment.  These subjects will be eligible for re-treatment for up to 17 cycles 
(approximately 1 year) with MK-3475 200 mg IV Q3W after they have experienced 
radiographic disease progression at the discretion of the investigator according to the 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 of the 
primary endpoint in this trial.  Subjects who were allocated to docetaxel who experience 
disease progression will be permitted to cross over to MK-3475 200 mg Q3W as long as 
Inclusion/Exclusion criteria defined in Section 7.1.5.5 are met.
 
 
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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 will have post-treatment follow-up for disease status, including initiating a non-
study cancer treatment and experiencing disease progression, until death, withdrawing 
consent, or becoming lost to follow-up.
The primary objectives of this trial are: 1) To compare the overall survival (OS) of 
previously-treated subjects with NSCLC in the strongly positive PD-L1 stratum treated with 
MK-3475 compared to docetaxel; 2) To compare progression-free survival (PFS) per 
RECIST 1.1 by independent radiologists’ review of previously-treated subjects with NSCLC 
in the strongly positive PD-L1 stratum treated with MK-3475 compared to docetaxel; 3) To 
evaluate OS of previously-treated subjects with NSCLC whose tumors express PD-L1 and 
are treated with MK-3475 compared to docetaxel; 4) To evaluate PFS per RECIST 1.1 by 
independent radiologists’ review of previously-treated subjects with NSCLC whose tumors 
express PD-L1 and are treated with MK-3475 compared to docetaxel, and; 5) Evaluate safety 
and tolerability profile of MK-3475 in previously-treated subjects with NSCLC in the 
strongly positive and overall PD-L1 stratums.
The study is considered to have met its primary objective in the primary population of 
subjects with overall positive or strongly positive PD-L1 expression if at least one MK-3475 
arm is superior to docetaxel either in PFS or in OS at an interim analysis or the final analysis.  
Please refer to Sections 3.2 and 3.3 for a listing of secondary and exploratory objectives.
Participation in this trial will be dependent upon supplying tumor tissue from a newly 
obtained formalin-fixed specimen from locations not radiated prior to biopsy; no new 
systemic antineoplastic therapy may be administered between the PD-L1 biopsy and
initiating study medication.  The specimen will be evaluated at a central laboratory facility 
for expression status of PD-L1 in a prospective manner.  Only subjects whose tumors express 
PD-L1 as determined by the central laboratory facility will be eligible for randomization in 
this study.  Patients will be stratified into one of two groups (strongly positive or weakly 
positive) on the basis of these results.
This trial will use an adaptive design based on pre-specified criteria, using an independent, 
external Data Monitoring Committee (DMC) to monitor safety and efficacy.  These analyses 
will be carried out in the strongly positive PD-L1 stratum first and then possibly in the 
overall PD-L1 positive population, with the former being primary analysis population.  Two 
formal interim analyses based on the data from the randomized cohort will occur during the 
conduct of this trial.  The first interim analysis will be triggered after 120 subjects in the 
strongly positive PD-L1 stratum have completed a minimum of 3 months of follow-up.  The 
primary objective of this analysis is to stop the study for futility or to discontinue one MK-
3475 arm if it is less efficacious than the other MK-3475 arm based on ORR in the strongly 
positive PD-L1 stratum. 
The second interim analysis is expected to occur after approximately 175 events of 
progression per RECIST 1.1 by independent radiologists’ review, and around 120 OS events
have occurred across three arms in the strongly positive PD-L1 stratum (approximately 123 
 
 
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progression events and 84 OS events between one MK-3475 arm and docetaxel arm under 
the alternative hypothesis). The purpose of the second interim analysis is to demonstrate 
superiority of MK-3475 in PFS and OS in the strongly positive PD-L1 stratum and the 
overall population of subjects with positive PD-L1 expressions. In addition, the trial may be 
stopped early at the recommendation of the DMC if the risk/benefit ratio to the trial 
population as a whole is unacceptable.  Details are described in Section 8.0 – Statistical 
Analysis Plan.
If one MK-3475 dose is dropped due to lack of efficacy, per the investigator’s discretion the 
subjects can continue to be treated with MK-3475 on the other dose.  The efficacy and safety 
data from these patients will not be used in the primary analysis, but will be used in 
supportive analyses.
2.2
Trial Diagram
The trial design is depicted in Figure 1.
 
 
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Figure 1
Trial Design
 
 
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
3.1
Primary Objective(s) & Hypothesis(es)
1) Objective:  To compare the overall survival (OS) of previously-treated subjects
with NSCLC in the strongly positive PD-L1 stratum treated with MK-3475 
compared to docetaxel.
Hypothesis:  MK-3475 prolongs OS in previously-treated subjects with NSCLC in 
the strongly positive PD-L1 stratum compared to docetaxel.
2) Objective:  To compare progression-free survival (PFS) per RECIST 1.1 by 
independent radiologists’ review of previously-treated subjects with NSCLC in the 
strongly positive PD-L1 stratum treated with MK-3475 compared to docetaxel.
Hypothesis: MK-3475 prolongs PFS per RECIST 1.1 by independent radiologists’ 
review in previously-treated subjects with NSCLC in the strongly positive PD-L1 
stratum compared to docetaxel.
3) Objective: To evaluate OS of previously-treated subjects with NSCLC whose 
tumors express PD-L1 and are treated with MK-3475 compared to docetaxel.
Hypothesis: MK-3475 prolongs OS in previously-treated subjects with NSCLC 
whose tumors express PD-L1 compared to docetaxel.
4) Objective: To evaluate PFS per RECIST 1.1 by independent radiologists’ review 
of previously-treated subjects with NSCLC whose tumors express PD-L1 and are 
treated with MK-3475 compared to docetaxel.
Hypothesis: MK-3475 prolongs PFS per RECIST 1.1 by independent radiologists’ 
review in previously-treated subjects with NSCLC whose tumors express PD-L1 
compared to docetaxel.
5) Objective: Evaluate safety and tolerability profile of MK-3475 in previously-
treated subjects with NSCLC in the strongly positive and overall PD-L1 stratums.
The study is considered to have met its primary objective if at least one MK-3475 arm is 
superior to docetaxel either in PFS or in OS at an interim analysis or the final analysis in the 
overall study population whose tumors express PD-L1 or the strongly positive PD-L1 
stratum.
3.2
Secondary Objective(s) & Hypothesis(es)
1) Objective: To evaluate overall response rate (ORR) per RECIST 1.1 by 
independent radiologists’ review in previously-treated subjects with NSCLC in the 
strongly positive PD-L1 stratum and in overall study population whose tumors 
express PD-L1 treated with MK-3475 compared to docetaxel. 
 
 
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2) Objective: To evaluate response duration per RECIST 1.1 by independent 
radiologists’ review in previously-treated subjects with NSCLC in the strongly 
positive PD-L1 stratum and in overall study population treated with MK-3475 
compared to docetaxel.
3.3
Exploratory Objectives
1) Objective: To evaluate PFS per immune-related response criteria (irRC) by 
investigators’ review in previously-treated subjects with NSCLC in the strongly 
positive PD-L1 stratum and in overall study population whose tumors express PD-
L1 treated with MK-3475 compared to docetaxel.
2) Objective: To evaluate ORR per irRC by investigators’ review in previously-
treated subjects with NSCLC in the strongly positive PD-L1 stratum and in overall
study population treated with MK-3475 compared to docetaxel.
3) Objective: To evaluate response duration per immune-related response criteria
(irRC) by investigators’ review in previously-treated subjects with NSCLC in the 
strongly positive PD-L1 stratum and in overall study population whose tumors 
express PD-L1 treated with MK-3475 compared to docetaxel.
4) Objective: To evaluate the influence of age of tumor specimen (archival vs. new) 
submitted for PD-L1 analysis on the primary endpoints of progression-free 
survival and overall survival.
5) Objective: To evaluate tumor volumetric changes of previously-treated subjects 
with NSCLC in the strongly positive PD-L1 stratum treated with MK-3475 
compared to docetaxel.
6) Objective: To explore the correlation of tumor volumetric changes with OS in 
previously-treated subjects with NSCLC in the strongly positive PD-L1 stratum 
with MK-3475 compared to docetaxel.
7) Objective: To evaluate changes in health-related quality-of-life assessments from 
baseline in previously-treated subjects with NSCLC in the strongly positive PD-L1 
stratum treated with MK-3475 compared to docetaxel using the EORTC QLQ C-
30 and EORTC QLQ LC-13.
8) Objective: To characterize utilities in previously-treated subjects with NSCLC in 
the strongly positive PD-L1 stratum treated with MK-3475 compared to docetaxel 
using the EuroQoL EQ-5D.
9) Objective: Characterize healthcare resource utilization in previously-treated 
subjects with NSCLC in the strongly positive PD-L1 stratum treated with MK-
3475 compared to docetaxel.
 
 
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4.0 BACKGROUND & RATIONALE
4.1
Background
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475.
Pharmaceutical and Therapeutic Background
4.1.1
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [1].  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various 
malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T 
cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; 
hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma.  Tumor-infiltrating 
lymphocytes can be expanded ex vivo and reinfused, inducing durable objective tumor 
responses in cancers such as melanoma [2] [3].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T 
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an 
immunoglobulin (Ig) superfamily member related to cluster of differentiation 28 (CD28) and 
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD L1 and/or PD-L2) [4] 
[5]. 
The structure of murine PD-1 has been resolved [6].  PD-1 and its family members are type I 
transmembrane glycoproteins containing an Ig-variable–type (IgV type) domain responsible 
for ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules.  
The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch motif.  
Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to 
the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta 
(PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 
T-cell signaling cascade [5] [7] [8] [9].  The mechanism by which PD-1 down-modulates T 
cell responses is similar to, but distinct from, that of CTLA-4, because both molecules 
regulate an overlapping set of signaling proteins [10] [11].  
Although healthy organs express little (if any) PD-L1, a variety of cancers were 
demonstrated to express abundant levels of this T-cell inhibitor.  High expression of PD-L1 
on tumor cells (and to a lesser extent of PD-L2) has been found to correlate with poor 
prognosis and survival in various cancer types, including RCC [12], pancreatic carcinoma
[13], hepatocellular carcinoma [14], and ovarian carcinoma [15].  Furthermore, PD-1 has 
been suggested to regulate tumor-specific T-cell expansion in subjects with MEL [16].
 
 
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The observed correlation of clinical prognosis with PD-L 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.
Several means of quantitatively scoring PD-L1 expression were evaluated using ROC curve 
analyses and assessment of positive and negative predictive values of potential strong/weak 
cutoffs. Based on the analyses performed in Protocol 001, a proportion score with a cutoff of 
50% or more of tumor cells staining for PD-L1 was selected as an optimal strong/weak 
cutoff. The best overall response rate of patients with strongly positive tumors in the training 
set by investigator-assessed irRC was 46% (95% CI: 30%, 61%) compared to 8% (95% CI: 
3%, 15%) in patients with weakly positive/negative tumors. The best overall response rate of 
patients with strongly positive tumors in the training set by independently-assessed RECIST 
was 37% (95% CI: 22%, 53%) compared to 11% (95% CI: 6%, 20%) in patients with weakly 
positive/negative tumors.  
Information on Other Trial-Related Therapy
4.1.2
Three products are approved in most major markets to treat patients who have failed first-line 
therapy, docetaxel, erlotinib, and pemetrexed.  Two studies, TAX317 and TAX320, formed 
the basis of approval of docetaxel for this indication.  TAX317 demonstrated superior overall 
survival for docetaxel at 75 mg/m2 Q3W compared to best supportive care (risk ratio 0.56, 
log rank test p-value 0.01).  The median overall survival in the TAX317 trial was 7.5 months 
for docetaxel compared to 4.6 months for best supportive care.  The 1-year survival rate was 
37% for docetaxel compared to 12% for best supportive care (p-value ≤ 0.05).  The response 
rate for docetaxel was 5.5% (95% CI: 1.1, 15.1) based on WHO response criteria [13].  
Similarly, TAX320 also demonstrated a superior 1-year survival rate for docetaxel at 
75 mg/m2 of 30% compared to 20% in the control arm of vinorelbine or ifosfamide (p-value 
≤ 0.05).  However, the risk ratio for overall survival was not statistically significant in the 
TAX320 study (risk ratio 0.8s, log rank test p-value 0.13).  The median overall survival in 
the TAX320 trial was 5.7 months for docetaxel versus 5.6 months for the control. The 
response rate for docetaxel in TAX320 was 5.7% (95% CI: 2.3%, 11.3%) based on WHO 
response criteria [17]. Thus, docetaxel was approved as an acceptable second-line therapy for 
patients with NSCLC.
Pemetrexed is also an approved second-line agent for NSCLC based on a trial attempting to 
demonstrate non-inferiority to docetaxel (median OS: 8.3 months pemetrexed vs. 7.9 months 
docetaxel, HR 0.99, p-value=0.226) [18].  Another study also demonstrated that pemetrexed 
provides an improvement in OS when administered in a first-line setting in combination with 
cisplatin compared to treatment with cisplatin/gemcitabine in patients with non-squamous 
(adenocarcinoma: n=847, 12.6 vs. 10.9 months, respectively; HR=0.84; 95% CI, 0.71 to 
0.99; P=.03; large-cell carcinoma: n = 153, 10.4 v 6.7 months, respectively; HR=0.67; 95% 
CI, 0.48 to 0.96; P=.03; nonsquamous: n=1,000, 11.8 v 10.4 months, respectively; HR = 
0.81; 95% CI, 0.70 to 0.94; P = .005)  [19].  Pemetrexed’s approved indication is limited to 
patients with NSCLC with non-squamous histology by both the FDA and EMA and is 
commonly used as part of first-line therapy in patients with non-squamous NSCLC.  So it is 
used less commonly as a second-line therapy.  
 
 
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Erlotinib is an inappropriate second-line therapy for patients with a good performance status 
who do not have an EGFR mutation.  More recently, the TAILOR trial has reported the 
median PFS for patients EGFR wild type is better when they are treated with docetaxel as 
opposed to erlotinib (HR 0.70 with 95% CI 0.53-0.94; p = 0.016) [20].  So, docetaxel is the 
most appropriate comparator in this second-line trial of patients with progressive NSCLC 
after a platinum-containing regimen. The most common adverse reactions for patients treated 
with docetaxel are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, 
thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, 
fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, 
and myalgia [17] [21] [22] [23].
4.2
Rationale
Rationale for the Trial and Selected Subject Population
4.2.1
While docetaxel is an accepted second-line standard of care for patients with NSCLC, the 
objective response rate is about 5-10%, median progression-free survival is about 3 months, 
and the median overall survival is about 7.5 months [17] [21] [22].  Improvements in OS are 
needed since no one with progressive NSCLC is cured.  
A large surgical series of resected NSCLC specimens revealed that about 25% of squamous 
and adenocarcinoma have tumor infiltrating lymphocytes (TILs) present [24].  These TILs 
often contain CD8+ T cells [24].  The presence of increased CD8+ cells in the tumor sets the 
stage for an immune-based response against the tumor if inhibition of the immune system can 
be abrogated.  Indeed, in a study of ipilimumab, an anti-CTLA4 monoclonal antibody, 
combined with first-line carboplatin and paclitaxel, a post-hoc subset analysis identified an 
improvement in OS that favored patients with squamous histology compared to placebo plus 
carboplatin and paclitaxel (HR 0.48 [95% CI 0.22-1.03]).  Results were not as favorable for 
patients with nonsquamous histology (HR 1.17 [95% CI 0.74-1.86]). These findings have 
led to the initiation of a Phase III trial in the same population with ipilimumab.
Please see the end of Section 4.1.1 which discusses the classification of tumors as strongly 
positive or weakly positive based on PD-L1 scoring. This study will compare monotherapy 
MK-3475 with standard of care docetaxel in patients with NSCLC.  Overall survival and PFS
in the strongly positive PD-L1 subpopulation are the primary endpoints of the trial, and are
accepted regulatory endpoints for this disease.  
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.  
Patients in the strongly positive PD-L1 subset who receive 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 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.
 
