Conditions: Non-small Cell Lung Cancer
Keywords: Programmed Cell Death-1 (PD1, PD-1) Programmed Cell Death 1 Ligand 1 (PDL1, PD-L1) Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 559
Healthy volunteers: no

Brief summary:
This is a study of carboplatin and paclitaxel or nano particle albumin-bound paclitaxel (nab-paclitaxel) with or without pembrolizumab (MK-3475, KEYTRUDA®) in adults with first line metastatic squamous non-small cell lung cancer (NSCLC).

The primary hypotheses are that treatment with pembrolizumab prolongs: 1) Progression-free Survival (PFS) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by a blinded central imaging vendor compared to placebo, and 2) Overall Survival (OS).

After analysis of interim results was conducted, the protocol was amended (Amendment 5) to allow participants the option to discontinue placebo in the control arm and to switch to pembrolizumab in the event of documented progressive disease as assessed by central review.

Detailed description:

Arms:
arm 1: Participants receive pembrolizumab 200 mg by intravenous (IV) infusion prior to chemotherapy on Day 1 of each 21-day cycle (Q3W) for up to 35 cycles (\~ 2 years) PLUS Investigator's choice of paclitaxel (200 mg/m\^2 by IV infusion on Day 1 of each 21-day cycle for 4 cycles) or nab-paclitaxel (100 mg/m\^2 by IV infusion on Days 1, 8, 15 of each 21-day cycle for 4 cycles) PLUS carboplatin area under the curve (AUC) 6 by IV infusion on Day 1 of each 21-day cycle for 4 cycles. arm 2: Participants receive normal saline as placebo by IV infusion prior to chemotherapy on Day 1 of each 21-day cycle for up to 35 cycles (\~ 2 years) PLUS Investigator's choice of paclitaxel (200 mg/m\^2 by IV infusion on Day 1 of each 21-day cycle for 4 cycles) or nab-paclitaxel (100 mg/m\^2 by IV infusion on Days 1, 8, 15 of each 21-day cycle for 4 cycles) PLUS carboplatin AUC 6 by IV infusion on Day 1 of each 21-day cycle for 4 cycles.

Interventions: intervention 1: Pembrolizumab intervention 2: Paclitaxel intervention 3: Nab-paclitaxel intervention 4: Carboplatin intervention 5: Saline placebo for pembrolizumab
Intervention descriptions: intervention 1: IV infusion intervention 2: IV infusion intervention 3: IV infusion intervention 4: IV infusion Carboplatin dose should not to exceed 900 mg. intervention 5: IV infusion

Protocol document:
Prot_SAP_001.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Randomized, Double-Blind, Phase III Study of 
Carboplatin-Paclitaxel/Nab-Paclitaxel 
Chemotherapy with or without Pembrolizumab 
(MK-3475) in First Line Metastatic Squamous Non-
small Cell Lung Cancer Subjects (KEYNOTE-407)
NCT02775435
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THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
SPONSOR:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Randomized, Double-Blind, Phase III Study of Carboplatin-Paclitaxel/Nab-Paclitaxel 
Chemotherapy with or without Pembrolizumab (MK-3475) in First Line Metastatic 
Squamous Non-small Cell Lung Cancer Subjects (KEYNOTE-407)
IND NUMBER:  116,833
EudraCT NUMBER:  2016-000229-38
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 11
SUMMARY OF CHANGES................................................................................................ 12
1.0
TRIAL SUMMARY.................................................................................................. 14
2.0
TRIAL DESIGN........................................................................................................ 15
Trial Design ........................................................................................................... 15
Trial Diagram........................................................................................................ 17
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 18
Primary Objective(s) & Hypothesis(es).............................................................. 18
Secondary Objective(s) & Hypothesis(es)........................................................... 18
Exploratory Objectives......................................................................................... 18
4.0
BACKGROUND & RATIONALE.......................................................................... 19
Background ........................................................................................................... 19
Pharmaceutical and Therapeutic Background .................................................... 19
Pre-clinical and Clinical Trials ........................................................................... 20
Ongoing Clinical Trials....................................................................................... 21
Information on Other Trial-Related Therapy...................................................... 22
Rationale................................................................................................................ 23
Rationale for the Trial and Selected Subject Population .................................... 23
Rationale for Dose Selection/Regimen/Modification......................................... 24
4.2.2.1
Rationale for the Use of Placebo ................................................................. 25
Rationale for Endpoints ...................................................................................... 25
4.2.3.1
Efficacy Endpoints....................................................................................... 25
4.2.3.2
Immune-related RECIST (irRECIST) ......................................................... 26
4.2.3.3
Patient Reported Outcomes.......................................................................... 27
EORTC QLQ-C30 and EORTC QLQLC13......................................... 27
EuroQol (EQ)-5D ................................................................................. 27
4.2.3.4
Safety Endpoints.......................................................................................... 27
4.2.3.5
Planned Exploratory Biomarker Research................................................... 28
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4.2.3.6
Future Biomedical Research........................................................................ 29
Benefit/Risk ........................................................................................................... 29
5.0
METHODOLOGY ................................................................................................... 30
Entry Criteria........................................................................................................ 30
Diagnosis/Condition for Entry into the Trial...................................................... 30
Subject Inclusion Criteria.................................................................................... 30
Subject Exclusion Criteria .................................................................................. 32
Trial Treatment(s) ................................................................................................ 34
Dose Selection/Modification .............................................................................. 37
5.2.1.1
Dose Selection (Preparation) ....................................................................... 37
5.2.1.2
Dose Modification (Escalation/Titration/Other).......................................... 37
Carboplatin and Paclitaxel or Nab-paclitaxel Chemotherapy 
Regimen................................................................................................ 38
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue........................................................................................... 38
Timing of Dose Administration.......................................................................... 44
5.2.2.1
Pembrolizumab/Saline Placebo ................................................................... 45
5.2.2.2
Paclitaxel...................................................................................................... 45
5.2.2.3
Nab-paclitaxel.............................................................................................. 45
5.2.2.4
Carboplatin................................................................................................... 45
5.2.2.5
Antiemetic Therapy ..................................................................................... 46
Trial Blinding...................................................................................................... 46
Randomization or Treatment Allocation............................................................ 46
Stratification.......................................................................................................... 47
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 47
Acceptable Concomitant Medications ................................................................ 47
Prohibited Concomitant Medications.................................................................. 47
Rescue Medications & Supportive Care............................................................. 48
Diet/Activity/Other Considerations..................................................................... 48
Diet...................................................................................................................... 48
Contraception...................................................................................................... 49
Use in Pregnancy ................................................................................................ 50
Subject Withdrawal/Discontinuation Criteria................................................... 50
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Subject Replacement Strategy............................................................................. 52
Beginning and End-of-Study Definition ............................................................. 52
Clinical Criteria for Early Trial Termination ................................................... 52
6.0
TRIAL FLOW CHART ........................................................................................... 53
Initial Treatment Phase........................................................................................ 53
Initial Treatment Phase – Cycles 1-4.................................................................. 53
Initial Treatment Phase – Cycles 5 and Beyond ................................................. 56
Second Course Phase (Retreatment)................................................................... 58
Crossover Phase .................................................................................................... 60
7.0
TRIAL PROCEDURES ........................................................................................... 62
Trial Procedures ................................................................................................... 62
Administrative Procedures.................................................................................. 62
7.1.1.1
Informed Consent......................................................................................... 62
General Informed Consent.................................................................... 62
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 63
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 63
7.1.1.3
Subject Identification Card .......................................................................... 63
7.1.1.4
Medical History ........................................................................................... 63
7.1.1.5
Prior and Concomitant Medications Review............................................... 63
Prior Medications.................................................................................. 63
Concomitant Medications..................................................................... 64
7.1.1.6
Assignment of Screening Number............................................................... 64
7.1.1.7
Assignment of Treatment/Randomization Number..................................... 64
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)................................... 64
Clinical Procedures/Assessments........................................................................ 64
7.1.2.1
Adverse Event (AE) Monitoring.................................................................. 64
7.1.2.2
Physical Exam.............................................................................................. 65
Full Physical Exam ............................................................................... 65
Directed Physical Exam........................................................................ 65
7.1.2.3
Vital Signs.................................................................................................... 65
7.1.2.4
12-Lead Electrocardiogram (ECG).............................................................. 65
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7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale ........... 65
7.1.2.6
Tumor Imaging and Assessment of Disease................................................ 65
Initial Tumor Imaging........................................................................... 66
Tumor Imaging During the Trial .......................................................... 66
End of Treatment and Follow-up of Tumor Imaging ........................... 67
Second Course (Retreatment) Tumor Imaging..................................... 67
RECIST 1.1 Assessment of Disease..................................................... 68
irRECIST Assessment of Disease......................................................... 69
7.1.2.7
Tumor Tissue Collection: PD-L1 Status...................................................... 72
Laboratory Procedures/Assessments .................................................................. 72