 
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While these 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 MK-3475 as they 
might be from docetaxel.
Rationale for Dose Selection/Regimen/Modification
4.2.2
In the first in human study (Protocol number 001, refer to IB), which treated a variety of 
tumor types, 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).  Dose level 
10 mg/kg Q3W was evaluated in previously treated patients with NSCLC in Part C of 
Protocol 001.  
In this study, pembrolizumab 2 mg/kg Q3W, pembrolizumab 10 mg/kg Q3W, and docetaxel
75 mg/m2 Q3W have been evaluated in 1033 subjects through response or progression. The 
final analysis was carried out when approximately 200 deaths occurred across the 3 study 
arms in the TPS≥50% stratum. The study’s final analysis results revealed that both MK-3475 
2 mg/kg and 10 mg/kg arms were associated with superior overall survival compared to the 
docetaxel arm in the PD-L1 strongly positive stratum as well as in the overall study 
population. 
Based on the positive outcome of the OS analysis, subjects in the docetaxel arm, who 
experienced disease progression, had the opportunity to crossover to MK-3475 2 mg/kg
Q3W treatment arm. This was the initial dose approved by the Food and Drug 
Administration (FDA) for treatment of melanoma subjects.  However, current clinical trials 
evaluating pembrolizumab are using a fixed dose of 200 mg Q3W.  Therefore, the dose of 
pembrolizumab for the second course and crossover portions of this trial will now be 200 mg 
Q3W.
The use of a fixed dose is based on PK findings summarized below. 
The PK profile of pembrolizumab is consistent with that of other humanized monoclonal 
antibodies, which typically have a low clearance and a limited volume of distribution.  A 
population PK model, which characterized the influence of body weight and other subject 
covariates on exposure using available data from 1139 subjects (from Keynote-001 and 
Keynote-002) has been performed.  The majority of these subjects (1077; 94.6%) had 
advanced melanoma.  The distribution of exposures from the 200 mg fixed dose were 
predicted to considerably overlap those obtained with the 2 mg/kg dose, and importantly, 
maintained individual subject exposures within the exposure range established in melanoma 
as associated with maximal clinical response.  This comparison also demonstrated that the 
200 mg Q3W regimen provided no substantive differences in PK variability (range of the 
distribution of individual exposures) as seen with weight-based dosing.
In translating to other solid tumor indications, similarly flat exposure-response relationships 
for efficacy and safety as observed in subjects with melanoma can be expected, as the 
antitumor effect of pembrolizumab is driven through immune system activation rather than 
 
 
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through a direct interaction with tumor cells, rendering it independent of the specific tumor 
type.  In addition, available PK results in subjects with melanoma, NSCLC, and other solid 
tumor types support a lack of meaningful difference in PK exposures obtained at tested doses 
among tumor types.
Rationale for Endpoints
4.2.3
4.2.3.1
Efficacy Endpoints
4.2.3.1.1 Primary
Overall Survival is the gold standard endpoint to demonstrate superiority of antineoplastic 
therapy.  Progression free survival 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.  RECIST 1.1 will be used to determine the dates of 
progression as this methodology is accepted by regulatory authorities.  Because the treatment 
assignment is unblinded regarding MK-3475 vs. docetaxel, images will be read by 
independent radiologists blinded to treatment assignment to minimize bias in the response 
assessments.
4.2.3.1.2 Secondary
Importantly, PFS will also be assessed by irRC as determined by the investigators.  ORR will 
be calculated by both methodologies, in addition to the duration of response.  All main 
analyses will be performed in the strongly positive PD-L1 stratum.
An analysis that includes all patients will be conducted for primary and secondary endpoints 
if the study is positive for that endpoint in the strongly positive PD-L1 stratum.
4.2.3.2
Patient Reported Outcomes
The EORTC QLQ-C30, EORTC QLQ-LC13, and EQ5D are not pure efficacy or safety 
endpoints because they are affected by both disease progression and treatment tolerability.
4.2.3.2.1 eEORTC QLQ-C30 and EORTC QLQ-LC13
The EORTC-QLQC30 is the most widely used cancer specific 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 [25] This instrument is translated and validated 
into more than 80 languages.  
In combining with EORTC QLQ C-30, 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) [26]. The 
EORTC QLQ-C30 and QLQ-LC13 are the most frequently utilized and reported patient-
 
 
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reported outcome measures in lung cancer clinical trials [27] [28]. The reliability, validity 
and practicality of these instruments have been reported [26] [29]. 
4.2.3.2.2 eEuroQol EQ-5D
The eEuroQol-5D (eEQ-5D) is a standardized instrument for use as a measure of health 
outcome.  The eEQ-5D will provide data for use in economic models and analyses including 
developing health utilities or 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 eEQ-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 
eEQ-5D will always be completed by patients first before completing the eEORTC QLQ C-
30 and EORTC LC-13. 
4.2.3.3
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on blood and tumor tissue specimens 
collected during this clinical trial.  This research may include genetic analyses (DNA), gene 
expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or the 
measurement of other analytes.  
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. 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, and/or to ensure that subjects receive the 
correct dose of the correct drug 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.
 
 
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5.0 METHODOLOGY
5.1
Entry Criteria
Diagnosis/Condition for Entry into the Trial
5.1.1
Male/Female subjects with NSCLC whose tumors express PD-L1 who have experienced 
disease progression after at least a platinum-containing systemic therapy of at least 18 years
of age will be enrolled in this trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
1) Be willing and able to provide written informed consent/assent for the trial.  
2) Be ≥18 years of age on day of signing informed consent.
3) Have a life expectancy of at least 3 months.
4) Have a histologically or cytologically confirmed diagnosis of non-small cell lung 
cancer (NSCLC) and have at least one measurable lesion as defined by RECIST 1.1.  
The target lesion(s) should also have bi-dimensional measurability for irRC 
evaluation on study.  
5) Have experienced investigator determined radiographic progression per RECIST 1.1 
of NSCLC after treatment with at least two cycles of a platinum-containing doublet 
for stage IIIB/IV or recurrent disease. The site’s study team must have reviewed pre-
trial images that are of diagnostic quality from at least 2 dates to determine that 
radiographic progression has occurred per RECIST 1.1 following initiation of the 
first-line platinum-containing doublet. A platinum-containing doublet is defined as a 
platinum-based cytotoxic systemic agent administered in the same cycle as another 
cytotoxic systemic chemotherapeutic agent. The central imaging vendor must have 
received these scans and have confirmed that they are of acceptable diagnostic quality
prior to randomization in this trial for a possible retrospective analysis of this 
eligibility criterion.  The central vendor will not be confirming eligibility prior to 
randomization.  Completion of treatment with a platinum-containing doublet as 
adjuvant therapy within one year of signing informed consent will satisfy the prior 
treatment requirement.  
a.
Subjects with an EGFR sensitizing mutation must also be able to demonstrate 
progression of disease on the EGFR tyrosine kinase inhibitor (either erlotinib, 
gefitinib, or afatinib) in a similar manner to that above for the platinum-
containing doublet.  Radiographic images that demonstrate progression after 
initiation of the EGFR tyrosine kinase inhibitor therapy and after initiation of 
the platinum-containing doublet must also be submitted similarly for subjects 
with an EGFR sensitizing mutation prior to randomization.  Subjects with an 
EGFR sensitizing mutation may have been treated previously with the 
 
 
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tyrosine kinase inhibitor separately from the platinum-containing doublet; the 
order of treatment does not matter, but progression of disease as determined 
by RECIST 1.1 must be demonstrable for both regimens.  An exception to this 
rule is the patient whose NSCLC tumor has an EGFR sensitizing mutation 
who receives four cycles of a platinum doublet, does not experience 
progression of disease, and begins therapy with an EGFR tyrosine kinase 
inhibitor as a maintenance therapy within 28 days of the last administration of 
the platinum doublet chemotherapy.  For this patient, only one set of images 
demonstrating progression on the EGFR tyrosine kinase inhibitor is required 
for submission to the independent imaging vendor for the patient to be 
eligible.
b. Subjects with an ALK translocation must also be able to demonstrate 
progression of disease on crizotinib in a similar manner to that above for the 
platinum-containing 
doublet. 
Radiographic 
images 
that 
demonstrate 
progression after initiation of crizotinib and after initiation of the platinum-
containing doublet must also be submitted similarly for subjects with an ALK 
translocation prior to randomization.  Subjects with an ALK translocation may 
have been treated previously with the tyrosine kinase inhibitor separately from 
the platinum-containing doublet; the order of treatment does not matter, but 
progression of disease as determined by RECIST 1.1 must be demonstrable 
for both regimens.
6) Have a performance status of 0 or 1 on the ECOG Performance Scale.
7) Have adequate organ function as indicated in Table 1 below:
 
 
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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 transfusions for 4 weeks
Renal
Creatinine OR
calculated creatinine clearance (CrCl)a
(GFR can also be used in place of creatinine 
or CrCl)
≤1.5 X upper limit of normal (ULN) OR
≥60 mL/min for subjects with creatinine levels > 1.5 X 
institutional ULN
Hepatic
Total bilirubin
≤  ULN 
AST (SGOT) and ALT (SGPT)
≤ 1.5 X ULN 
Alkaline Phosphatase
≤ 2.5 X ULN 
Endocrine
Thyroid stimulating hormone (TSH)
Within normal limitsb
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
Activated Partial Thromboplastin Time 
(aPTT)
≤1.5 X ULN unless the subject is receiving anticoagulant therapy
≤1.5 X ULN unless the subject is receiving anticoagulant therapy
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 (or free T3) and free T4 are within the 
normal limits.
8) Have provided tissue for PD-L1 biomarker analysis from a newly obtained formalin-
fixed tumor tissue from a recent biopsy of a tumor lesion not previously irradiated; no 
systemic antineoplastic therapy may be administered between the PD-L1 biopsy and
initiating study medication.  Although patients using tyrosine kinase inhibitors prior 
to treatment on this protocol may continue using these until it is time to begin the 
appropriate wash out period for these medications.  For patients in whom obtaining a 
new tumor biopsy will be medically inappropriate, the investigator may appeal to the 
Sponsor’s study clinical director, and if there is agreement, 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. Needle or excisional 
biopsies, or resected tissue is required.  
a.
Investigators must be able to produce the source documentation of the EGFR 
mutation status or ALK translocation status.  If unable to test for these 
molecular changes, formalin-fixed paraffin-embedded tumor tissue of any age 
should be submitted to a central laboratory designated by the Sponsor for such 
testing.  Subjects will not be randomized until EGFR mutation and ALK 
translocation status is available in source documentation at the site.
 
 
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b. 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.
c.
If a patient is known to have a mutation in KRAS, then testing for an EGFR 
mutation or for an ALK translocation will not be required given that all of 
these molecular alterations are mutually exclusive in patients with non-
squamous NSCLC.
d. For patients enrolled who are known to have a tumor of predominantly 
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.
9) Have a PD-L1 positive (either strongly or weakly) tumor as determined by IHC at a 
central laboratory.  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.
10) 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. 
11) Female subject of childbearing potential has a negative urine or serum pregnancy test.  
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.  The serum pregnancy test must be negative for the subject to be 
eligible.
12) Female subjects may be enrolled in the trial if they are:
-
of non-childbearing potential which is defined as: 

a female patient ≥ 45 years of age and has not had menses for greater than 
2 years,

a female who is amenorrheic for < 2 years without a hysterectomy and 
oophorectomy and an FSH value in the postmenopausal range upon pretrial 
(screening) evaluation,
and/or

a female who is status post hysterectomy, oophorectomy or tubal ligation.  
Documented hysterectomy or oophorectomy must be confirmed with medical 
records of the actual procedure or confirmed by an ultrasound.  Tubal ligation 
must be confirmed with medical records of the actual procedure otherwise the 
 
 
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subject will be excluded.  Information must be captured appropriately within 
the site's source documents.
-
of childbearing potential who are willing to use either 2 adequate barrier methods 
or a barrier method plus a hormonal method of contraception to prevent 
pregnancy, or to abstain from heterosexual activity throughout the trial, starting 
with the screening visit (Visit 1) through 120 days after the last dose of MK-3475.  
Such methods of contraception, or abstinence from heterosexual activity, are 
required from the screening visit (Visit 1) through 180 days after the last dose of 
docetaxel.  Please see Section 5.7.2 for a list of acceptable birth control methods.
13) Male subjects with a female partner(s) of child-bearing potential must agree to use 2 
adequate barrier methods or a barrier method plus a hormonal method of 
contraception to prevent pregnancy, or to abstain from heterosexual activity 
throughout the trial starting with the screening visit (Visit 1) through 120 days after 
the last dose of MK-3475 is received.  Such methods of contraception, or abstinence 
from heterosexual activity, are required from the screening visit (Visit 1) through 
180 days after the last dose of docetaxel.  If their partner is pregnant, males must 
agree to use a condom and no additional method of contraception is required for the 
pregnant partner. 
14) Subject may also provide consent/assent for Future Biomedical Research.  However, 
the subject may participate in the main trial without participating in Future 
Biomedical Research.
Subject Exclusion Criteria
5.1.3
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 
using an investigational device within 30 days of the first dose of trial treatment.  The 
30 day window should be applied to the last dose of an antineoplastic investigational 
agent or last use of an investigational device with antineoplastic intent.
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).
5) Has received prior systemic cytotoxic chemotherapy, antineoplastic biological 
therapy (e.g., cetuximab), 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 
 
 
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dose of trial treatment; received prior tyrosine kinase inhibitor therapy or completed 
palliative radiotherapy 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, anti-CD137, 
or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including 
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation 
or checkpoint pathways) or has participated in another MK-3475 clinical trial.
7) Has a known history of prior malignancy except if the patient has undergone 
potentially curative therapy with no evidence of that disease recurrence for 5 years 
since initiation of that therapy.
-
Note: The time requirement for no evidence of disease for 5 years does not 
apply to the NSCLC tumor for which a subject is enrolled in this trial.  The 
time requirement also does not apply to subjects who underwent successful 
definitive resection of basal cell carcinoma of the skin, superficial bladder 
cancer, squamous cell carcinoma of the skin, or in situ cervical cancer.
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 4 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. The two brain MRIs that 
were used to make the determination of stable disease must be submitted to the 
central imaging vendor, preferably while the subject is undergoing screening.  These 
images should be submitted retrospectively for subjects that have already been 
randomized. 
9) Has an active autoimmune disease, or a documented history of autoimmune disease, 
or a syndrome that requires systemic steroids or immunosuppressive agents.  Subjects
with vitiligo or resolved childhood asthma/atopy would be exception to this rule.  
Subjects that require inhaled steroid or local steroid injections will not be excluded 
from the study.  Subjects with hypothyroidism not from autoimmune disease and 
stable on hormone replacement will not be excluded from the study.
10) Has had an allogeneic tissue/solid organ transplant.
11) Has interstitial lung disease or a history of pneumonitis that required oral or 
intravenous glucocorticoids to assist with management.  Lymphangitic spread of the 
NSCLC is not exclusionary.  
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.
 
 
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14) Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
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) Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit (Visit 1) through 120
days after the last dose of MK-3475 or 180 days after the last dose of docetaxel.
20) Subjects that require treatment with a strong inhibitor of CYP3A4 will be excluded.  
They 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.
5.2
Trial Treatments
Trial treatment should begin on the day of randomization or as close as possible to the date 
on which treatment is allocated/assigned.
Treatments to be used in this trial are outlined below in Table 2 and Section 5.2.2
 
 
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Table 2
Trial Treatments
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment 
Period
MK-3475
2 mg/kg
Q3W
IV infusion
Day 1 of each cycle
MK-3475 
10 mg/kg
Q3W
IV infusion
Day 1 of each cycle
MK-3475
200 mg
Q3W
IV infusion
Day 1 of each cycle
Docetaxel 
75 mg/m2
Q3W
IV infusion
Day 1 of each cycle
If one dose arm is dropped due to lack of efficacy, per the investigator’s discretion the subjects can 
continue to be treated with the other dose. The MK-3475 dosing interval may be increased due to 
toxicity as described in Section 5.2.1.2.  
In the midst of the study, the preparation of MK-3475 will change from a lyophilized preparation to a 
liquid preparation.
Dose Selection/Modification
5.2.1
5.2.1.1
Dose Selection
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 MK-3475 infusion solution will be based on the 
subject’s weight in kilograms (kg).  Details on the dose calculation, preparation and 
administration are provided in the Procedures Manual.
Docetaxel will be prepared and administered as per the approved product label.
5.2.1.2
Dose Modification
Docetaxel
Refer to approved product label for subjects receiving docetaxel.
MK-3475
Adverse events associated with pembrolizumab exposure may represent an immunologic 
etiology. These immune-related AEs (irAEs) may occur shortly after the first dose or several 
months after the last dose of pembrolizumab treatment and may affect more than one body 
system simultaneously. Therefore, early recognition and initiation of treatment is critical to 
reduce complications.  Based on existing clinical trial data, most irAEs were reversible and 
could be managed with interruptions of pembrolizumab, administration of corticosteroids 
and/or other supportive care. For suspected irAEs, ensure adequate evaluation to confirm 
etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, 
endoscopy, skin biopsy may be included as part of the evaluation. Based on the severity of 
irAEs, withhold or permanently discontinue pembrolizumab and administer corticosteroids. 
Dose modification and toxicity management guidelines for irAEs associated with 
pembrolizumab are provided in Table 3. 
 
 
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Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated, first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2
Withhold 

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor 
participants 
for 
signs 
and 
symptoms of pneumonitis

Evaluate 
participants 
with 
suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment

Add 
prophylactic 
antibiotics 
for 
opportunistic infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal 
pain, blood or mucus in stool with or 
without fever) and of bowel perforation 
(ie, peritoneal signs and ileus).

Participants with ≥ Grade 2 diarrhea 
suspecting 
colitis 
should 
consider 
GI 
consultation and performing endoscopy to 
rule out colitis. 

Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion.
Grade 4
Permanently 
discontinue
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
AST / ALT 
elevation or 
Increased 
bilirubin
Grade 2
Withhold

Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent), followed by taper

Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable
Grade 3 or 4 
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent), followed by taper
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
Newly 
onset 
T1DM or 
Grade 
3 
or 
4 
hyperglycemia 
associated 
with 
evidence of -cell 
failure
Withhold

Initiate 
insulin 
replacement 
therapy 
for 
participants 
with 
T1DM 

Administer anti-hyperglycemic in 
participants with hyperglycemia 

Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes.
Hypophysitis
Grade 2
Withhold

Administer 
corticosteroids 
and 
initiate hormonal replacements as 
clinically indicated.  

Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4 
Withhold 
or 
permanently 
discontinue1
Hyperthyroidism 
Grade 2
Continue 

Treat with non-selective beta-
blockers 
(eg, 
propranolol) 
or 
thionamides, as appropriate 

Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hypothyroidism
Grade 2-4
Continue 

Initiate 
thyroid 
replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care

Monitor for signs and symptoms of thyroid 
disorders. 
Nephritis and 
Renal 
dysfunction
Grade 2
Withhold 

Administer 
corticosteroids 
(prednisone 
1-2 
mg/kg 
or 
equivalent), followed by taper.

Monitor changes of renal function
Grade 3 or 4 
Permanently 
discontinue
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Myocarditis
Grade 1 or 2
Withhold

Based 
on 
severity 
of 
AE 
administer corticosteroids

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
All other 
immune-related 
AEs
Intolerable/ 
persistent Grade 2
Withhold

Based on type and severity of AE 
administer corticosteroids 

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3
Withhold 
or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include 
and 
not 
limited 
to:  
Guillain-Barre 
Syndrome, 
encephalitis
Grade 
4 
or 
recurrent Grade 3 
Permanently 
discontinue
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
 
 
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Dose modification and toxicity management of infusion
reactions related to 
pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion reactions, including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 4. 
Table 4
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption 
not 
indicated; 
intervention 
not indicated
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable, in the opinion of the investigator.
None
Grade 2
Requires 
therapy 
or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); 
prophylactic 
medications 
indicated 
for ≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs, as medically 
indicated, until the subject is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g. from 
100 mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab
with:
Diphenhydramine 50 mg po 
(or 
equivalent 
dose 
of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic).
 
 
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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 study drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during 
the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov
Other allowed dose interruption for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Subjects should be 
placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in the patient's 
study record.
Timing of Dose Administration
5.2.2
Trial treatment should be administered on Day 1 of each cycle after all procedures / 
assessments have been completed except for the post-infusion PK sample time points listed 
in the Trial Flow Chart. Trial treatment may be administered up to 3 days after Day 1 of 
each cycle due to administrative reasons only.
The specific time of MK-3475 administration (e.g., time of the week for first administration; 
time of the day for each administration) should take into consideration PK sampling time 
points and study visit procedures.
All trial treatments will be administered on an out-patient basis. 
 
 
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5.2.2.1
MK-3475
MK-3475 will be administered as a 30 minute IV infusion Q3W (treatment cycle intervals
may be increased due to toxicity as described in Section 5.2.1.2). 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).  Therefore, start and stop times 
of infusion is required for PN010 so that appropriate monitoring of protocol specified 
duration time may be performed.
The Pharmacy Manual contains specific instructions for MK-3475 dose calculation, 
reconstitution, preparation of the infusion fluid, and administration. 
5.2.2.2
Docetaxel 
Docetaxel 75 mg/m2 will be administered as an IV infusion over 1 hour every Q3W.  All 
patients 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 irRC
approximately 9 weeks 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
5.2.3
5.2.3.1
Treatment Trial Blinding
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.
5.2.3.2
Biomarker Trial Blinding
A double-blind technique will be used for the level PD-L1 positivity of randomized subjects.  
The subject, the investigator and Sponsor personnel or delegate(s) who are involved in the 
treatment or clinical evaluation of the subjects are unaware of the PD-L1 status.
5.3
Randomization or Treatment Allocation
Randomization will occur centrally using an IVRS/IXRS There are 3 treatment arms.  
Subjects will be assigned randomized treatment in an 1:1:1 ratio to MK-3475 10 mg/kg
Q3W, MK-3475 2 mg/kg Q3W, or docetaxel 75 mg/m2 Q3W.  If one MK-3475 dose is 
 
 
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dropped during the trial then all subsequent subjects will be randomized in a 1:1 ratio to the 
other dose of MK-3475 or docetaxel in an unblinded fashion.
5.4
Stratification
Randomization will be stratified according to the following factors:

Extent of tumoral PD-L1 expression (Strongly positive vs. Weakly positive)

Geographic region of the enrolling site (East Asia vs. non-East Asia)

Eastern Cooperative Oncology Group (ECOG) Performance Scale (0 vs. 1).
5.5
Concomitant Medications (allowed & prohibited)
Drugs specifically prohibited in the exclusion criteria are not allowed during the ongoing 
trial.  Listed below are some specific restrictions for concomitant therapy use during the 
course of the trial.  If there is a clinical indication for one of these or other medications 
specifically prohibited during the trial, discontinuation from trial therapy may be required.  
The investigator should discuss any questions regarding this with the local Clinical Monitor. 
The final decision on any supportive therapy rests with the investigator and/or the subject's 
primary physician.  However, the decision to continue the subject on trial therapy requires 
the mutual agreement of the investigator, the Sponsor and the subject.
Acceptable Concomitant Medications
5.5.1
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date will also be included on the CRF.
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
5.5.2
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.
 
 
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
Investigational agents other than MK-3475.

Radiation therapy (Treatment and Second Course Phases).

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.

Glucocorticoids for any purpose other than adverse event management or for use as a 
pre-medication for docetaxel.  

Strong inhibitors of the CYP3A4 enzymes (a common list of such agents may be 
found in Appendix 12.8). Subjects in the crossover phase and second course are 
allowed to receive strong inhibitors of the CYP3A4 enzymes.
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.  Pre-medication with corticosteroid for side effect prophylaxis for docetaxel is 
permitted.
The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
5.6
Rescue Medications & Supportive Care
Supportive Care Guidelines
5.6.1
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. Refer to approved product label for subjects receiving docetaxel.
MK-3475
Subjects should receive appropriate supportive care measures, as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 5.2.1.2, (Table 3).  Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids.  Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased.  For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
 
 
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bacterial or viral infection, which might require additional supportive care.  The treatment 
guidelines are intended to be applied when the investigator determines the events to be 
related to pembrolizumab. 
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance.  Refer to Table 3 in Section 
5.2.1.2 for guidelines regarding dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
5.7
Diet/Activity/Other Considerations
Diet
5.7.1
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting.
Contraception
5.7.2
MK-3475 may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
MK-3475 has transient adverse effects on the composition of sperm.  Docetaxel can cause 
fetal harm if administered to pregnant women.  Therefore, non-pregnant, non-breast-feeding 
women may be enrolled if they are considered of non-reproductive potential.  For this trial, 
male subjects will be considered to be of non-reproductive potential if they have azoospermia 
(whether due to having had a vasectomy or due to an underlying medical condition).  
Female subjects will be considered of non-reproductive potential if they meet one of the 
following criteria: 

She is postmenopausal, defined as at least 12 months with no menses without an 
alternative medical cause.  In women <45 years of age who are not using hormonal 
contraception or hormonal replacement therapy, a high follicle stimulating hormone 
(FSH) level in the postmenopausal range may be used to confirm a post-menopausal 
state.  In the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient.

She had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening.

She has a congenital or an acquired condition that prevents childbearing.
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving trial drug and for 120 days after the 
last dose of trial drug by complying with one of the following: 

Practice abstinence from heterosexual activity.
 
 
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Abstinence (relative to heterosexual activity) can be used as the sole method of contraception 
if it is consistently employed as the subject’s preferred and usual lifestyle and if considered 
acceptable 
by 
local 
regulatory 
agencies 
and 
European 
Research 
Councils 
(ERCs)/Institutional Review Boards (IRBs).  Periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods, etc.) and withdrawal are not acceptable methods of 
contraception. 

Use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡:

Single method (one of the following is acceptable):
o
Intrauterine device (IUD)
o
Vasectomy of a female subject’s male partner 
o
Contraceptive rod implanted into the skin

Combination method (requires use of two of the following):
o
Diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)
o
Cervical cap with spermicide (nulliparous women only)  
o
Contraceptive sponge (nulliparous women only) 
o
Male condom or female condom (cannot be used together)
o
Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites in 
this country/region.
Subjects should be informed that taking the trial medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the trial.  In order to participate in 
the trial, subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of trial medication initiation (or 14 days prior to the initiation 
of trial medication for oral contraception) throughout the trial period up to 120 days after the 
last dose of pembrolizumab and up to 180 days after last dose of docetaxel.  If there is any 
question that a subject of childbearing potential will not reliably comply with the 
requirements for contraception, that subject should not be entered into the trial. 
 
 
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Use in Pregnancy
5.7.3
If a female subject inadvertently becomes pregnant while on treatment with docetaxel or 
MK-3475, the subject will immediately be removed from trial treatment.  The site will 
contact the subject at least monthly and document the subject’s status until the pregnancy has
been completed or terminated.  The outcome of the pregnancy will be reported to the Sponsor
without delay and within 24 hours if the outcome is a serious adverse experience (e.g., death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn).  The study investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
Sponsor.  If a male subject impregnates his female partner the study personnel at the site 
must be informed immediately and the pregnancy reported to the Sponsor and followed as 
described above and in Section 7.2.2.
Use in Nursing Women
5.7.4
It is unknown whether docetaxel or MK-3475 is excreted in human milk.  Since many drugs 
are excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment.
5.8
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.
For subjects participating in the optional crossover phase the same rules of 
discontinuation will apply. Subjects will continue treatment until disease progression 
occurs or as outlined in Section 7.1.5.6.  
A subject must be discontinued from treatment (but may continue to be monitored in the
post-treatment follow up portion of the trial) for any of the following reasons:

The subject or legal representative (such as a parent or legal guardian) withdraws 
consent

Documented disease progression
 
 
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Note: If a subject has confirmed progression of disease by irRC, 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 the next scheduled time point 
(i.e., every 63 +/- 7 days). Clinical Stability is defined as:
1. Absence of symptoms and signs indicating clinical significant progression 
of disease (including worsening of laboratory values) indicating disease 
progression.
2. No decline in ECOG performance status.
3. 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 uninterrupted delivery of MK-3475 every 3 weeks and no documented 
progression of disease, or 35 administrations of study medication, whichever is later

Intercurrent illness that prevents further administration of treatment

Investigator’s decision to withdraw the subject

The subject has a confirmed positive serum pregnancy test

Noncompliance with trial treatment or procedure requirements

The subject is lost to follow-up

Administrative reasons
If an MK-3475 treated subject attains an investigator-determined confirmed CR according to 
irRC, has been treated for at least six months with MK-3475, and has at least two treatments 
with MK-3475 beyond the date when the initial CR was declared, the subject and 
investigator may consider stopping therapy with MK-3475.  Subjects who discontinue MK-
3475 after attaining a CR (or have experienced a PR or SD after 35 administrations of MK-
3475) and then experience radiographic disease progression according to irRC will be 
eligible for re-treatment with MK-3475 in the Second Course Phase at the discretion of the 
investigator as described in Section 7.1.5.4.  
Docetaxel may be discontinued when a subject has received the maximum number of cycles 
permitted by the local regulatory authority.
 
 
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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, becoming lost to follow-up or 
entering the Second Course Phase.  After documented disease progression each subject will 
either move into the Second Course Phase or be followed for overall survival until death or 
withdrawal of consent. 
5.9
Subject Replacement Strategy
A subject that discontinues from the trial will not be replaced.
5.10 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 trial 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 receiving ongoing treatment will be discontinued from this study and 
enrolled in a pembrolizumab extension study, when available. Subjects who are eligible for 
crossover to pembrolizumab will be considered for the extension study on a case-by-case 
basis.  
5.11 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 futility at the recommendation of the DMC if the first
interim analysis results show neither MK-3475 dose schedule is superior to docetaxel.
2. The trial will be stopped early for efficacy at the recommendation of the DMC if the 
second interim analysis results show MK-3475 is superior to docetaxel in OS.
3. The trial will be stopped early at the recommendation of the DMC if the risk/benefit ratio 
to the trial population as a whole is unacceptable.
Statistical criteria for stopping the trial are provided in Section 8.0 – Statistical Analysis Plan 
and the DMC charter.
Enrollment will not be halted during either of the planned interim analyses.
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.
 
 
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5.12 Post 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.  Possible 
choices of subsequent therapy include:

Docetaxel

Erlotinib

Gemcitabine

Vinorelbine
The exact subsequent treatment(s) used will be at the discretion of the investigator and 
determined by the interests of the subject.  
Subjects randomized to docetaxel who experience progression of their cancer are not 
permitted to enroll in MK-3475 PN001 subsequently.
 
 
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6.0 TRIAL FLOW CHART
6.1
Treatment Phase
MK-3475 2 and 10 mg/kg Q3W and Docetaxel Arms
6.1.1
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 
to 
35
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
Clinical Procedures / Assessments
Review 
Adverse 
Events 6, 7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Full 
Physical 
Examination
X
X
X
X
X
X21
Directed 
Physical 
Examination
X
X
X
X
X
X
X
X
X
X21
X
Vital 
Signs 
and 
Weight 8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
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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 
to 
35
Discontinuation 
Visit
Scheduling Window 
(Days):2
± 3
± 3
± 
3
± 3
± 3
±3
± 3
±3
±3
± 3
± 3
± 3
± 3
12-Lead ECG
X
ECOG 
Performance 
Status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pulmonary 
Function 
Testing22
X
Laboratory Procedures / Assessments: analysis performed by local laboratory
Pregnancy 
Test 
-
Urine or Serum β-
HCG 9
X
PT/INR and aPTT 10
X 11
CBC 
with 
Differential12
X 11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Comprehensive  
Chemistry Panel12
X 11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis12
X 11
X
X
X
X13
X
T3/FT3, 
FT4 
and 
TSH 12, 14
X 11
X
X
X
X
X
X
X 13
X
ALK 
Translocation 
Testing23
X 
EGFR 
Mutation 
Testing23
X 
Laboratory Procedures / Assessments: analysis performed by central laboratory
Blood 
for
Future 
Biomedical 
Research15 (optional)
X
Efficacy Measurements
Tumor Imaging 16, 17
X
X
X
X
X
X16
X
Patient Reported Outcomes (PRO)
EuroQol EQ-5D 18
X
X
X
X
X
X13
X
EORTC QLQ-C3018
X
X
X
X
X
X13
X
 
 
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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 
to 
35
Discontinuation 
Visit
Scheduling Window 
(Days):2
± 3
± 3
± 
3
± 3
± 3
±3
± 3
±3
±3
± 3
± 3
± 3
± 3
EORTC QLQ LC-13 18
X
X
X
X
X
X13
X
Health 
Economic 
Assessment 18
X
X
X
X
X13
X
Tumor Biopsies / Archival Tissue Collection
Tumor 
Tissue 
Collection 
X19
X20
X20
X20
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 MK-3475 treatment cycle interval may be increased due to toxicity according to the dose modification guidelines provided in Section 
5.2.1.2.  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 first dose of trial treatment through Week 54, and then every 12 weeks (84± 7 days) 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 Section 12.2.
5
Prior medications - Record all medications taken within 30 days of Visit 1 and all treatments for a prior cancer other than NSCLC even if taken greater than 30 days prior to 
Visit 1 (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 Section 7.2.
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
All AEs of unknown etiology associated with trial treatment exposure should be evaluated to determine if it is possibly an ECI. (See the separate guidance document in the 
administrative binder regarding identification, evaluation and management of AEs of a potential immunologic etiology).
8
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at Visit 1 only.
9
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.
10 Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
11 Laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment. See Section 7.1.3 for details regarding laboratory tests. 
12 After Cycle 1, lab samples can be collected up to 48 hours 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.  
13 Perform every 4 cycles after Cycle 13; perform thyroid testing every other cycle.
14 Thyroid function tests will be performed by a central laboratory only if the local laboratory is unable to perform this service.
15 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 Section 12.2. 
 
 
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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 
to 
35
Discontinuation 
Visit
Scheduling Window 
(Days):2
± 3
± 3
± 
3
± 3
± 3
±3
± 3
±3
±3
± 3
± 3
± 3
± 3
16 The initial tumor imaging will be performed within 30 days prior to the first dose of trial treatment.  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 30 days prior to the first dose of trial treatment.  On-study imaging will be performed 
every 9 weeks (63 7 days) after the first dose of trial treatment through Week 54, and then every 12 weeks (84± 7 days), or more frequently if clinically indicated.  The 
timing for imaging studies should follow calendar days and should not be adjusted for delays in cycle starts or extension of MK-3475 cycle frequencies. The same imaging 
technique should be used in a subject throughout the trial.  Local reading (investigator assessment with site radiology reading) will be used to determine eligibility and for 
subject management; Sponsor will collect radiological assessments for a potential retrospective analysis by a central vendor.  The processes for image collection and 
transmission to the central vendor are in the investigator Imaging Operations Manual (IIOM). 
17 After the first documentation of progression (if the subject is clinically stable) or response per irRC repeat imaging for confirmation is required. Confirmatory imaging scan
should be performed at the next scheduled time point (i.e., every 63 +/- 7 days).  
18 PROs are to be administered by trained site personnel and completed electronically by subjects in the following order: EuroQol EQ-5D first, then EORTC QLQ C-30, and 
lastly the EORTC LC-13.  It is most relevant and strongly recommended that ePROs are administered prior to study drug administration, adverse event evaluation and 
disease status notification. HEA will be completed by qualified site personnel after the subject completes all other questionnaires.   
19 Tumor tissue for biomarker analysis from an archival tissue sample (acceptable for EGFR and ALK testing) or newly obtained formalin fixed tumor tissue from a recent
biopsy of a tumor lesion not previously irradiated (required for PD-L1 determination; acceptable for EGFR and ALK testing) must be provided and received by the central 
vendor before randomization. No systemic antineoplastic therapy may have been received by the patient between the time of the biopsy for PD-L1 testing and the first 
administration of study medication. 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.
20 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. Detailed instructions for tissue collection, processing and shipment are provided in the Procedures Manual. Patients who agree to undergo these 
additional, optional tumor biopsies while receiving MK-3475 may not have them under CT-guidance.
21 Perform a full physical examination every 3 cycles after Cycle 12.  Otherwise, perform a directed physical examination the day of the study treatment visit.
22 Pulmonary function tests should include an assessment of forced vital capacity, forced expiratory flow between 25 and 75 percent of FVC (FEF25-75), forced expiratory 
volume in one second, peak expiratory flow (PEF) and diffusion capacity.  Additionally, oxygen saturation as assessed by pulse oximetry is required. Perform at baseline 
and subsequently at the discretion of the investigator. Hemoglobin must be obtained within 3 days of pulmonary function testing.
23 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.
 