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 72
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations........................................ 74
7.1.3.3
Patient-Reported Outcomes (PROs) ............................................................ 74
7.1.3.4
Blood for RNA Analyses and Biomarker Analyses (plasma, serum).......... 74
7.1.3.5
Planned Genetic Analysis Sample Collection.............................................. 74
7.1.3.6
Future Biomedical Research Sample Collection ......................................... 75
Other Procedures................................................................................................. 75
7.1.4.1
Withdrawal/Discontinuation........................................................................ 75
Withdrawal From Future Biomedical Research ................................... 75
7.1.4.2
Blinding/Unblinding .................................................................................... 76
7.1.4.3
Calibration of Critical Equipment................................................................ 76
Visit Requirements.............................................................................................. 76
7.1.5.1
Screening...................................................................................................... 77
7.1.5.2
Treatment Period Visit................................................................................. 77
7.1.5.3
Post-Trial...................................................................................................... 77
Safety Follow-up Visit.......................................................................... 78
Follow-up Visits ................................................................................... 78
Survival Follow-up ............................................................................... 78
7.1.5.4
Survival Status ............................................................................................. 78
7.1.5.5
Second Course Phase................................................................................... 78
7.1.5.6
Crossover Phase........................................................................................... 79
7.1.5.7
Crossover Assessments and Procedures ...................................................... 80
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Assessing and Recording Adverse Events .......................................................... 80
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 81
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 81
Immediate Reporting of Adverse Events to the Sponsor.................................... 82
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 Adverse Event Reporting............ 83
Evaluating Adverse Events................................................................................. 84
Sponsor Responsibility for Reporting Adverse Events ...................................... 87
TRIAL GOVERNANCE AND OVERSIGHT................................................... 87
Scientific Advisory Committee........................................................................... 87
Executive Oversight Committee......................................................................... 87
Data Monitoring Committee............................................................................... 87
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 88
Statistical Analysis Plan Summary ..................................................................... 88
Responsibility for Analyses/In-House Blinding ................................................. 90
Hypotheses/Estimation......................................................................................... 90
Analysis Endpoints ............................................................................................... 90
Efficacy Endpoints.............................................................................................. 90
Safety Endpoints ................................................................................................. 91
Analysis Populations............................................................................................. 91
Efficacy Analysis Populations ............................................................................ 91
Safety Analysis Populations ............................................................................... 91
Statistical Methods................................................................................................ 92
Statistical Methods for Efficacy Analyses.......................................................... 92
8.6.1.1
Progression-Free Survival (PFS) ................................................................. 92
8.6.1.2
Overall Survival (OS) .................................................................................. 93
8.6.1.3
Objective response rate (ORR) and Duration of Response (DOR) ............. 94
8.6.1.4
Analysis Strategy for Key Efficacy Endpoints............................................ 94
Statistical Methods for Safety Analyses ............................................................. 95
Summaries of Demographic and Baseline Characteristics and Other 
Analyses.............................................................................................................. 97
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Interim Analyses ................................................................................................... 97
Multiplicity ............................................................................................................ 97
Objective Response Rate .................................................................................... 98
Progression-free Survival.................................................................................... 99
Overall Survival.................................................................................................. 99
Sample Size and Power Calculations ................................................................ 100
Subgroup Analyses and Effect of Baseline Factors ......................................... 101
Extent of Exposure.............................................................................................. 101
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 101
Investigational Product ...................................................................................... 101
Packaging and Labeling Information ............................................................... 102
Clinical Supplies Disclosure............................................................................... 102
Storage and Handling Requirements................................................................ 103
Discard/Destruction/Returns and Reconciliation ............................................ 103
Standard Policies................................................................................................. 103
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 104
Confidentiality..................................................................................................... 104
Confidentiality of Data ..................................................................................... 104
Confidentiality of Subject Records................................................................... 104
Confidentiality of Investigator Information...................................................... 104
Confidentiality of IRB/IEC Information........................................................... 105
Compliance with Financial Disclosure Requirements..................................... 105
Compliance with Law, Audit and Debarment ................................................. 105
Compliance with Trial Registration and Results Posting Requirements...... 107
Quality Management System............................................................................. 107
Data Management............................................................................................... 107
Publications ......................................................................................................... 108
11.0
LIST OF REFERENCES....................................................................................... 109
12.0
APPENDICES......................................................................................................... 113
Code of Conduct for Clinical Trials.................................................................. 113
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Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 116
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 120
List of Abbreviations .......................................................................................... 131
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............. 134
ECOG Performance Status................................................................................ 135
Country-specific Information: Extension Study in China.............................. 136
13.0
SIGNATURES......................................................................................................... 137
Sponsor's Representative ................................................................................... 137
Investigator.......................................................................................................... 137
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values..................................................... 31
Table 2
Trial Treatment.................................................................................................... 35
Table 3
Dose Modifications and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations................................................................... 39
Table 4
Pembrolizumab Monotherapy, Coformulations or IO Combinations Infusion 
Reaction Dose Modification and Treatment Guidelines ..................................... 43
Table 5
Imaging and Treatment after First Radiologic Evidence of PD.......................... 71
Table 6
Laboratory Tests.................................................................................................. 73
Table 7
Evaluating Adverse Events ................................................................................. 85
Table 8
Censoring Rules for Primary and Sensitivity Analyses of PFS .......................... 93
Table 9
Analysis Strategy for Key Efficacy Endpoints.................................................... 95
Table 10
Analysis Strategy for Safety Parameters............................................................. 96
Table 11
Summary of Interim and Final Analyses Strategy .............................................. 97
Table 12
Possible Alpha-levels and Approximate ORR Difference Required to 
Demonstrate Efficacy for ORR at IA1................................................................ 98
Table 13
Efficacy Boundaries and Properties for Progression-free Survival Analyses..... 99
Table 14
Efficacy Boundaries and Properties for Overall Survival Analyses ................. 100
Table 15
Product Descriptions ......................................................................................... 102
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LIST OF FIGURES
Figure 1
Study Schema...................................................................................................... 17
Figure 2
Imaging and Treatment for Clinically Stable Subjects After First Radiologic 
Evidence of PD Assessed by the Site.................................................................. 71
Figure 3
Type I Error Reallocation Strategy Following Closed Testing Principle ........... 98
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 08
25-JUL-2022
Global amendment, including China: Added language to allow participants in 
the crossover phase of the study to be eligible for second-course treatment 
with pembrolizumab and to allow participants in first-course follow-up to be 
eligible for second-course treatment for longer than 2 years.
Amendment  07
04-JAN-2022
Global amendment, including China: Added
language regarding the 
enrollment of subjects in a pembrolizumab extension study upon study 
completion.
Amendment 06
30-OCT-2019
China amendment: Interim results were positive and therefore subjects are to 
be given the option of discontinuing placebo treatment.
Amendment 05
28-JUN-2018
Global amendment: Interim results were positive and therefore subjects are to 
be given the option of discontinuing placebo treatment.
Amendment 04
20-NOV-2017
China amendment: The statistical design was updated to optimize the study 
for the identification of long-term treatment effect in OS and PFS.
Amendment 03
13-NOV-2017
The statistical design was updated to optimize the study for the identification 
of long-term treatment effect in OS and PFS.
Amendment 02
26-OCT-2017
The statistical design was updated to optimize the study for the identification 
of long-term treatment effect in OS and PFS.
Amendment 01
27-JUL-2017
China amendment: To extend the enrollment period beyond the global study 
to achieve required number of Chinese subjects and events to investigate 
efficacy and safety in Chinese NSCLC subjects.
Original Protocol
24-MAR-2016
Not applicable.
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
1.1
7.1.5.5
Trial Summary
Second Course Phase
Language
added 
to 
allow 
participants in the crossover 
phase of the study to receive 
second course treatment if 
eligible.
To 
expand 
the 
treatment 
opportunities of eligible study 
participants in the crossover 
phase.
7.1.5.3
Post-Trial
Specification 
that 
study 
participants will be followed 
for up to 2 years replaced with 
specification 
that 
study 
participants will be followed 
for disease status.