 
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6.2
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 
Every 12 Weeks (± 7 days) 
or as directed by the 
Sponsor
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
± 3 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
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 and Weight 5
X
X
X
Efficacy Measurement
Tumor Imaging 6
X 7
X7
X7
X7
Laboratory Procedures/Assessments: analysis performed by local laboratory
CBC with Differential 8
X
Comprehensive  Chemistry Panel 8
X
T3/FT3, FT4 and TSH 9
X
Patient Reported Outcomes
EuroQoL EQ-5D 10
X
EORTC QLQ-C30 10
X
EORTC QLQ LC-13 10
X
Health Economic Assessment 10
X
1
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last dose of trial treatment regardless of initiation of new antineoplastic 
treatment. Subjects who are eligible per the requirements in Section 7.1.5.4 for treatment with MK-3475 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.
2
Subjects who discontinue trial treatment for a reason other than disease progression will move into the Follow-up Phase and should be assessed by radiologic imaging to 
monitor disease status every 9 weeks (63 ± 7 days) through Week 54, and then every 12 weeks (84± 7 days) thereafter. Follow-up Visit 1 should be scheduled 3 months 
 
 
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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) through Week 54 and then every 12 weeks (84 ± 7 days) thereafter 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, death, or entering the Second Course Phase, whichever occurs first. 
3
Once a subject experiences disease progression (and does not continue into the Second Course Phase) or starts a new antineoplastic therapy, the subject moves into the 
Survival Follow-up Phase and should be contacted by telephone approximately every 12 weeks 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 participants who do not/will 
not have a scheduled study visit or study contact during the Sponsor defined time period will be contacted for their survival status (excluding participants that have 
withdrawn consent or have a death event previously recorded).
4
Record all AEs occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment), ECIs, and irAEs occurring within 90 
days of the last dose of trial treatment or the start of new anti-cancer treatment, whichever comes first. After this time, report only SAEs and ECIs 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.  Unless a subject enters the Second Course Phase, imaging should continue until the
start of a new antineoplastic therapy, documented disease progression, or death, whichever occurs first.  Subjects who enter the Second Course Phase will be assessed every
12 weeks (84 ± 7 days) by radiologic imaging as described in the Second Course Phase Flow Chart.
7
Subjects who discontinue trial treatment due to reasons other than disease progression should continue to be assessed every 9 weeks (63 ± 7 days) through Week 54 and then 
every 12 weeks (84 ± 7 days) thereafter by radiologic imaging calculated from the study treatment start day.
8
See Section 7.1.3 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 electronically by subjects in the following order: EuroQol EQ-5D first, 
then EORTC QLQ C-30, and lastly the EORTC LC-13.  It is most relevant and strongly recommended that ePROs are administered prior to study drug administration, 
adverse event evaluation and disease status notification.  HEA will be completed by qualified site personnel after the subject completes all other questionnaires. Once the 
subjects enter the crossover, ePROs will not be collected for crossover subjects,
 
 
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6.3
Second Course Phase
Second Course Phase for MK-3475 200 mg Q3W Arms
6.3.1
Trial Phase
Second Course Treatment Cycles1
End of 
Treatment
Treatment Cycle / Scheduled 
Time
1
2
3
4
5
6
7
8
9
10
11
12
13
14 to 17
Discontinuat
ion Visit
Scheduling Window (Days):2
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
Administrative Procedures
Eligibility Criteria3
X
Concomitant Medications4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Trial Treatment Administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Procedures / Assessments
Review Adverse Events 5, 6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Full Physical Examination
X
X
X
X
X
X7
Directed Physical Examination
X
X
X
X
X
X
X
X
X7
X
Vital Signs and Weight 8
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
Laboratory Procedures / Assessments: analysis performed by local laboratory
Pregnancy Test - Urine or Serum 
β-HCG 9
X
PT/INR and aPTT 10
X 11
CBC with Differential12
X 11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Comprehensive Chemistry Panel12
X 11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis12
X 11
X
X
X
X13
X
T3/FT3, FT4 and TSH 12, 14
X 11
X
X
X
X
X
X
X 13
X
Efficacy Measurements
Tumor Imaging 15, 16
X
X
X
X
X
X15
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); however the treatment cycle interval may be increased due to toxicity according to the dose modification guidelines provided in Section 5.2.1.2.  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 
12 weeks (84 7 days) from the first dose of trial treatment regardless of any treatment delays.
2
In general, the window for each visit is 3 days unless otherwise specified.
3
Review Secord Course Phase eligibility criteria in Section 7.1.5.4 prior to administering the first dose of trial treatment.
 
 
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4
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 ECI as defined in Section 7.2.
5
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.
6
All AEs of unknown etiology associated with trial treatment exposure should be evaluated to determine if it is possibly an ECI.  (See the separate guidance document in the 
administrative binder regarding identification, evaluation and management of AEs of a potential immunologic etiology).
7
Perform a full physical examination every 3 cycles after Cycle 13.  Otherwise, perform a directed physical examination the day of the study treatment visit.
8
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.
9
For women of reproductive potential, 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.
10 Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
11 Laboratory tests for determining eligibility for Second Course Phase are to be performed within 10 days prior to the first dose of MK-3475. See Section 7.1.3 for details 
regarding laboratory tests.  
12 After the first dose, lab samples can be collected up to 48 hours 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.  
13 Perform every 4 cycles after Cycle 13; perform thyroid testing every other cycle.
14 Thyroid function tests will be performed by a central laboratory only if the local laboratory is unable to perform this service.
15 The Second Course Cycle 1 scan may have been performed up to 30 days prior to the first dose of trial treatment in the Second Course Phase.  Imaging will be performed 
every 12 weeks (84 7 days) after the first dose of Second Course Phase trial treatment or more frequently if clinically indicated.  The timing of imaging should follow 
calendar days and should not be adjusted for delays in cycle starts or extension of MK-3475 cycle frequencies. The same imaging technique should be used in a subject 
throughout the trial.  Local reading (investigator assessment with site radiology reading) will be used to for subject management; Sponsor will collect radiological 
assessments for retrospective analysis by a central vendor.  The processes for image collection and transmission to the central vendor are in the investigator Imaging 
Operations Manual (IIOM). 
16 After the first documentation of progression (if the subject is clinically stable) or responses per irRC, confirmatory imaging. Confirmatory imaging scan should be
performed at the next scheduled time point (i.e., every 63 +/- 7 days).
 
 
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6.4
Second Course 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 12 weeks 
(84 days) after 
Month 6 
Every 12 Weeks
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
± 3 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
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 and Weight 5
X
X
X
Efficacy Measurement
Tumor Imaging 6
X 6
X
X
X
Laboratory Procedures/Assessments: analysis performed by local laboratory
CBC with Differential 7
X
Comprehensive Chemistry Panel7
X
T3/FT3, FT4 and TSH 8
X
1
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last dose of trial treatment regardless of initiation of new antineoplastic 
treatment. Subjects who are eligible per the requirements in Section 7.1.5.4 for treatment with MK-3475 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.
2
Subjects who discontinue trial treatment for a reason other than disease progression will move into the Follow-up Phase and should be assessed by radiologic imaging to 
monitor disease status every 12 weeks (84 ± 7 days).  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 by radiologic imaging to monitor disease status, development of drug 
related SAEs and ECIs, and initiation of new antineoplastic therapy every 12 weeks (84 ± 7 days).  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 every 12 weeks 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 participants who do not/will not have a scheduled study visit or study contact during the Sponsor defined 
time period will be contacted for their survival status (excluding participants that have withdrawn consent or have a death event previously recorded).
 
 
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4
Record all AEs occurring within 30 days after the last dose of trial treatment..  Report all SAEs (related and unrelated to trial treatment), ECIs, and irAEs occurring within 
90 days of the last dose of trial treatment or the start of new anti-cancer treatment, whichever comes first. After this time, report only SAEs and ECIs 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.  Subjects, who discontinue trial treatment due to reasons other than disease 
progression, should continue to be assessed by radiologic imaging every 12 weeks (84 7 days), calculated from the first date of study treatment, until the start of a new 
antineoplastic therapy, documented disease progression, or death, whichever occurs first.  
7
See Section 7.1.3 for list of laboratory tests.
8
Analysis will be performed by a central laboratory only if the local laboratory is unable to perform this service.
 
 
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6.5
Crossover Phase
Subjects who were randomized to docetaxel and had experienced disease progression while receiving docetaxel in the study or who, 
after participating in the study, started subsequent anti-cancer therapy and then experienced progression are eligible for the Crossover 
Phase.
Subjects who discontinue study treatment of the Crossover Phase will follow the same Post-Treatment Follow-up Phase Flow Chart.
Treatment Cycles1
End of 
Treatment
Survival 
Follow-up
Treatment Cycle / 
Scheduled Time
17
2
3
4
5
6
7
8
9
10
11
12
13
14 
through 
35
Discontinuation 
Visit
Every 
12 Weeks
Scheduling Window 
(Days):2
± 3
± 3
± 3
± 
3
± 3
± 
3
± 3
± 
3
±
3
± 
3
± 
3
± 3
± 3
Administrative Procedures
Informed Consent
X
Inclusion/Exclusion Criteria
X
Previous 
Anti-Cancer 
Therapy10
X
Prior 
and 
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical 
Procedures 
/ 
Assessments
Review Adverse Events 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Full Physical Examination
X
X
X
X
X
X12
X
Directed 
Physical 
Examination
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs and Weight 
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
Laboratory Procedures / Assessments: analysis performed by 
local laboratory
CBC  with Differential 9
X3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PT/INR and aPTT 
X3
Comprehensive 
Serum 
Chemistry Panel
X3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X3
X
X
X
X11
X
 
 
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Treatment Cycles1
End of 
Treatment
Survival 
Follow-up
Treatment Cycle / 
Scheduled Time
17
2
3
4
5
6
7
8
9
10
11
12
13
14 
through 
35
Discontinuation 
Visit
Every 
12 Weeks
Scheduling Window 
(Days):2
± 3
± 3
± 3
± 
3
± 3
± 
3
± 3
± 
3
±
3
± 
3
± 
3
± 3
± 3
T3/FT3, FT4 and TSH 4, 5
X3
X
X
X
X
X
X
X 4
X
Efficacy Measurements
Survival Status
X13
Tumor Imaging 6
X
X
X
X
X6
X
Study Drug Administration
MK-34758
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1
In general, assessments/procedures are to be performed on Day 1 of crossover study and prior to the first dose of study medication and for each dose of following cycle 
unless otherwise specified. Progressive disease from docetaxel or subsequent anti-cancer therapies based on investigator’s assessment (either radiographic or clinical) is 
required.  Treatment cycles are 3 weeks (21-days).  Imaging will be performed every 9 weeks (63 ± 7 days) from the first dose of trial treatment regardless of any treatment 
delays through Week 54, and then every 12 weeks (84 ± 7 days) thereafter.
2
In general, the window for each visit is 3 days unless otherwise specified. 
3
Laboratory tests are to be performed within 10 days prior to the first dose of trial treatment. See Section 7.1.3 for details regarding laboratory tests.  
4
Perform thyroid testing every other cycle.
5
Thyroid function tests will be performed by a central laboratory only if the local laboratory is unable to perform this service.
6   Baseline imaging for the crossover phase should be done within 30 days of the first dose of crossover study medication. On study imaging will be performed every 9 weeks 
(63 ± 7 days) after the first dose of trial treatment through Week 54, and then every 12 weeks (84 ± 7 days) thereafter, or more frequently if clinically indicated.  The timing 
for imaging studies should follow calendar days and should not be adjusted for delays in cycle starts or extension of MK-3475 cycle frequencies.  The same imaging 
technique should be used in a subject throughout the trial.  Local reading (investigator assessment with site radiology reading) will be used to determine eligibility and for 
subject management.  Images done in the study including baseline scan should be submitted to a central imaging vendor. The processes for image collection and transmission 
to the central vendor are in the investigator Imaging Operations Manual (IIOM).
7
Screening can initiate when investigator decides subjects meet inclusion and exclusion criteria for the crossover phase. Wash out period from last dose of docetaxel or anti-
cancer therapy is left to investigator discretion while ensuring that patient will have adequate time to recover from any AEs of the previous anti-cancer therapies.  
8
Wash out period from last dose of docetaxel or anti-cancer therapy is left to investigator discretion while ensuring that patient will have adequate time to recover from any 
AEs of the previous anti-cancer therapies.  Subjects will continue in trial until progressive disease is confirmed as assessed by irRC as determined by the investigators or up 
to two years from initiation of a new anti-cancer therapy, whichever comes first.
9
After cycle 1, lab samples can be collected up to 48 hours prior to the scheduled time point.
10 If patient is entering the Crossover Phase after experiencing an anti-cancer therapy, the previous anti-cancer therapy must be recorded in the EDC system.
11  Perform every 4 cycles after cycle 13.
12  Perform every 3 cycles after cycle 13.
13. 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 12 weeks 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 participants who do not/will not have a 
scheduled study visit or study contact during the Sponsor defined time period will be contacted for their survival status (excluding participants that have a 
death event previously recorded)
 
 
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7.0 TRIAL PROCEDURES
7.1
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
7.1.1.1
Informed Consent
The investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial or Future Biomedical Research.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
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 after the subject provides written 
informed consent.
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 starting the trial.  In addition, record all treatments for a prior cancer 
other than NSCLC even if taken greater than 30 days prior to Visit 1. 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.
 
 
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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.
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 still 
occur approximately 30 days after last dose of study therapy.  Once new antineoplastic 
therapy has been initiated the subject will move into survival follow-up after the 30 day 
safety visit.
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 Randomization Number
All eligible subjects will be randomly allocated to trial treatment and will receive a 
randomization number.  The randomization number identifies the subject for all procedures 
occurring after randomization.  Once a randomization number is assigned to a subject, it can 
never be re-assigned to another subject.
A single subject cannot be assigned more than 1 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 
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.
 
 
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The instructions for preparing and administering MK-3475 will be provided in the 
Procedures Manual.
Docetaxel will be prepared and administered as per the approved product label.
Clinical Procedures/Assessments
7.1.2
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.  Following the guidance described in Section 7.2.3.2., certain irAEs should also be 
reported to the Sponsor as ECIs. 
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.  Clinically significant abnormal findings should be recorded as medical 
history. The timepoints for full physical exam are described in Section 6 - Trial Flow Chart.
After the first dose of trial treatment new clinically significant abnormal findings should be 
recorded as AEs.
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.
 
 
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7.1.2.3
Vital Signs
The investigator or qualified designee will take vital signs 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.  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.  
Additional timepoints for standard 12-lead ECG are described in Section 6 – Trial Flow 
Chart.  
An analysis of subjects receiving MK-3475 from protocol number 001 which correlates their 
QTc interval with PK parameters will occur several months after the initiation of PN010 to 
demonstrate that the upper bound of the confidence interval for median change in QTc from 
baseline to maximum steady state plasma concentration of MK-3475 is not above 20 
milliseconds. When data from this analysis demonstrates that MK-3475 has a low likelihood 
of increasing the QTc interval, the collection of ECG data in this study during treatment will 
discontinue. Sites will be notified via Administrative Memo of this change.  Enough on 
treatment ECG data has been collected such that further collection is not required.  A 
significant prolongation of the QTc interval by MK-3475 has not been observed.
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
Pulmonary Function Tests
Pulmonary function tests should include an assessment of forced vital capacity, forced 
expiratory flow between 25 and 75 percent of FVC (FEF25-75), forced expiratory volume in 
one second and peak expiratory flow (PEF) and diffusion capacity.  Additionally, oxygen 
saturation as assessed by pulse oximetry is required. These tests should be performed at 
baseline and subsequently at the discretion of the investigator. Hemoglobin must be obtained 
within 3 days of pulmonary function testing. 
Laboratory Procedures/Assessments
7.1.3
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.
 
 
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7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry, Urinalysis and Other)
Laboratory tests are specified in Table 5.
Table 5
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
PT (INR)
Hemoglobin
Alkaline phosphatase
Glucose
aPTT
Platelet count
Alanine aminotransferase 
(ALT)
Protein
Triiodothyronine
(T3) or Free 
Triiodothyronine
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)
Anti-MK-3475 Antibodies
Uric acid
PK
Calcium
Blood for FBR
Chloride
GFR
Glucose
Phosphorus
Potassium
Sodium
Magnesium
Total Bilirubin  
Direct and indirect 
Bilirubin
Total protein
Blood Urea Nitrogen
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.
** White Blood Cell Differential (Absolute) is required. White Blood Cell Differential (%) is required only if 
customarily reported in your region. If White Blood Cell Differential (%) is not normally done then these fields 
can be left blank and no comment is required.
*** If this test is not done as part of local standard of care, this test does not need to be performed.  
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 48 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.
 
 
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7.1.3.2
Pharmacokinetic Evaluations
7.1.3.2.1 Blood Collection for Serum MK-3475
Sample collection, storage and shipment instructions for serum samples will be provided in 
the operations/laboratory manual.
The timepoints for PK blood sampling are described in Section 6 - Trial Flow Chart.
In protocol amendment 13 and beyond, PK and ADA samples will not be collected.
7.1.3.3
Anti-MK-3475 Antibodies
Sample collection, storage and shipment instructions will be provided in the 
operations/laboratory manual.
In protocol amendment 13 and beyond, PK and ADA samples will not be collected.
7.1.3.4
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.
7.1.3.5
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
7.1.4.1
Tumor Imaging
The site’s study team must have reviewed pre-trial images from at least 2 dates to confirm 
that radiographic progression has occurred per RECIST 1.1 following initiation of the first-
line platinum-containing doublet. The central imaging vendor must have received these 
scans prior to randomization in this trial for a possible retrospective analysis of this eligibility 
criterion. The central imaging vendor must also confirm that pre-trial scans are of diagnostic 
quality prior to randomization.
The initial tumor imaging will be performed within 30 days prior to the first dose of trial 
treatment.  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 30 days prior to the 
first dose of trial treatment.  On-study imaging will be performed every 9 weeks (63 ± 
 
 
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7 days) after the first dose of trial treatment, and every 12 weeks (84 ± 7 days) from Week 54 
onward.  Imaging may be performed more frequently if clinically indicated.  CT timing 
should follow calendar days and should not be adjusted for delays in cycle starts or extension 
of MK-3475 cycle frequencies.  
After the first documentation of progression (if the subject is clinically stable), or response 
per irRC, confirmatory scans will be performed as at the next scheduled time point (e.g. 
every 63 ±7 days). 
After the first documentation of progression it is at the discretion of the investigator to keep a 
clinically stable subject on trial treatment or to stop trial treatment until repeat imaging 
performed at the next scheduled time point (i.e., every 63 +/- 7 days) confirms progression.  
Clinical Stability is defined as:
1. Absence of symptoms and signs indicating clinical significant progression of disease 
(including worsening of laboratory values) indicating disease progression.
2. No decline in ECOG performance status.
3. Absence of rapid progression of disease or progressive tumor at critical anatomical 
sites (e.g., cord compression) requiring urgent alternative medical intervention.
Subjects that are deemed clinically unstable are not required to have repeat imaging for 
confirmation. If progression is confirmed, then the subject will be discontinued from trial 
treatment.  If progression is not confirmed, then the subject should resume/continue trial 
treatment and have their next scan according to their current imaging schedule (every 
9 weeks [63 ± 7 days] from first dose of study treatment through Week 54, and every 
12 weeks [84 ± 7 days] thereafter).  When feasible, subjects should not be discontinued until 
progression is confirmed.
Imaging during the follow-up period is to be repeated every 9 weeks (63 ± 7 days) from 
C1D1 through Week 54, and every 12 weeks (84 days ± 7 days) thereafter, for subjects who 
discontinue trial treatment for reasons other than disease progression until the subject 
experiences confirmed disease progression or starts a new antineoplastic therapy.  Subjects 
who move into the Second Course Phase will continue to have scans performed every 
12 weeks (84 days ± 7 days) relative to C1D1 of Second Course Phase until the subject 
experiences confirmed disease progression or starts a new antineoplastic therapy.
Disease progression for trial eligibility will be according to RECIST 1.1 criteria; however 
disease response on trial will be assessed using irRC (see Section 12.6) by investigators. A 
central group of independent radiologists will review all on-study images to make response 
assessments per RECIST 1.1 (see Section 12.7).  Local reading (investigator assessment with 
site radiology reading) will be used to determine eligibility and for subject management; 
Sponsor will collect radiological assessments per inclusion criteria 5 for a potential 
retrospective analysis of subject eligibility by a central vendor.  
 
 
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The same imaging technique should be used in a subject throughout the trial.  The processes 
for image collection, processing and transmission to the central vendor are in the investigator
Imaging Operations Manual (IIOM).
7.1.4.2
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 electronically by subjects prior to all 
other study procedures in the following order: EuroQol EQ-5D first, then EORTC QLQ C-
30, and lastly the EORTC LC-13 at the time points specified in the Trial Flow Chart. It is
most relevant and strongly recommended that ePROs are administered prior to study drug 
administration, adverse event evaluation and disease status notification.
In protocol amendment 13 and beyond, ePROs will not be collected for crossover 
subjects.
The health economic assessment (HEA) form will be completed by qualified site personnel
after the subject completes all other questionnaires.  The form captures non-study related 
healthcare visits, including healthcare provider visits, emergency room (ER) visits, and 
hospitalizations (including admission and discharge dates and primary discharge diagnosis).
7.1.4.3
Tumor Tissue Collection
Tumor tissue for biomarker analysis from a newly obtained formalin fixed biopsy of a tumor 
lesion not previously irradiated must be received by the central vendor before randomization
for determination of PD-L1 expression; no systemic antineoplastic therapy may be 
administered between the PD-L1 biopsy and initiating study medication.
Only subjects 
whose tumors demonstrate evidence of PD-L1 expression (on the neoplastic cells) are 
eligible for enrollment.  Patients will be stratified between strongly positive and weakly 
positive PD-L1 expression before randomization.  A fine needle aspirate or cytologic 
specimen will not be acceptable.  Needle or excisional biopsies, or resected tissue is required.  
Newly obtained formalin fixed specimens are required.
Archival material may be used for determination of EGFR and ALK status.  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 
MK-3475.  Patients who agree to undergo these additional, optional tumor biopsies while 
receiving MK-3475 may not have them under CT guidance.
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.
 
 
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7.1.4.4
Withdrawal/Discontinuation
When a subject discontinues/withdraws prior to trial completion, 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.
7.1.4.4.1 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 
writing to 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.
7.1.4.5
Blinding/Unblinding
Study treatment is open label in this study.
Visit Requirements
7.1.5
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.
 
 
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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 women of reproductive potential, a urine pregnancy test will be performed within 
72 hours prior to first dose of trial treatment.  If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test, performed by the local study site 
laboratory, will be required.

Tumor imaging must be performed within 30 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 up at 
scheduled visits until the start of new antineoplastic therapy, disease progression, pregnancy, 
death, withdrawal of consent, or is lost to follow-up.  Except for those who withdraw 
consent, subjects will enter the survival follow-up phase.  If the subject experienced a CR, 
PR, or SD during the treatment Phase on MK-3475, and then experiences PD at any time 
during that follow-up period, he/she will be eligible to receive up to 17 cycles (approximately 
1 year) of therapy with MK-3475 in the Second Course Phase.  After the Second Course 
Phase subjects should be followed up until the start of new antineoplastic therapy, disease 
progression, death, or is lost to follow-up., with no option for retreatment with MK-3475 on 
study.
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.  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 
 
 
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treatment with MK-3475 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 by radiologic imaging to monitor disease status and initiation of new 
antineoplastic therapy every 9 weeks (63 ± 7 days) through Week 54, and every 12 weeks 
(84 ± 7 days) thereafter.  Unless otherwise noted in the flow chart, every effort should be 
made to collect subject information on the start of new antineoplastic therapy, disease 
progression, death.
Subjects who are eligible to receive treatment with MK-3475 in the Second Course Phase 
according to the criteria in Section 7.1.5.4 will move from the follow-up phase to the Second 
Course Phase when they experience disease progression.  Subjects who discontinue trial 
treatment from the Second Course Phase for a reason other than disease progression will 
move into the Follow-up Phase and should continue to be assessed every 12 weeks (84 ± 
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) through Week 54 and every 12 weeks 
(84 ± 7 days) thereafter 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, disease progression,
and 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 (63 ± 7 days)
through Week 54 and every 12 weeks (84 ± 7 days) thereafter until PD is identified.  Once 
the subject stops the imaging assessments for this protocol (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 every 12 weeks to assess for survival status.  Post-study treatments
and the subject’s response to them will also be collected.
 
 
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7.1.5.3.4 Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to but not limited to an external Data 
Monitoring Committee (eDMC) review, or updated final analysis.
Upon Sponsor 
notification, all participants who do not/will not have a scheduled study visit or study contact 
during the Sponsor defined time period will be contacted for their survival status (excluding 
participants that have a previously recorded death event in the collection tool).
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.  Subjects who were randomized 
to receive MK-3475 may be eligible to receive MK-3475 200 mg IV Q3W in the Second 
Course Phase of this study for up to 17 cycles (approximately 1 year) if the subject:

Stopped their initial treatment with MK-3475 after attaining an investigator-
determined confirmed CR according to irRC, was treated for at least six months with 
MK-3475, and received at least two treatments with MK-3475 beyond the date when 
the initial CR was declared.  A CR by irRC means that all index lesions have resolved 
(none have bidimensional measurements), all non-index lesions have disappeared, 
and no new lesions have been identified.  These findings must be confirmed on 
subsequent imaging performed at the next scheduled time point (i.e., every 63 +/- 7 
days) for the call of CR by irRC to be appropriate.  So the patient will have no 
evidence of metastatic cancer in order for the subject and his/her physician to 
consider the subject’s participation in this Second Course Phase.

Experienced an investigator-determined confirmed radiographic disease progression 
according to irRC after stopping their initial treatment with MK-3475 due to 
achievement of a confirmed CR or have experienced 35 administrations of MK-3475.

Did not receive any anti-cancer treatment since the last dose of MK-3475.

Have a life expectancy of at least 3 months.

Have a performance status of 0 or 1 on the ECOG Performance Scale.

Have adequate organ function as indicated in Table 1.

Female subject of childbearing potential has a negative urine or serum pregnancy test.  
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.  The serum pregnancy test must be negative for the subject to be 
eligible.

Be willing to adhere to the contraception requirements (see Section 5.7.2)
 
 
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
Does not meet the following exclusion criteria:
o
Is receiving systemic steroid therapy ≤7 days prior to the first dose of trial 
treatment or receiving any other form of immunosuppressive medication.
a) Corticosteroid use on study after Cycle 1 for management of AEs, 
SAEs, and events of clinical interest (ECIs), as a pre-medication for IV 
contrast allergies/reactions or if considered necessary for a subject’s 
welfare, is allowed.
b) Subjects who receive daily steroid replacement therapy serve as an 
exception to this rule. Daily prednisone at doses of 5 to 7.5 mg (or 
hydrocortisone equivalent doses) is an example of replacement 
therapy.
c) Subjects who use inhaled steroids for the control of asthma serve as an 
exception to this rule.
o
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).
o
Has an active autoimmune disease, or a documented history of autoimmune 
disease, or a syndrome that requires systemic steroids or immunosuppressive 
agents.  Subjects with vitiligo or resolved childhood asthma/atopy would be 
exception to this rule.  Subjects that require inhaled steroid or local steroid 
injections will not be excluded from the study.  Subjects with hypothyroidism 
not from autoimmune disease and stable on hormone replacement will not be 
excluded from the study. 
o
Has had an allogeneic tissue/solid organ transplant.
o
Has interstitial lung disease or a history of pneumonitis that required oral or 
intravenous glucocorticoids to assist with management.  Lymphangitic spread 
of the NSCLC is not exclusionary.  
o
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.
o
Has an active infection requiring intravenous systemic therapy.
o
Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies).
 
 
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o
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.
o
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.
o
Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
o
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).

Subjects will be re-treated at MK-3475 200 mg Q3W.
An objective response or 
progression of disease that occurs during the Second Course Phase for a patient will 
not be counted as an event for the primary analysis of either endpoint in this trial.
7.1.5.5
Crossover for Subjects in the Docetaxel Arm to MK-3475 200 mg Arm
Subjects who were randomized to the docetaxel arm and had experienced disease progression 
(either clinically or radiographically) while receiving docetaxel in PN010 or from subsequent 
anti-cancer therapy, are eligible for the crossover phase to receive MK-3475 200 mg Q3W.  
Subjects who permanently discontinued from the study by withdrawal of consent are not 
eligible for crossover. 
There are no laboratory requirements or limitations to enter the Crossover Phase.  Subjects 
will have laboratory assessments while receiving study treatment as outlined in the Crossover 
Flow Chart in Section 6.5.
7.1.5.5.1 Inclusion Criteria for Optional Crossover from docetaxel to MK-3475 200 mg 
arm
In order to be eligible for participation in the crossover phase, the subject must:

Be willing and able to provide written informed consent/assent for the trial.  

Have been randomized into the docetaxel arm of MK-3475 PN010 study and taken at 
least one dose of study medication

Have experienced disease progression (either clinical or radiographic, as assessed by 
the investigator) from docetaxel or other subsequent anti-cancer therapies.

Have a performance status of 0 or 1 on the ECOG Performance Scale.
 
 
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
Subjects with known and treated brain metastasis are eligible provided they are 
clinically stable, and brain metastases have been treated. Steroid use for symptom 
control is allowed but the total daily dose should be ≤ 10 mg of prednisone or its 
equivalent.

Have baseline imaging scan done within 30 days of the first dose of MK-3475

Have adequately recovered from adverse events of previous anti-cancer therapy.

Be willing to adhere to the contraception requirements (see Section 5.7.2).
7.1.5.5.2 Exclusion Criteria for Optional Crossover from docetaxel to MK-3475 
200 mg arm
The subject must be excluded from participating in the trial if the subject:

Has withdrawn consent from study (MK-3475 PN010).

Have active pneumonitis of Grade 2 or greater or history of pneumonitis requiring 
systemic steroid therapy.

Has received thoracic radiation therapy of > 30 Gy within 6 months have active and 
untreated brain metastasis 
7.1.5.6
Crossover Assessments and Procedures
Crossover subjects can initiate treatment with MK-3475 200 mg Q3W after their last dose of 
docetaxel or after their last dose of chemotherapy once investigators confirm that subjects are 
meeting inclusion and exclusion criteria for the Crossover Phase as listed in Section 7.1.5.5.
The subject will then start the Crossover Phase as outlined in Crossover Flow Chart in 
Section 6.5. Subjects must have baseline imaging scans performed within 30 days prior to the 
first dose in the Crossover Phase.  On study, imaging will be performed every 9 weeks (63 ± 
7 days) after the first dose of crossover trial treatment through Week 54, and every 12 weeks 
(84 ± 7 days) thereafter, or more frequently, if clinically indicated.  Local reading 
(investigator assessment with site radiology reading) will be used to determine eligibility and 
for subject management.  All scans performed during the study should be submitted to the 
imaging vendor for independent, central reading. 
Subjects who attain irCR per irRC will have an option to hold MK-3475 while continuing in 
the trial.  Subjects will continue in trial until progressive disease is confirmed as assessed by 
irRC as determined by the investigators or up to two years from starting crossover therapy 
with MK-3475 200 mg Q3W, whichever comes first.  Subjects who discontinue study 
medication in the Crossover Phase will follow the post treatment phase procedures as 
outlined in Section 6.2.  Crossover subjects will not be eligible for second course phase as 
outlined in Section 6.3.
 
 
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Post Final Analysis Activities
7.1.6
If at IA2 or the final analysis the DMC recommends a crossover of patients from docetaxel to 
MK-3475 treatment based on OS data, all patients with a randomization number in this study, 
if they still meet certain inclusion criteria, may be offered further therapy with MK-3475; the 
details of which will be discussed in a future communication.
7.2
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Progression of the cancer under study is not considered an adverse event.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 30 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
 
 
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Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
In this trial, an overdose is any dose higher than 20% over the prescribed dose.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product (or 180 
days for subjects assigned to docetaxel), or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, whichever is earlier, must be reported by the 
investigator. All reported pregnancies must be followed to the completion/termination of the 
pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
 
 
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Immediate Reporting of Adverse Events and Incidents to the Sponsor 
7.2.3
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. 
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 6 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 (reference Section 7.2.3.3 for additional details), whether or not related to 
the Sponsor's product, must be reported within 24 hours to the Sponsor either by electronic 
media or paper. Electronic reporting procedures can be found in the EDC data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time 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.
 
 
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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 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, 
whether or not related to the Sponsor’s product, must be reported within 24 hours to the 
Sponsor, either by electronic media or paper.  Electronic reporting procedures can be found 
in the EDC data entry guidelines.  Paper reporting procedures can be found in the 
Investigator Trial File Binder (or equivalent).
Events of clinical interest for this trial include:
A. 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. 
B. 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.
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an immune-
related event.  Subjects who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes.  If lab results or symptoms indicated a 
possible immune-related ECI then additional testing should be performed to rule out other 
etiologic causes.  If no other cause was found, then it is assumed to be immune-related.
ECIs that occur to any subject from the date of first dose through 90 days following cessation 
of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, whether or not related to the Sponsor's product, must 
 
 
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be reported within 24 hours to the Sponsor either by electronic media or paper.  Sponsor 
Contact information can be found in the Investigator Trial File Binder.
7.2.3.3
Protocol-Specific Exceptions to Serious 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, unless there is 
evidence suggesting a causal relationship between the drug and the event. Any such event 
will be submitted to the Sponsor within 24 hours either by electronic or paper media.
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.
7.2.3.4
Device Events
For this protocol, an Adverse Device Event (ADE) is any adverse health outcome related to 
the use of the in vitro diagnostic product (IVD).  ADEs include any malfunction or 
deterioration in the characteristics and/or performance of the IVD, as well as any inadequacy 
in the labeling or the instructions for use, that directly or indirectly, led to, or could have led 
to a death or serious deterioration of the patient’s health.  
A serious deterioration in the state of health can include:
1. Life-threatening illness or injury;
2. Permanent impairment of a body function or permanent damage to a body structure;
3. A condition necessitating medical or surgical intervention to prevent 1 or 2;
4. A condition that requires hospitalization or significant prolongation of existing 
hospitalization; or
5. Fetal distress, fetal death or any congenital abnormalities or birth defects.
In addition, any false positive or false negative test results, whether or not they impact the 
patient’s health, must be reported.
Any such event, including follow up to an event, that occurs to any patient from the time the 
consent is signed through the end of the study, must be reported within 24 hours to the 
Sponsor either by electronic media or paper.  Sponsor Contact information can be found in 
the Investigator Trial File Binder.
 
 
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Additionally, any such event considered by an investigator who is a qualified physician to be 
related to the IVD that is brought to the attention of the investigator at any time after the 
study also must be reported immediately to the Sponsor.
All such events must be followed up for outcome.
Evaluating Adverse Events
7.2.4
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 6
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 [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); 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 U.S. CLINICAL 
MONITOR 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
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.
7.3
TRIAL GOVERNANCE AND OVERSIGHT
Scientific Advisory Committee
7.3.1
This trial was developed in collaboration with a Scientific Advisory Committee (SAC).  The 
SAC comprises both Sponsor and non-Sponsor scientific experts who provide input with 
respect to trial design, interpretation of trial results and subsequent peer-reviewed scientific 
publications.
Trial Steering Committee
7.3.2
This trial will be conducted in consultation with a Trial Steering Committee. The Trial 
Steering Committee comprises:

Sponsor personnel 

Investigators participating in the trial 

Consulting therapeutic-area experts and clinical trialists 
The Trial Steering Committee will provide guidance on the operational aspects of the trial, 
evaluate recommendations from the Data Monitoring Committee (DMC) and make 
recommendations to the Executive Oversight Committee (EOC).  
Specific details regarding responsibilities and governance of the Trial Steering Committee 
will be described in a separate charter.
Executive Oversight Committee
7.3.3
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 (DMC) regarding the trial.
Data Monitoring Committee
7.3.4
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (DMC) will monitor the interim data from this trial.  The voting 
members of the committee are external to the Sponsor.  The members of the DMC must not 
be involved with the trial in any other way (e.g., they cannot be trial investigators) and must 
have no competing interests that could affect their roles with respect to the trial. The DMC 
will include 3 clinicians experienced in Lung Cancer and 1 external statistician; this is in 
addition to the unblinded trial statistician who will be a non-voting member of the 
committee. 
 