To allow study participants in 
first-course follow-up to be 
eligible 
for 
second-course 
treatment for longer than 2 
years.
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
Title Page
12.1
Title Page
Code of Conduct for Clinical 
Trials
Sponsor 
entity 
name 
and 
address changed.
Merck Sharp & Dohme Corp. 
underwent an entity name and 
address change to Merck Sharp 
& Dohme LLC, Rahway, NJ, 
USA. This conversion resulted 
only in an entity name change 
and update to the address.
5.1
Entry Criteria
Language 
related 
to 
the 
collection of demographic data 
added.
To clarify the collection, use, 
and confidentiality of 
demographic data provided by 
study participants.
5.1.2
5.7.2
Subject Inclusion Criteria
Contraception
Contraception 
requirements 
clarified.
To specify the requirements 
during and after treatment with 
chemotherapy vs. 
pembrolizumab.
5.2
Trial Treatments
Study 
intervention 
table 
updated.
To align with the EU CTR.
7.1.5.5
Second Course Phase
Eligibility for second course 
phase updated from 17 cycles 
to 35 treatments.
To align with the program 
standard.
Throughout as applicable
Throughout as applicable
Typographical corrections and 
minor 
administrative 
edits
made.
To correct typographical errors 
and clarify intended meaning.
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1.0 TRIAL SUMMARY
Abbreviated Title
Phase III study of carboplatin and paclitaxel or nano particle albumin-
bound paclitaxel (nab-paclitaxel) with or without pembrolizumab in first 
line metastatic squamous NSCLC.
Sponsor Product Identifiers
MK-3475
pembrolizumab
Trial Phase
Phase III
Clinical Indication
Treatment of metastatic squamous non-small cell lung cancer
Trial Type
Interventional
Type of control
Placebo-control
Route of administration
Intravenous
Trial Blinding
Double-blind
(Select Groups)
There are 2 treatment arms:

Pembrolizumab plus carboplatin and paclitaxel or nab-paclitaxel

Saline placebo plus carboplatin and paclitaxel or nab-paclitaxel
Number of trial subjects
Approximately 560 subjects will be enrolled in the global trial.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 4 years
from the time the first subject (or their legally acceptable representative) 
provides documented informed consent until the last subject’s last study-
related contact.
Duration of Participation
Each subject will participate in the study from the time the subject (or 
their legally acceptable representative) provides documented informed 
consent through the final contact. After a screening phase of up to 28 
days, eligible subjects will receive assigned treatment on Day 1 of each 3-
week (Q3W) dosing cycle. All subjects will receive up to a maximum of 
4 cycles of carboplatin, paclitaxel or nab-paclitaxel and pembrolizumab 
or saline placebo. Treatment with pembrolizumab or saline placebo will 
continue until total of 35 treatment administrations of pembrolizumab or
saline placebo 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 the trial treatment or procedure requirements 
or administrative reasons. Because of positive interim results, this study is 
being unblinded. Subjects assigned to the placebo arm may discontinue 
treatment with normal saline placebo and have the option of receiving 
pembrolizumab. Subjects on pembrolizumab arm will continue until total 
of 35 treatment administration.
Subjects who experience documented disease progression verified by 
central imaging vendor will have treatment assignment unblinded and be 
able to continue on open-label pembrolizumab monotherapy in the 
Crossover Phase. The details are outlined in Section 7.1.5.6.
Subjects who attain a complete response verified by central imaging 
vendor and have been on pembrolizumab/ therapy for ≥ 8 cycles, may
consider stopping trial treatment. These subjects, as well as those subjects 
assigned to the pembrolizumab arm or who crossover to the 
pembrolizumab arm who
stop trial therapy after 35 treatment 
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administrations for reasons other than disease progression or 
intolerability, may be eligible for re-treatment with pembrolizumab in the 
Second Course Phase after they have experienced radiographic disease 
progression at the discretion of the investigator according to the criteria in 
Section 7.1.5.5.
After the end of treatment, each subject will be followed for a minimum 
of 30 days for adverse event monitoring even if the subject started new 
antineoplastic treatment (serious adverse events will be collected for up to 
90 days following cessation of Sponsor’s product, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier). Subjects will have post-treatment follow-up for 
disease status, including radiographic imaging every 12 weeks, until 
initiating a non-study cancer treatment, experiencing disease progression, 
death, withdrawing consent, or becoming lost to follow-up.