 
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The DMC will make recommendations to the EOC regarding steps to ensure both subject 
safety and the continued ethical integrity of the trial.  Also, the DMC will review interim trial 
results, consider the overall risk and benefit to trial participants (see Section 8.1.5 and 8.2.9 -
Interim Analyses) 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 DMC 
reports, minutes, and recommendations will be described in a separate charter that is 
reviewed and approved by the DMC.  The DMC will monitor the trial at an appropriate 
frequency, as described in the detailed DMC charter.  The DMC will also make 
recommendations to the Sponsor protocol team regarding steps to ensure both subject safety 
and the continued ethical integrity of the trial.
A DMC recommendation will be communicated to the Sponsor as agreed to in the 
Collaboration agreement.
8.0 STATISTICAL ANALYSIS PLAN
8.1
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this trial. Full detail is in 
Section 8.2 - Statistical Analysis Plan (SAP).
Efficacy Analyses
8.1.1
The intention-to-treat (ITT) population in the strongly positive PD-L1 stratum and the overall 
positive PD-L1 population will serve as the primary population for the analyses of efficacy 
data in this trial.  The primary efficacy endpoints are overall survival (OS) (i.e., the time from 
randomization to death due to any cause) and progression-free survival (PFS) (i.e., time from 
randomization to documented progressive disease or death due to any cause, whichever 
occurs first) per RECIST 1.1 based on blinded independent radiologists’ review. Type I error 
is strongly controlled at 2.5% (one-sided) for tests of PFS and OS in both the strongly 
positive PD-L1 stratum and the overall PD-L1 positive population. The secondary objectives 
for this trial are overall response rate (ORR) and response duration per RECIST 1.1 based on 
blinded independent radiologists’ review. The same endpoints will be applied to analyses of
the overall population. In addition, PFS, ORR and response duration per irRC based on 
investigators’ reviews will also be provided for both populations. An outline of the analysis 
strategy for key efficacy endpoints is presented in Table 7 below.
 
 
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Table 7
Primary Analysis Strategy for Key Efficacy Endpoints in Strongly Positive PD-L1 
Stratum
Endpoint/Variable
(Description, Time 
Point)
Statistical Method
Analysis Population
Missing Data Approach
Primary:
Overall survival
Stratified Log-rank test 
Cox model with Efron’s 
tie handling method for 
estimation
ITT
Model based
Progression-free 
survival (RECIST 1.1)
Stratified Log-rank test 
Cox model with Efron’s 
tie handling method for 
estimation
ITT
Model based
Secondary:
Overall response rate 
(RECIST 1.1)
Stratified Miettinen and 
Nurminen method
ITT
Subjects with missing 
data are considered non-
responders
Response duration 
(RECIST 1.1)
Summary statistics using 
Kaplan-Meier method
All responders in ITT
Non-responders are 
excluded in analysis
Safety Analyses
8.1.2
The All Patients as Treated (APaT) population in the strongly positive PD-L1 stratum and the 
overall positive PD-L1 population will be used for the primary analysis of safety data in this 
study. 
Investigators will be asked to report adverse experiences at every visit on this study (at least 
every 3 weeks during treatment) using Common Terminology Criteria for Adverse Events, 
Version 4.0. The attribution to drug, time-of-onset, duration of the event, its resolution, and 
any concomitant medications administered will be reported. AEs will be analyzed and 
reported for between arm differences in various parameters, including but not limited to all 
AEs, SAEs, fatal AEs, and laboratory changes. The AE analyses proposed below are 
supplemental analyses to improve understanding of the relative AEs between MK-3475 and 
docetaxel and account for the differences in treatment duration between treatment arms.
To properly account for potential difference in follow-up time between the study arms, which 
is expected to be longer in the MK-3475 arm, the same time-to-event analysis methods as for 
OS will be used for Tier 1 AE and Grade 3-5 AE based on the time to first event (i.e., the 
stratified log-rank test will be used for testing the time to AEs, and the stratified Cox model 
with Efron's tie handling method will be used for estimating the hazard ratio and its 95% 
confidence interval). Exploratory analysis of the same nature for other AEs that are suspected 
to have differential follow-up time may also be carried out.
In addition, the p-value and 95% confidence interval for between-treatment difference in the 
percentage of patients with Grade 3-5 AE overall as well as per cycle for the first four cycles, 
and the between-treatment difference in the Grade 3-5 AE incidence density adjusted for 
treatment exposure (duration is defined as from first dose of study drug to 30 days after last 
 
 
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dose of study drug) will be calculated using the stratified Miettinen and Nurminen method
[30]. 
Further, pre-specified adverse events of clinical interest include the following events that are 
determined to be immune-related by the investigator: 1) Grade ≥ 3 diarrhea 2) Grade ≥ 2
colitis, 3) Grade ≥ 2 pneumonitis, 4) Grade ≥ 3 hypo- or hyperthyroidism.  P-values and 95% 
confidence intervals will be provided for between-treatment differences in the percentage of 
patients with these events.
Power and Sample Size 
8.1.3
The study will randomize subjects in a 1:1:1 ratio into two MK-3475 arms and one docetaxel 
arm. The sample size for subjects with strongly positive PD-L1 is targeted at approximately 
460, and the overall sample size for this study is projected to be approximately 920.  
The study is event driven (i.e., number of subjects and follow-up time are subject to change 
but number of events is not) and will complete after approximately 200 deaths have been 
observed across three arms in the strongly positive PD-L1 stratum (approximately 140 
deaths between one MK-3475 arm and the docetaxel arm under the alternative hypothesis).
With 140 deaths between one MK-3475 arm and control, the study has over 81% power to 
detect a 0.55 hazard ratio at the final analysis, where 0.825% alpha is allocated to the two 
MK-3475 vs. docetaxel comparisons using Hochberg procedure. The assumptions for the 
sample size and power calculations are specified in Section 8.2.7.
Multiplicity Adjustment
8.1.4
The multiplicity strategy specified in this section will be applied to the strongly positive PD-
L1 stratum and the overall positive PD-L1 population for the testing of primary hypotheses. 
The Hochberg step-up procedure will be used for multiple comparisons on an efficacy 
endpoint if both MK-3475 arms continue to study completion. The type I error rates are all 
one-sided.
The overall type I error is strongly controlled at 2.5% (one-sided) with 0.35% allocated to 
PFS and 2.15% allocated to OS hypothesis.  PFS will be tested in the strongly positive PD-
L1 stratum at 0.25% at the second interim analysis (primary analysis of PFS) and at 0.1% at 
the final analysis for long-term PFS effect. At each analysis, if both MK-3475 arms 
demonstrate superior PFS in the strongly positive PD-L1 stratum, the corresponding alpha 
will be rolled into OS testing at the final analysis. 
OS will be tested in the strongly positive PD-L1 stratum at 0.5% at the second interim
analysis, and at ≥0.825% at the final analysis. At the second interim analysis, only if both
MK-3475 arms demonstrate superior OS in the strongly positive PD-L1 stratum, will OS in 
the overall positive PD-L1 population be sequentially tested at the same alpha level. At the 
final analysis, OS in the strongly positive PD-L1 stratum and the overall positive PD-L1 
population will be tested simultaneously, with available alpha split evenly between the two 
tests (see Section 8.2.6 for details).
 
 
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Since the above alpha allocation strategy does not depend on number of events, it remains 
valid in case actual number of events at an interim analysis or final analysis differs from 
planned number of events. Based on emerging external data, this testing strategy on PD-L1 
may be modified to improve the efficiency of the design before unblinding the biomarker 
data. Should it happen, a protocol amendment will be issued to document the change which 
is not expected to impact the conduct of the trial.
Interim Analyses
8.1.5
There are two planned interim analyses in this trial.
Table 8 summaries the strategy and timing of each interim analysis. Accrual will continue 
during Interim Analyses.  The details of interim analyses are provided in the DMC Charter. 
Table 8
Summary of Interim Analysis Strategy
Interim Analysis 
Number
Key Endpoints for 
Interim Analysis
Anticipated 
Approximate 
Timing of Analysis 
(from study start)
Sample size 
expected at time of
analysis 
(Three arms)
Primary Purpose of 
Analysis
Interim Analysis 1
ORR
App. 10 months 
120 in strongly
positive 
PD-L1 
stratum
with 3 
months 
of 
minimum 
follow-up
Discontinue one MK-
3475 arm  for lack of 
efficacy 
OR 
discontinue 
both 
arms for futility
Interim Analysis 2 
(primary PFS 
analysis and 
interim OS 
analysis)
PFS/OS
App. 19 months
App. 
414 
(around 175 PFS 
events
across 
three arms) in 
strongly positive 
PD-L1 stratum
Demonstrate 
superiority of MK-
3475 in PFS
Demonstrate 
superiority of MK-
3475 in OS after
approximately 120 
deaths have been 
observed 
across 
three 
arms 
in 
strongly 
positive 
PD-L1 stratum
Final Analysis
OS/PFS
App. 30 months
App. 460
(around 200 OS
events 
across 
three arms) in  
strongly positive 
PD-L1 stratum
Demonstrate 
superiority of MK-
3475 in OS
Demonstrate long-
term PFS effect of 
MK-3475 
 
 
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8.2
Statistical Analysis Plan
Responsibility for Analyses/In-House Blinding
8.2.1
The statistical analysis of the data obtained from this study will be the responsibility of the
Clinical Biostatistics department of the SPONSOR.
Although the trial is open label, analyses or summaries generated by randomized treatment 
assignment, actual treatment received will be limited to clinical safety monitoring and 
documented. The study team at the Sponsor consisting of clinical, statistical, statistical 
programming and data management personnel, will be blinded to subject-level PD-L1 
biomarker results.  An unblinded Sponsor clinical scientist will have access to the subject-
level PD-L1 results for the purpose of data review and will have no other responsibilities 
associated with the study.  A summary of PD-L1 biomarker prevalence may be provided to 
the study team at the Sponsor by the IVRS vendor or an external unblinded statistician.    
The IVRS vendor will generate the randomized allocation schedule(s) for study treatment 
assignment for this protocol, and the randomization will be implemented in IVRS.
Planned interim analyses are described in Section 8.2.9. Study enrollment will be ongoing at 
the time of any interim analysis.  Access to the allocation schedule for this study will be 
restricted to an external unblinded statistician and, as needed, a scientific programmer 
performing the interim analysis, who will have no other responsibilities associated with the 
study.
Treatment-level results of the interim analysis will be provided by an external unblinded 
statistician to the eDMC.  Key enrollment metrics and study data in the PD-L1 strongly 
positive stratum will also be monitored by the external unblinded statistician to inform the 
timing of interim and final analysis. Limited additional SPONSOR personnel may be 
unblinded to the treatment level results of the interim analyses, if required, in order to act on 
the recommendations of the eDMC or facilitate regulatory filing after an interim analysis.  
The extent to which individuals are unblinded with respect to results of interim analyses will 
be documented by the unblinded statistician.
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 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 committee may be 
unblinded to results at the treatment level in order to act on these recommendations.  
Additional logistical details and data monitoring guidance will be provided in the eDMC 
Charter.  Key aspects of the interim analyses are described in Section 8.2.9.
Prior to final study unblinding, the external unblinded statistician will not be involved in any 
discussions regarding modifications to the protocol, statistical methods, identification of 
protocol violators, or data validation efforts after the interim analyses.
 
 
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Hypotheses/Estimation
8.2.2
Objectives and hypotheses of the study are stated in Section 3. The study is considered to 
have met its primary objective if at least one MK-3475 arm is superior to docetaxel either in 
PFS or in OS at an interim analysis or the final analysis in subjects with strongly positive 
PD-L1 expression or overall positive PD-L1 population.
Analysis Endpoints
8.2.3
8.2.3.1
Efficacy/Immunogenicity Endpoints
Primary
There are two primary endpoints of this study: overall survival (OS) and progression-free-
survival (PFS) per RECIST 1.1.
Overall Survival
Overall survival (OS) is defined as the time from randomization to death due to any cause. 
Subjects without documented death at the time of the final analysis will be censored at the 
date of the last follow-up.
Progression-Free-Survival (PFS) per RECIST 1.1
Progression-free survival is defined as the time from randomization to the first documented 
disease progression per RECIST 1.1 based on blinded independent radiologists’ review or 
death due to any cause, whichever occurs first. See Section 8.2.5.1.3 for definition of 
censoring.
Secondary
Overall Response Rate (ORR)
Overall response rate is defined as the proportion of the subjects in the analysis population 
who have a complete response (CR) or partial response (PR). Responses are based on blinded 
independent radiologists’ review per RECIST 1.1. Responses based on investigator’s 
assessments using irRC will also be assessed.
Progression-Free-Survival (PFS) per irRC
Progression-free survival is defined as the time from randomization to the first documented 
disease progression per irRC based on investigators’ review or death due to any cause, 
whichever occurs first. See Section 8.2.5.1.3 for definition of censoring.
 
 
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Response Duration
For subjects who demonstrated CR or PR, response duration is defined as the time from first 
documented evidence of CR or PR until disease progression or death. Response duration for 
subjects who have not progressed or died at the time of analysis will be censored at the date 
of their last tumor assessment.  Response duration will be calculated for RECIST 1.1 based 
on blinded independent radiologists’ review and for irRC based on investigators’ review.
8.2.3.2
Safety Endpoints
Safety measurements are as described in Section 7.
8.2.3.3
Patient Reported Outcomes analysis
EORTC-QLQC30, EORTC QLQ LC-13, EuroQoL EQ-5D, Health Economic Assessment 
and tumor volumetric changes will be assessed in the exploratory analysis. The EORTC 
QLQ-C30, EORTC QLQ-LC13, and EQ5D are not pure efficacy or safety endpoints because 
they are affected by both disease progression and treatment tolerability.
Analysis Populations
8.2.4
8.2.4.1
Efficacy Analysis Populations
The analysis of primary efficacy endpoints are based on the intention-to-treat (ITT) 
population, i.e., subjects will be included in the treatment group to which they are 
randomized. A supportive analysis will be conducted in the full analysis set (FAS) that 
excludes those who did not meet the critical eligibility criteria or discontinued before 
receiving any dose of assigned treatment. 
The primary efficacy analysis will be carried out in the ITT population of the strongly
positive PD-L1 stratum and the overall ITT population, including subjects with both strongly
and weakly positive PD-L1 expressions.
Details on the approach to handling missing data are provided in Section 8.2.5 Statistical 
Methods.
8.2.4.2
Safety Analysis Populations
The All Patients as Treated (APaT) population will be used for the analysis of safety data in 
this study. The APaT 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 trial treatment they actually received for the analysis of safety data. Subjects who take 
incorrect trial treatment for the entire treatment period will be included in the treatment group 
corresponding to the trial treatment actually received. At least one laboratory or vital sign 
measurement obtained subsequent to at least one dose of trial treatment is required for 
inclusion in the analysis of each specific parameter. To assess change from baseline, a 
baseline measurement is also required.
 
 
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The primary safety analysis will be based on the APaT population in the strongly positive 
PD-L1 stratum. In addition, the pooled safety data from both the strongly and weakly
positive PD-L1 strata will also be summarized in the secondary safety analysis.
Details on the approach to handling missing data for safety analyses are provided in Section
8.2.5 Statistical Methods.
Statistical Methods
8.2.5
Statistical testing and inference for safety analyses are described in Section 8.2.5.2. Efficacy 
results that will be considered to be statistically significant after consideration of the strategy 
for controlling the Type I error are described in Section 8.2.6, Multiplicity. Nominal p-values 
may be computed for other efficacy analyses as a measure of strength of association between 
the endpoint and the treatment effect rather than formal tests of hypotheses.
8.2.5.1
Statistical Methods for Efficacy Analyses
The overall type I error rate for this study is strictly controlled at 2.5% (one-sided) that 
allows the trial to declare positive in either OS or PFS in the strongly positive PD-L1 
stratum. Strong control of Type I error also extends to the analysis of OS in the overall PD-
L1 positive population.
The strategy to address multiplicity issues with regard to multiple treatment comparisons, 
multiple efficacy endpoints, and interim analyses is described in Section 8.2.6, Multiplicity 
and Section 8.2.9, Interim Analyses.
8.2.5.1.1 Overall Survival (OS)
The Kaplan-Meier method will be used to estimate the survival curves, as well as the overall 
survival rate at 1 year by treatment group. The treatment difference in survival will be 
assessed by the stratified log-rank test.  A stratified Cox proportional hazard model with 
Efron's method of tie handling will be used to assess the magnitude of the treatment 
difference (i.e., the hazard ratio).  The hazard ratio and its 95% confidence interval from the 
stratified Cox model with a single treatment covariate will be reported.  The same 
stratification factors used for randomization (see Section 5.4) will be applied to both the 
stratified log-rank test and the stratified Cox model.  
Since subjects in the control arm are expected to discontinue treatment earlier compared to 
subjects in the MK-3475 arm, and subjects discontinued docetaxel treatment may receive 
other PD-1 treatments similar to MK-3475 after discontinuation, the Rank Preserving 
Structural Failure Time (RPSFT) model proposed by Robins and Tsiatis [31] will be used to 
control for receipt of non-study treatment.  The RPSFT model provides a randomization-
based estimate of treatment effect (RBEE) corrected for the bias induced by crossover. The 
Kaplan-Meier estimates of the OS rate at 4 months (when most cross-overs are likely to 
occur), one year and other time points of interest will also be compared between the two 
treatment groups to explore the confounding effect of subsequent treatments. To further 
account for the possible confounding effect, a sensitivity analysis of OS that censors subjects
 
 
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at the time of initiation of new therapy will be performed and an OS analysis that treats 
initiation of new therapy as a time-dependent binary covariate will also be conducted. In case 
the proportional hazards assumption doesn’t hold, Fleming and Harrington’s weighted log-
rank test or other methods, as appropriate, will be conducted, after proper adjustment of the 
crossover effect over time.
Restricted mean survival time (RMST) estimate of OS over time may be calculated as 
an exploratory analysis.
8.2.5.1.2 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 stratified log-rank 
test.  A stratified Cox proportional hazard model with Efron's method of tie handling will be 
used to assess the magnitude of the treatment difference (i.e., hazard ratio) between the 
treatment arms.  The hazard ratio and its 95% confidence interval from the stratified Cox 
model with Efron's method of tie handling and with a single treatment covariate will be 
reported. The same stratification factors used for randomization (see Section 5.4) will be 
applied to both the stratified log-rank test and the stratified Cox model.  
Since disease progression is assessed periodically, progressive disease (PD) can occur any 
time in the time interval between the last assessment where PD was not documented and the 
assessment when PD is documented.  For the primary analysis, for the subjects who have PD, 
the true date of disease progression will be approximated by the date of first assessment at 
which PD is objectively documented, regardless of discontinuation of trial treatment.  Death 
is always considered as a confirmed PD event. Subjects without documented PD/death will 
be censored at the last disease assessment date.
There are three sensitivity analyses with a different set of censoring rules and PD event 
definitions under various scenarios.  The first sensitivity analysis is the same as the primary 
analysis except that it censors at the last disease assessment without PD when PD or death is 
documented after more than one missed disease assessment.  The second sensitivity analysis 
is the same as the primary analysis except that it considers discontinuation of treatment or 
initiation of new anticancer treatment, whichever occurs later, to be a PD event for subjects
without documented PD or death.  The third sensitivity analysis is the same as the second 
sensitivity analysis except that it censors at the last disease assessment when there is No PD 
and no death and new anticancer treatment is initiated. The censoring rules for primary and 
sensitivity analyses are summarized in Table 9. 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 [32], will be used as a supportive analysis for the 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.
 
 
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Table 9
Censoring Rules for Primary and Sensitivity Analyses of PFS
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
Sensitivity 
Analysis 3
No PD and no 
death; 
new 
anticancer 
treatment 
is 
not 
initiated
Censored 
at 
last 
disease assessment 
Censored 
at 
last 
disease assessment 
Censored at last 
disease assessment 
if still on study 
therapy; 
progressed 
at 
treatment 
discontinuation 
otherwise
Censored at last 
disease assessment
No PD and no 
death; 
new 
anticancer 
treatment 
is 
initiated
Censored 
at 
last 
disease 
assessment 
before 
new 
anticancer treatment
Censored 
at 
last 
disease 
assessment 
before new anticancer 
treatment
Progressed at date 
of new anticancer 
treatment
Censored at last 
disease assessment
PD 
or 
death 
documented after ≤ 
1 missed disease 
assessment
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or 
death
Progressed at date 
of documented PD 
or death
Progressed at date 
of documented PD 
or death
PD 
or 
death 
documented after ≥ 
2 missed disease 
assessments
Progressed at date of 
documented PD or 
death
Censored 
at 
last 
disease 
assessment 
prior to the  ≥ 2 
missed 
disease 
assessment
Progressed at date 
of documented PD 
or death
Progressed at date 
of documented PD
or death
In addition to the sensitivity analyses, an exploratory analysis of PFS2, defined as the time 
from randomization to second/subsequent disease progression after initiation of new anti-
cancer therapy, or death from any cause, whichever first, will be carried out.  Patients alive 
and for whom a second objective disease progression has not been observed will be censored 
at the last time known to be alive and without second objective disease progression. If 
progression after new anti-cancer therapy cannot be measured, time from randomization until 
treatment discontinuation, progression or death after new anti-cancer therapy will be 
measured. 
Restricted mean survival time (RMST) estimate of PFS over time may be calculated as an 
exploratory analysis.
8.2.5.1.3 Overall Response Rate (ORR)
Stratified Miettinen and Nurminen’s method [30] will be used for comparison of the overall 
response rates between the treatment groups.  A 95% confidence interval for the difference in 
response rates between each MK-3475 arm and the control will be provided.  A p-value for 
the difference in response rate between two MK-3475 arms will be provided for dose 
selection at interim analyses.  The same stratification factors used for randomization (see 
Section 5.4) will be applied to the analysis. A subgroup analysis of ORR will be carried out 
in patients that have been followed up for 27 weeks, including early drop-outs.
 
 
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8.2.5.1.4 Response Duration
If sample size permits, response duration will be summarized descriptively using Kaplan-
Meier medians and quartiles.  Only the subset of subjects who show a complete response or 
partial response will be included in this analysis. 
8.2.5.1.5 Exploratory Analyses
An exploratory analysis of pooled MK-3475 arm vs. docetaxel will be carried out for PFS or 
OS at the second interim analysis and the final analysis. This pooled analysis will be 
conducted in the strongly positive PD-L1 stratum as well as the overall PD-L1 positive 
population. The same stratified Cox proportional hazard model as that for the primary 
analysis will be used to assess the magnitude of the treatment difference between the pooled 
MK-3475 arm and docetaxel. The Kaplan-Meier method will be used to estimate the survival 
curves.
EORTC-QLQC30, EORTC QLQ LC-13, EuroQoL EQ-5D, Health Economic Assessment
and tumor volumetric changes will be summarized as part of the exploratory analysis. Details 
will be provided in a separate document on analysis plan before any unblinding. 
The correlation of tumor volumetric changes with OS will be explored by appropriate 
methods such as the Cox model with the time-dependent covariate of tumor volumetric 
changes.
8.2.5.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, vital signs, and ECG measurements.
The analysis of safety results will follow a tiered approach (Table 10).  The tiers differ with 
respect to the analyses that will be performed.  Safety parameters or adverse experiences of 
special interest that are identified a priori constitute “Tier 1” safety endpoints that will be 
subject to inferential testing for statistical significance with p-values and 95% confidence 
intervals provided for between-group comparisons.  Other safety parameters will be 
considered Tier 2 or Tier 3.  Tier 2 parameters will be assessed via point estimates with 95% 
confidence intervals provided for between-group comparisons; only point estimates by 
treatment group are provided for Tier 3 safety parameters.
Adverse experiences (specific terms as well as system organ class terms) and predefined 
limits of change in laboratory, vital signs, and ECG parameters that are not pre-specified as 
Tier-1 endpoints will be classified as belonging to "Tier 2" or "Tier 3", based on the number 
of events observed.  Membership in Tier 2 requires that at least 4 subjects in any treatment 
group exhibit the event; all other adverse experiences and predefined limits of change will 
belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will always include zero when treatment 
 
 
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groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences.  Because many 95% confidence intervals 
may be provided without adjustment for multiplicity, the confidence intervals should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of the between-group differences in adverse experiences 
and predefined limits of change.
Continuous measures such as changes from baseline in laboratory, vital signs, and ECG
parameters that are not pre-specified as Tier-1 endpoints will be considered Tier 3 safety 
parameters.  Summary statistics for baseline, on-treatment, and change from baseline values 
will be provided by treatment group in table format.  In addition, summary statistics for the 
difference between treatment groups will also be provided, along with nominal p-values for 
between-group differences.  Mean change from baseline over time will be plotted with the 
corresponding standard errors.  
To properly account for the potential difference in follow-up time between the study arms, 
which is expected to be longer in the MK-3475 arm, an important analysis of Tier 1 AE and 
Grade 3-5 AE will be based on the time to first event using the same time-to-event analysis 
methods as for OS (i.e., the stratified log-rank test will be used for testing the time to AEs, 
and the stratified Cox model with Efron's tie handling method will be used for estimating the 
hazard ratio and its 95% confidence interval). For other AEs with potentially differential 
follow-up time, such analysis may also be explored.
In addition, the p-value and 95% confidence interval for between-treatment difference in the 
percentage of subjects with Grade 3-5 AE overall as well as per cycle for the first four cycles, 
and the between-treatment difference in the Grade 3-5 AE incidence density adjusted for 
treatment exposure (AE duration is defined as from first dose of study drug to 30 days after 
last dose of study drug) will be calculated using the stratified Miettinen and Nurminen 
method [30]. 
Further, pre-specified adverse events of clinical interest include the following events that are 
determined to be immune-related by the investigator: 1) Grade ≥ 3 diarrhea 2) Grade ≥ 2
colitis, 3) Grade ≥ 2 pneumonitis, 4) Grade ≥ 3 hypo- or hyperthyroidism will be collected as 
Tier 1 events.  P-values and 95% confidence intervals will be provided for between-treatment 
differences in the percentage of subjects with these events.
 
 
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Table 10 Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
Gr ≥ 3 Diarrhea 
with 
a 
potential 
immunologic 
etiology
X
X
X
Gr ≥ 2 Colitis with 
a 
potential 
immunologic 
etiology
X
X
X
Gr ≥ 2 Pneumonitis 
with 
a 
potential 
immunologic 
etiology
X
X
X
Gr ≥ 3 Hypo- or 
hyperthyroidism 
with 
a 
potential 
immunologic 
etiology
X
X
X
Tier 2
Any AE
X
X
Any Grade 3-5 AE
X
X
Any Serious AE
X
X
Onset and Duration 
of First Grade 3-5 
AE
X
X
Any Drug-Related 
AE
X
X
Any Serious and 
Drug-Related AE
X
X
Any Grade3-5 and 
Drug-Related AE
X
X
Dose Modification 
due to AE
X
X
Discontinuation due 
to AE
X
X
Death
X
X
Specific AEs, SOCs 
(including 
≥4 
of 
subjects in one of 
the 
treatment 
groups)
X
X
Tier 3
Specific AEs, SOCs 
(incidence <4 of 
subjects in all of the 
treatment groups)
X
Change 
from 
Baseline 
Results 
(Labs, ECGs, Vital 
Signs)
X
 
 
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8.2.5.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs.  No statistical hypothesis tests will be performed on these 
characteristics.  The number and percentage of subjects randomized, and the primary reason 
for discontinuation will be displayed.  Demographic variables (such as age) and baseline 
characteristics will be summarized by treatment either by descriptive statistics or categorical 
tables.
The reasons for exclusion from the ITT population (if any) will be summarized.
Multiplicity
8.2.6
The overall type I error is strongly controlled at 2.5% (one-sided) with 0.35% allocated to 
PFS and 2.15% allocated to OS hypothesis. 
For PFS, 0.25% will be spent at the second interim analysis (primary analysis of PFS) and 
0.1% will be spent at the final analysis to capture the long-term PFS effect. At each analysis, 
the Hochberg step-up procedure will be used for PFS testing in the strongly positive PD-L1 
stratum, giving equal weights to the two MK-3475 arms, if neither is discontinued prior to 
that analysis. At each analysis, a gate-keeping testing procedure will be used for adjustment 
over the strongly positive PD-L1 stratum and the overall PD-L1 positive population. If both 
MK-3475 arms demonstrate superior PFS in the strongly positive stratum, PFS will be tested 
in the overall PD-L1 positive population at the same alpha level.
For OS, 0.5% will be spent at the second interim analysis, and 1.65% will be allocated to the 
final analysis. The Hochberg step-up procedure will be used for OS testing at each analysis, 
giving equal weights to the two MK-3475 arms, if neither is discontinued prior to that 
analysis. At the second interim analysis, a gate-keeping testing procedure will be used for 
adjustment over the strongly positive PD-L1 stratum and the overall PD-L1 positive 
population: only if both MK-3475 arms demonstrate superior OS in the strongly positive 
stratum, will OS be tested sequentially in the overall PD-L1 positive population at the same 
alpha level. At the final analysis, a Bonferroni correction will be used to adjust for the OS 
tests in strongly positive PD-L1 stratum and in the overall PD-L1 positive population: the 
strongly positive PD-L1 stratum and the overall PD-L1 positive population will be tested at 
α/2 each, where α will be between 1.65% and 2.00% and the actual alpha level depends on 
whether or not both MK-3475 arms are superior in PFS for the overall positive population at 
the second interim analysis and the final analysis. See Figure 2 for the multiplicity strategy 
diagram for the study.
 
 
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Figure 2
Multiplicity Strategy
Sample Size and Power Calculations
8.2.7
The study will randomize subjects in a 1:1:1 ratio into two MK-3475 arms and one docetaxel 
arm. The sample size for subjects with strongly positive PD-L1 is targeted at approximately 
460, and the overall sample size for this study is projected to be approximately 920.  
The study is event driven (i.e., the number of subjects and follow-up time are subject to 
change but the number of events is not) and will complete after approximately 200 deaths 
have been observed across three arms from the strongly positive PD-L1 stratum. The sample 
size calculation is based on the following assumptions for subjects in the strongly positive 
PD-L1 stratum: 1) overall survival follows an exponential distribution with a median of 9 
months in the control arm, 2) the hazard ratio between MK-3475 and control is 0.60, 3) an 
enrollment period of 16 months and a minimum of 8 months follow-up after enrollment 
completion, 4) a dropout rate of 2% in 12 months.  The assumed median overall survival time 
of 9 months for subjects treated with docetaxel is based on historical data on docetaxel [18], 
and the possible positive prognostic nature of high PD-L1 expression levels. The median OS 
in docetaxel could be greater or less than 9 months in patients with strongly positive PD-L1 
expression if PD-L1 expression is prognostic for docetaxel.  
PFS analysis: the primary PFS analysis will be carried out at the second interim analysis, 
which occurs after approximately 175 PFS events across three arms have accumulated in the 
strongly positive PD-L1 stratum. An alpha of 0.250% will be allocated to PFS in the strongly 
positive stratum at this analysis. This interim analysis has >85% power to detect a 0.5 hazard 
ratio at alpha=0.250% in the strongly positive PD-L1 stratum using the Hochberg procedure 
 
 
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when there are 123 PFS events between one MK arm and the docetaxel arm under the 
alternative hypothesis. 
An analysis of long-term PFS effect will be carried out at the final analysis at 0.1% alpha 
(one-sided) in the strongly positive PD-L1 stratum. It is expected that approximately 345 PFS 
events would have been observed across three arms (approximately 240 PFS events between 
one MK arm and the docetaxel arm) in the strongly positive PD-L1 stratum at this analysis 
under the alternative hypothesis. This will give >95% power to detect a 0.5 hazard ratio, and 
88% power to detect a 0.6 hazard ratio at alpha=0.1%. 
OS analysis: Two analyses of OS will be carried out: the first OS analysis will be carried out 
at the second interim analysis, by which time approximately 120 deaths are expected to have 
been observed across three arms; the final OS analysis will be carried out when 
approximately 200 deaths have occurred across three arms in the strongly positive PD-L1 
stratum. At the second interim analysis, with approximately 84 deaths between two treatment 
arms, the study has at least 47% (32%) power to detect a 0.55 (0.60) hazard ratio at 
alpha=0.5% (one-sided) in the PD-L1 strongly positive stratum; at the final analysis, with 
approximately 140 deaths between two treatment arms, the study has at least 81% (65%) 
power to detect a 0.55 (0.60) hazard ratio at alpha=0.825% (one-sided) in the PD-L1 strongly 
positive stratum under a Hochberg procedure for the two MK-3475 vs. docetaxel 
comparisons. Figure 3 shows the study power for OS superiority in the PD-L1 strongly 
positive stratum at the second interim and final analysis. Approximately 550 deaths are 
expected to have been observed across three arms in the overall PD-L1 positive population at 
the final analysis. With 378 death observed between two treatment arms, the study has at
least 80% power to detect a 0.70 hazard ratio at alpha=0.825% (one-sided) in the overall PD-
L1 positive population using Hochberg procedure for the two comparisons versus docetaxel.
Figure 4 shows the study power for OS superiority in the overall PD-L1 positive population 
at the final analysis. Details on the final analysis are summarized in section 8.2.9.3.
 
 
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Figure 3
Power for OS Superiority in the PD-L1 Strongly Positive Stratum under Various 
Hazard Ratios using Hochberg Procedure at the Second Interim Analysis (IA2) 
and the Final Analysis (FA)
 
 
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Figure 4
Power for OS Superiority in the Overall PD-L1 Positive Population under Various 
Hazard Ratios using Hochberg Procedure at the Final Analysis (378 deaths
between two groups)
Subgroup Analyses and Effect of Baseline Factors
8.2.8
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 
endpoint will be estimated and plotted within each category of the following classification 
variables:

Age category (≤65 vs. >65 years)

Sex (female, male)

Race (white, non-white)

ECOG status (0 vs. 1)

Geographic region of enrolling site (East Asia, non-East Asia)

Ethnicity (East Asian, non-East Asian)
 
 
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
Previous chemotherapy regimen (types with greater than 10% subjects in the control 
group)

ALK translocation status (translocated vs. wild type)

EGFR mutation status (wild type vs. mutant)

Age of tumor specimen (archival vs. new) 
The consistency of the treatment effect will be assessed descriptively via summary statistics 
by category for the classification variables listed above. These subgroup analyses will be 
carried out in both the strongly positive PD-L1 stratum and the overall positive population.
The treatment effect in the subgroup of subjects who were enrolled after the PD-L1 
strong/weak cut point became available will also be explored.
Interim Analyses
8.2.9
There are two planned interim analyses. Enrollment will not be put on hold during the 
interim analyses.
First Interim Analysis
The first IA occurs after the first 120 randomized subjects in the strongly positive PD-L1 
stratum have a minimum of 3 months follow-up (approximately 10 months after 
randomization of the first subject). 
The primary objective of this analysis is to stop the trial or discontinue one MK-3475 arm if 
the overall unconfirmed and confirmed response data per RECIST 1.1 indicate futility. The 
decision rules are nonbinding, and are subject to modification based on emerging external 
data. As guidance, if the p-value of the difference of response rates (MK-3475 vs. docetaxel) 
is greater than 20% (two-sided) in the strongly positive PD-L1 stratum for both MK-3475 
arms, the study may be terminated. A <13% difference (e.g., <23% vs. 10% in docetaxel for 
both MK arms) will approximately meet the criterion for study discontinuation. In addition, 
if the p-value of the difference of response rates between the two MK-3475 arms is less than 
2.5% (two-sided) in the strongly positive stratum, the MK-3475 arm with the lower response 
rate may be discontinued from the trial. A< 23% difference (e.g., 33% vs. 10%) will 
approximately meet the criterion for discontinuing one of the MK-3475 arms. The futility 
stopping criteria are non-binding and the totality of the data including tumor volumetric 
change, PFS, OS and safety data based on these subjects as well as all enrolled subjects will 
be reviewed by the DMC to facilitate decisions.  See Table 11 for the operating 
characteristics at the first IA.
 