All subjects will be followed for overall survival until death, lost to 
follow up or withdrawal of consent.
A list of abbreviations used in this document can be found in Section 12.4.
2.0 TRIAL DESIGN
Trial Design
This is a worldwide, randomized, placebo-controlled with active treatment, parallel-group, 
multi-site, double-blind trial of IV pembrolizumab (also known as MK-3475) combined with 
carboplatin-paclitaxel/nab-paclitaxel chemotherapy versus saline placebo combined with 
carboplatin-paclitaxel/nab-paclitaxel chemotherapy in subjects with metastatic squamous 
NSCLC who have not previously received systemic therapy for metastatic disease (1L).
Approximately 560 eligible subjects will be enrolled into this trial to examine the efficacy of 
pembrolizumab combined with chemotherapy compared to chemotherapy alone. Subjects 
will be randomized 1:1 as indicated below:
•
Arm 1: Pembrolizumab 200 mg (Day 1) + carboplatin AUC 6 (D1) + paclitaxel 200
mg/m2 (D1) OR nab-paclitaxel 100 mg/m2 (D1, D8, D15) Q3W for 4 cycles followed by 
pembrolizumab 200 mg (D1) Q3W until progression.
•
Arm 2: Saline placebo + carboplatin AUC 6 (D1) + paclitaxel 200 mg/m2 (D1) OR nab-
paclitaxel 100mg/m2 (D1, D8, D15) Q3W for 4 cycles followed by saline placebo (D1) Q3W
until progression.
Because of positive interim results, this study was unblinded so that subjects assigned to the 
placebo arm (Arm 2) may discontinue treatment with normal saline placebo and have the 
option of receiving pembrolizumab if there is documented progressive disease by central 
radiological review.
Randomization Ratio
Randomized 1:1 to either receive pembrolizumab combined with 
carboplatin and investigators choice of paclitaxel or nab-paclitaxel, or 
saline placebo combined with carboplatin and investigators choice of 
paclitaxel or nab-paclitaxel.
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Subjects will receive up to 4 cycles of pembrolizumab or saline placebo with chemotherapy 
followed by pembrolizumab or saline placebo Q3W as maintenance therapy. Please refer to 
Figure 1 for detailed study design.
Subjects will be stratified by paclitaxel vs. nab-paclitaxel, PD-L1 status (TPS ≥1% vs. <1%; 
PD-L1 non-evaluable subjects will be included with the TPS <1% group), and geographic 
region of the enrolling site (East Asia vs. non-East Asia) prior to randomization.
After randomization, subjects will be evaluated with radiographic imaging to assess response 
to treatment with the schedule outlined in Section 7.1.2.6.2; treatment-based decisions should 
be made using irRECIST (details are provided in Section 7.1.2.6.6 and the Merck TIP Sheet). 
All imaging obtained on study will be submitted to a blinded independent central imaging 
vendor who will assess the images using RECIST 1.1 for determination of ORR and PFS by 
RECIST 1.1. AE monitoring will be ongoing throughout the trial and graded in severity 
according to the guidelines outlined in the NCI CTCAE, version 4.0.
Treatment with pembrolizumab or saline placebo will continue until a total of 35 treatments 
have been administered, subject withdrawal, or other discontinuation criteria is met as 
outlined in Section 5.8.
Treatment-based decisions will be made by local radiological review based on irRECIST and 
the disease progression will be verified by central radiological review. At the time of 
documented progression verified by a blinded independent central imaging vendor review 
per RECIST 1.1, subjects will have treatment assignment unblinded and be able to continue 
therapy in the Crossover Phase as indicated below:
1. Subjects who had received saline placebo will be able to receive open-label 
pembrolizumab monotherapy for a total of 35 treatments.
2. Subjects who had received pembrolizumab, but are deemed to be benefiting 
clinically despite progression, will be able to receive open-label pembrolizumab 
monotherapy to complete a total of 35 treatments.
The details regarding Crossover Phase is outlined in Section 7.1.5.6.