 
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Table 11 Operating Characteristics at IA1 for Futility Stopping (With 40 subjects/arm in the 
strongly positive PD-L1 stratum)
True Response Rate
Prob (Observed RR 
difference  >23%)
Prob (Observed RR difference  
>13%)
40%
76%
96%
35%
59%
90% 
30%
39%
78%
25%
21%
60%
20%
8%
38% 
15%
2%
19%
10% response rate is assumed for the other treatment.
There is no intention to stop the trial for efficacy at this analysis.
Second Interim Analysis
The second interim analysis will be conducted after approximately 175 PFS events have been 
observed across three arms from the strongly positive PD-L1 stratum (approximately 123 
PFS events between one MK-3475 arm and the docetaxel arm under the alternative 
hypothesis). The primary objective of this interim analysis is to demonstrate superiority in 
PFS for subjects with strongly positive PD-L1 expression at the 0.25% significance level. 
PFS is determined by RECIST 1.1 based on blinded independent radiologists’ review. The 
Hochberg step-up procedure will be used for PFS testing. If the p-value for both MK arms is 
<0.25%, both MK arms are superior to docetaxel arm in PFS; if the least significant (larger) 
p-value is >0.25% then the most significant (smaller) p-value needs to be compared with 
0.125% (or 0.25%/2). A p-value of 0.25% (one-sided) for PFS approximately corresponds to 
an empirical hazard ratio of 0.603 (or approximately >2.0 months of improvement if median 
PFS in docetaxel is 3 months) and a p-value of 0.125% (or 0.25%/2) approximately 
corresponds to an empirical hazard ratio of 0.580 (or approximately >2.2 months of 
improvement if median PFS in docetaxel is 3 months). A positive finding on PFS may lead to 
regulatory filing for drug approval upon discussion with regulatory agencies. There is no 
intention to change the conduct of study based on the PFS at this analysis. If both MK-3475 
arms demonstrate superior PFS in the strongly positive stratum, PFS will be tested in the 
overall PD-L1 positive population at the same alpha level, using the same Hochberg step-up 
procedure.
At the second interim analysis, OS will also be tested at the 0.5% level. Approximately 120 
deaths will be observed across three arms in the strongly positive PD-L1 stratum. The 
Hochberg step-up procedure will be used for OS testing. Only after both MK-3475 arms 
demonstrate superior OS to docetaxel in the strongly positive stratum, will OS be tested 
sequentially in the overall PD-L1 positive population at the same alpha level. Based on the 
Hochberg procedure, if the p-value for both MK arms is <0.5%, both MK arms are superior 
to the docetaxel arm in OS; if the least significant (larger) p-value is >0.5% then the most 
significant (smaller) p-value needs to be compared with 0.25% (or 0.5%/2). With 120 OS 
events across three arms, approximately 84 OS events are expected to be between one MK-
 
 
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3475 and docetaxel arm under the alternative hypothesis. At 0.5% alpha, both MK arms are 
superior to docetaxel in OS if both MK arms have an observed hazard ratio of approximately 
0.570 or less (> 6.8 months of improvement when the median OS in docetaxel is 9 months); 
only one MK arm is superior to docetaxel in OS if one MK arm has an observed HR of 
approximately 0.542 or less (>7.6 months of improvement when median OS in docetaxel is 9 
months) but the other MK arm has an observed HR of > 0.570. If both MK-3475 arms 
demonstrate superior OS in the strongly positive stratum, OS will be tested in the overall PD-
L1 positive population at the same alpha level, using the same Hochberg step-up procedure.
Final Analysis
The final analysis will be carried out when approximately 200 deaths have occurred across 
three arms in the strongly PD-L1 positive stratum (approximately 140 deaths between one 
MK-3475 arm and the docetaxel arm under the alternative hypothesis). 
If both MK-3475 arms proceed to study completion, the Hochberg step-up procedure will be 
used for OS and PFS testing (MK vs. docetaxel) at the final analysis, giving equal weights to 
the two MK- 3475 arms. 
Alpha for OS at the final analysis (αos) will be between 1.65% and 2.00%, and the actual 
alpha level depends on whether or not both MK-3475 arms demonstrate superiority in PFS 
for the overall PD-L1 positive population at the second interim analysis and the final 
analysis. A Bonferroni procedure will be used for the adjustment over the strongly positive 
PD-L1 stratum and the overall PD-L1 positive population. OS will be tested in the PD-L1 
strongly positive stratum and the overall PD-L1 positive population each at the same adjusted 
alpha level (αos/2). 
Based on the Hochberg procedure, if the p-value for both MK arms is <αos/2, both MK arms 
are superior to docetaxel in OS; if the least significant (larger) p-value is > αos/2 then the 
most significant (smaller) p-value needs to be compared with αos/4. With 0.825% alpha for 
OS in PD-L1 strongly positive stratum at the final analysis, both MK-3475 arms are superior 
to docetaxel if both MK-3475 arms have an observed HR of approximately 0.667 or less for 
both MK arms (> 4.5 months of improvement in OS); only one MK arm is superior to 
docetaxel if one MK arm has an observed HR of approximately 0.640 or less (>5.1 months of 
improvement in OS) but the other MK arm has an observed HR of > 0.667. Table 12 shows 
the empirical bars for a positive OS in PD-L1 strongly positive stratum at the final analysis. 
Similarly, Table 13 shows the empirical bars for a positive OS in the Overall PD-L1 positive 
population at the final analysis.
 
 
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Table 12 Approximate empirical bars for a positive OS in the PD-L1 strongly positive 
stratum at the final analysis based on outcomes in PFS for the overall PD-L1 
positive population
IA2
(alpha = 0.25% for 
PFS)
Final analysis
(alpha = 0.1% for 
PFS)
Nominal 
alpha for 
OS in PD-
L1 strong 
positive
Both MK arms are 
superior in OS at FA
Empirical hazard ratio1
(empirical median 
improvement in month2)
Only One MK arm is 
superior in OS at FA
Empirical hazard ratio1
(empirical median 
improvement in month2)
At least one MK 
arm does not have 
superior PFS
At least one MK 
arm does not have 
superior PFS
0.825%
0.667 (4.5 m.)
0.640 (5.1 m.)
At least one MK 
arm does not have 
superior PFS
Both MK arms 
have superior PFS 
0.875%
0.669 (4.4 m.)
0.642 (5.0 m.)
Both MK arms 
have superior PFS 
At least one MK 
arm does not have 
superior PFS
0.95%
0.673 (4.4 m.)
0.645 (5.0 m.)
Both MK arms 
have superior PFS 
Both MK arms 
have superior PFS 
1.00%
0.675 (4.3 m)
0.647 (4.9 m.)
1 Observed treatment effect which may lead to statistical significance based on 140 deaths between one MK arm and 
docetaxel arm in the PD-L1 strongly positive stratum, and half of allocated alpha as a conservative estimate under 
Hochberg procedure 
2 Median survival for docetaxel is assumed to be 9 months
Table 13 Approximate empirical bars for a positive OS in the overall PD-L1 positive 
population at the final analysis based on outcomes in PFS for the overall PD-L1 
positive population
IA2
(alpha = 0.25% for 
PFS)
Final analysis
(alpha = 0.1% for 
PFS)
Nominal 
alpha for 
OS in PD-
L1 strong 
positive
Both MK arms are 
superior in OS at FA
Empirical hazard ratio1
(empirical median 
improvement in month2)
Only One MK arm is 
superior in OS at FA
Empirical hazard ratio1
(empirical median 
improvement in month2)
At least one MK 
arm does not have 
superior PFS
At least one MK 
arm does not have 
superior PFS
0.825%
0.781 (2.5 m.)
0.762 (2.8 m.)
At least one MK 
arm does not have 
superior PFS
Both MK arms 
have superior PFS 
0.875%
0.783 (2.5 m.)
0.764 (2.8 m.)
Both MK arms 
have superior PFS 
At least one MK 
arm does not have 
superior PFS
0.95%
0.786 (2.5 m.)
0.766 (2.8 m.)
Both MK arms 
have superior PFS 
Both MK arms 
have superior PFS 
1.00%
0.787 (2.4 m.)
0.767 (2.7 m.)
1 Estimated treatment effect which may lead to statistical significance based on 378 deaths between one MK arm and 
docetaxel arm in the overall PD-L1 positive population
2 Median survival for docetaxel is assumed to be 9 months
 
 
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Compliance (Medication Adherence)
8.2.10
Drug accountability data for trial treatment will be collected during the study.  Compliance 
with trial treatment administration will be measured by subjects: 1) receiving unscheduled 
study agent infusions/injections; 2) missing an infusion/injection.  Numbers and percentages 
of subjects and infusion/injection visits with any deviation in these measures will be reported 
for the ITT population.
Extent of Exposure
8.2.11
The extent of exposure will be summarized as duration of treatment in cycles.  Dose intensity 
will also be summarized as appropriate.
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
9.1
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 14.  
Table 14 Product Description
Product Name & Potency
Dosage Form
MK-3475 50 mg
Lyophilized Powder for Injection
MK-3475 100 mg/ 4 mL
Solution for Injection
Docetaxel 80 mg/ 4 mL
Solution for Injection
All other supplies not indicated in Table 14 above will be provided centrally by the Sponsor 
or locally by the trial site or subsidiary, 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 will be responsible for recording the lot number, manufacturer and expiry date 
of any locally purchased product.
 
 
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9.2
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Vials will be provided in an open label fashion for subject dosing.
9.3
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, potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
9.4
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.
9.5
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.
9.6
Standard Policies
Trial site personnel will have access to a central electronic randomization system 
(IVRS/IWRS system) to allocate subjects, to assign drug to subjects and to manage the 
distribution of clinical supplies. Each person accessing the IVRS system must be assigned an 
individual unique PIN.  They must use only their assigned PIN to access the system, and they 
must not share their assigned PIN with anyone.
10.0ADMINISTRATIVE AND REGULATORY DETAILS
10.1 Confidentiality
Confidentiality of Data
10.1.1
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 
 
 
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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
10.1.2
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
10.1.3
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
 
 
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10.2 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.
10.3 Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/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.
 
 
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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 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 discarding 
trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
 
 
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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.
10.4 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.
10.5 Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
10.6 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 by the Sponsor.
 
 
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10.7 Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
 
 
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the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
 
 
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11.0
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Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et 
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Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev 
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Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 
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Sheppard K-A, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, et al. PD-1 
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Riley JL. PD-1 signaling in primary T cells. Immunol Rev 2009;229:114-25.
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SV, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct 
mechanisms. Mol Cell Biol 2005;25(21):9543-53.
[11]
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and 
autoimmunity. Immunol Rev 2010;236:219-42.
 
 
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with outcome in neoadjuvant chemotherapy-treated ovarian carcinoma. Cancer 
Immunol Immunother 2010;59(6):909-19.
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Suzuki H, Chikazawa N, Tasaka T, Wada J, Yamasaki A, Kitaura Y, et al. 
Intratumoral CD8+ T/FOXP3+ cell ratio is a predictive marker for survival in 
patients with colorectal cancer. Cancer Immunol Immunother 2010;59:653-61.
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Chew V, Tow C, Teo M, Wong HL, Chan J, Gehring A, et al. Inflammatory 
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Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of 
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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 [with Erratum]. J Clin Oncol 
2000;18:2354-62.
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Hanna N, Shepherd FA, Fossella FV, Pereira JR, de Marinis F, von Pawel J, et 
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lung cancer. J Clin Oncol 2008;26(21):3543-51.
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Garassino MC, Martelli O, Bettini A, Floriani I, Copreni E, Lauricella C, et al. 
TAILOR: A phase III trial comparing erlotinib with docetaxel as the second-line 
treatment of NSCLC patients with wild-type (wt) EGFR: Metastatic non-small 
cell lung cancer [Abstract No. LBA7501].  American Society of Clinical 
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[21]
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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(10):2095-103.
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Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, et 
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non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 
2004;22(9):1589-97.
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initial U.S. Approval: 1996: 2011.
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Ruffini E, Asioli S, Filosso PL, Lyberis P, Bruna MC, Macrì L, et al. Clinical 
significance of tumor-infiltrating lymphocytes in lung neoplasms. Ann Thorac 
Surg. 2009 Feb;87(2):365-71; discussion 371-2.
[25]
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.
[26]
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. Eur J Cancer 
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[27]
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.
[28]
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quality of life. Health Policy. 1990 Dec;16(3):199-208.
[29]
Bottomley A, Efficace F, Thomas R, Vanvoorden V, Ahmedzai SH. Health-
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[31]
Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials 
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Finkelstein DM. A proportional hazards model for interval-censored failure time 
data. Biometrics 1986;42:845-54.
 
 
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12.0APPENDICES
12.1 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

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. 

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.

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
1.
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. 
2.
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.
3.
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.  
4.
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
1.
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.
2.
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.
3.
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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12.2 Collection and Management of Specimens for Future Biomedical Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease.  A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics 
as related to drug response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the 
influence of variations in DNA sequence on drug response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The DNA and leftover tumor tissue specimen(s) collected in the current trial will be used 
to study various causes for how subjects may respond to a drug.  The DNA and leftover 
tumor tissue specimen(s) collected during the main study 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 enters and is removed by the body, how a drug 
works, other pathways a drug may interact with, or other aspects of disease.  
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, 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.
Subjects are not required to participate in the Future Biomedical Research sub-trial in 
order to participate in the main trial.
 
 
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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 to any specimens, test results, or medical information once the 
specimens have been rendered de-identified.  Subjects who decline to sign the Future 
Biomedical Research informed consent will not have the specimen collected nor will 
they be discontinued from the main trial.
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.
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 
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.  
 
 
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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 
writing to 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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12.3 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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12.4 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, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. 
Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair.
 
 
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12.5 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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12.6 Immune Related Response Criteria 
For all patients who experience disease progression on study, the date noted for of disease 
progression is the time of the scan where it is originally detected, and not the following date 
of the confirmatory scan. 
Definitions of measurable and non-measurable disease 
Measurable disease: Neoplastic masses that can be precisely measured in 2 in-plane 
perpendicular diameters. Both its longest diameter and its longest perpendicular must be 
greater than or equal to 10 mm or 2 times the axial slice thickness if axial slice thickness is 
greater than 5mm. Lymph nodes must have a short-axis line-length of ≥ 15 mm.  Malignant 
lymph nodes must be measurable in 2 perpendicular diameters. Both its longest diameter and 
its longest perpendicular must be greater than or equal to 15 mm.  The quantitative endpoint 
will be defined as the product of the longest diameter with its longest perpendicular. 
Non-measurable disease: Non-measurable lesions are those that are not suitable for 
quantitative assessment over time. These include:
1) Neoplastic masses which are too small to measure, because their longest 
uninterrupted diameter or longest perpendicular are less than 10 mm.
2) Neoplastic masses whose boundaries cannot be distinguished.  This includes masses 
which cannot be demarcated from surrounding tissue because of inadequate contrast, 
masses with overly complex morphology, or those with highly heterogeneous tissue 
composition.  
3) Other types of lesions that are confidently felt to represent neoplastic tissue, but 
difficult to quantify in a reproducible manner. These include bone metastases, 
leptomeningeal 
metastases, 
malignant 
ascites, 
pleural/pericardial 
effusions, 
inflammatory breast disease, lymphangitis cutis/pulmonis, cystic lesions, ill defined 
abdominal masses, etc.
For irRC, only target lesions selected at baseline and measurable new lesions are taken 
into account. 
At the baseline tumor assessment, the sum of the products of the two largest perpendicular 
diameters (SPD) of all index lesions (five lesions per organ, up to 10 visceral lesions and five 
cutaneous index lesions) is calculated.  
At each subsequent tumor assessment, the SPD of the index lesions and of new, measurable 
lesions (≥ 5 X 5 mm; up to 5 new lesions per organ: 5 new cutaneous lesions and 10 visceral 
lesions) are added together to provide the total time-point tumor burden.
 
 
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Overall response using irRC:

Complete Response (irCR): Complete disappearance of all tumor lesions (whether 
measureable or not, and no new lesions).  CR must be confirmed by repeated, 
consecutive assessments performed at the next scheduled time point (i.e., every 63 +/-
7 days). 

Partial Response (irPR): Decrease in SPD of 50% or greater by a consecutive 
assessment performed at the next scheduled time point (i.e., every 63 +/- 7 days).

Stable Disease (irSD): Failure to meet criteria for irCR or irPR, in absence of irPD.  

Progressive Disease (irPD): At least 25% increase in SPD relative to nadir 
(minimum recorded tumor burden) Confirmation by a repeat, consecutive assessment 
performed at the next scheduled time point (i.e., every 63 +/- 7 days).  
Please note other key differences between irRC and the original WHO criteria:
New measurable lesions will be incorporated into the SPD 
New non measurable lesions do not define progression but preclude irCR 
Non-index lesions contribute to defining irCR (complete disappearance required).
See the Investigators Imaging Operations Manual (IIOM) for more details.
REFERENCE
IrRC for the current protocol is adopted from the following reference:
Wolchok, JD, Hoos, A, O’Day S, et al., Guidelines for the Evaluation of Immune Therapy 
Activity in Solid Tumors: Immune-Related Response Criteria. Clinical Cancer Research, 
2009 Dec 1;15(23):7412-20.  Epub 2009 Nov 24.
 
 
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12.7 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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12.8 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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Product:  MK-3475 (SCH 900475)
Page 148
Protocol/Amendment No.: 010-17 
MK-3475-010-17 Final Protocol
9-Feb-2018
Confidential
13.0 SIGNATURES
13.1 Sponsor's Representative
TYPED NAME                                 SIGNATURE                                   DATE
_________________________      ____________________________     __________
13.2 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                                 SIGNATURE                                   DATE
_________________________      ____________________________     __________
 
 
04V5FR