Subjects who attain a CR verified by central radiological review may consider stopping trial 
treatment. These subjects, as well as those subjects assigned to the pembrolizumab arm or 
who crossover to the pembrolizumab arm who stop trial therapy after 35 treatment 
administrations for reasons other than disease progression or intolerability, may be eligible 
for re-treatment with open-label pembrolizumab monotherapy after they have experienced 
radiographic disease progression at the discretion of the investigator according to defined 
criteria in Section 7.1.5.5. This re-treatment will be the Second Course Phase. Response or 
progression in the Second Course Phase will not count toward the ORR and PFS endpoints in 
this trial.
After the end of treatment, each subject will be followed for a minimum of 30 days for AE 
monitoring. SAEs will be collected for up to 90 days after the end of treatment or 30 days 
following cessation of treatment if the subject initiates new cancer therapy, whichever is 
earlier. Subjects will have post-treatment follow-up for disease status, until initiating a non-
study cancer treatment, experiencing disease progression, death, withdrawing consent, or 
becoming lost to follow-up.
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This trial has dual primary endpoints: 1) PFS per RECIST 1.1 by a blinded independent
central imaging vendor review and 2) OS. The trial will be considered positive if the 
hypothesis test for either one of these primary endpoints is successful. Other secondary 
endpoints include ORR and DOR per RECIST 1.1 by a blinded independent central imaging 
vendor review, and safety as assessed by a variety of parameters of AEs. Exploratory 
analyses include PFS by investigator-assessed irRECIST, ORR by investigator-assessed 
irRECIST, PFS, OS and ORR in different PD-L1 subgroups and PFS, OS and ORR in 
subgroups based on the choice of taxane therapy. Drug-drug interaction studies and quality of 
life assessments are further exploratory endpoints.
Participation in this trial will be dependent upon supplying tumor tissue for PD-L1 testing. 
The details of tumor tissue requirements are outlined in Section 7.1.2.7. The specimen will be 
evaluated at a central laboratory facility for expression status of PD-L1 in a prospective 
manner to enable stratification. In terms of stratification, PD-L1 non-evaluable subjects will 
be grouped with the TPS <1% group.
There are 4 analyses planned for this study: 3 IAs and the final analysis. Results from the 3
IAs will be reviewed by an external data monitoring committee. The details regarding the 
timing and purpose of each analysis are provided in Section 8.7.
See Appendix 12.7 for country-specific information.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
Trial Diagram
The trial design is depicted in Figure 1.
Figure 1
Study Schema
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
In 1L subjects with metastatic squamous NSCLC receiving investigator’s choice of SOC
chemotherapy (ie, carboplatin and a taxane):
1. Objective: Evaluate progression free survival (PFS) per RECIST 1.1 as assessed by a 
central imaging vendor in subjects treated with pembrolizumab compared to placebo.
Hypothesis: Pembrolizumab prolongs PFS by RECIST 1.1 as assessed by a central 
imaging vendor compared to placebo.
2. Objective: Evaluate overall survival (OS) in subjects treated with pembrolizumab 
compared to placebo.
Hypothesis: Pembrolizumab prolongs OS compared to placebo.
Secondary Objective(s) & Hypothesis(es)
In 1L subjects with metastatic squamous NSCLC receiving investigator’s choice of SOC
chemotherapy (ie, carboplatin and a taxane):
1. Objective: Evaluate the objective response rate (ORR) and duration of response
(DOR) per RECIST 1.1 as assessed by a central imaging vendor in subjects treated 
with pembrolizumab compared to placebo.
Hypothesis: Pembrolizumab improves ORR per RECIST 1.1 as assessed by a central
imaging vendor compared to placebo.
2. Objective: Evaluate the safety and tolerability profile of pembrolizumab.
Exploratory Objectives 
In 1L subjects with metastatic squamous NSCLC receiving investigator’s choice of SOC of 
chemotherapy (ie, carboplatin and a taxane):
1) Objective: Evaluate pembrolizumab compared to placebo with respect to:
a.
PFS per RECIST 1.1 as assessed by investigator review in the next line of 
therapy (PFS2).
b. PFS per irRECIST as assessed by site investigator.
c.
ORR and DOR per irRECIST as assessed by site investigator.
d. PFS and ORR per RECIST 1.1 as assessed by central imaging vendor and OS
by PD-L1 status (≥1% vs. <1%) and by taxane (investigators choice of 
paclitaxel or nab-paclitaxel).
2) To investigate the relationship between pembrolizumab treatment and biomarkers 
predicting response (eg, PD-L2, genetic variation, serum PD-L1) utilizing newly 
obtained or archival FFPE tumor tissue and blood, including serum and plasma.
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3) To evaluate changes in health-related quality-of-life assessments from baseline in the 
overall study population and by PD-L1 expression level using the EORTC QLQ-C30 
and EORTC QLQ-LC13.
4) To characterize utilities in subjects treated with pembrolizumab and chemotherapy 
compared to saline placebo and chemotherapy using the EuroQoL(EQ)-5D.
5) To characterize the pharmacokinetic characteristics of carboplatin, paclitaxel/nab-
paclitaxel treatment, and pembrolizumab.
6) To identify molecular (genomic, metabolic and/or proteomic) biomarkers that may be 
indicative of clinical response/resistance, safety, pharmacodynamic activity, and/or 
the mechanism of action of pembrolizumab and other treatments.
4.0 BACKGROUND & RATIONALE
Background
Refer to the IB/approved labeling for detailed background information on MK-3475.
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [1]. Accumulating evidence shows a correlation 
between TILs in cancer tissue and favorable prognosis in various malignancies [2] [3] [4] [5]
[6] [7] [8]. In particular, the presence of CD8+ T cells and the ratio of CD8+ effector T cells / 
FoxP3+ regulatory T cells seems to correlate with improved prognosis and long-term 
survival in solid malignancies such as ovarian, colorectal and pancreatic cancer, 
hepatocellular carcinoma, malignant melanoma and RCC. TILs can be expanded ex vivo and 
re-infused, inducing durable objective tumor responses in cancers such as melanoma [9] [10].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T  
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2)
[11] [12]. The mechanism by which PD-1 down modulates T-cell responses is similar to, but 
distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling 
proteins [13] [14]. PD-1 was shown to be expressed on activated lymphocytes including 
peripheral CD4+ and CD8+ T cells, B cells, Tregs and natural killer cells [15] [16]. The 
ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a 
variety of cell types, including non-hematopoietic tissues as well as in various tumors. Both 
ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in the 
extracellular region and contain short cytoplasmic regions with no known signaling motifs. 
Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell 
receptor. PD-L1 is expressed at low levels on various non-hematopoietic tissues, most 
notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed on 
antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments. 
PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 
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serves to dampen unwarranted T-cell function in peripheral tissues [17]. 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 [18], pancreatic carcinoma [19], hepatocellular 
carcinoma [20], and ovarian carcinoma. [21] Furthermore, PD-1 has been suggested to 
regulate tumor-specific T-cell expansion in subjects with melanoma [22].
PD-1/PD-L1 pathway plays a critical role in tumor-immune evasion and should be 
considered as an attractive target for therapeutic intervention. The prognostic implications of 
PD-L1 expression in NSCLC are currently being investigated in ongoing epidemiologic 
studies as well as KEYNOTE-001 and KEYNOTE-010,
the Phase 2/3
trial of 
pembrolizumab vs. docetaxel in previously treated subjects with advanced or metastatic 
NSCLC.
Pre-clinical and Clinical Trials
Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated anti-tumor responses 
as a monotherapy in models of squamous cell carcinoma, pancreatic carcinoma, melanoma,
and colorectal carcinoma. Blockade of the PD-1 pathway effectively promoted CD8+ T-cell 
infiltration into the tumor and the presence of IFN-gamma, granzyme B and perforin, 
indicating that the mechanism of action involved local infiltration and activation of effector 
T-cell function in vivo [21] [23] [24] [25] [26] [27]. In-house experiments have confirmed 
the in vivo efficacy of PD-1 blockade as a monotherapy as well as in combination with 
chemotherapy in syngeneic mouse tumor models (see the IB).
Pembrolizumab is a highly selective humanized mAb that binds to the PD-1 receptor and 
directly blocks the interaction between PD-1 and its ligands, thereby enhancing tumor 
regression and ultimately immune rejection (see the IB). Pembrolizumab is being 
investigated in various oncology indications including melanoma, NSCLC, RCC, breast 
cancer, multiple myeloma, microsatellite unstable tumors, and head and neck cancer. 
Pembrolizumab [Keytruda (US)], is approved for treatment of melanoma in several 
countries; in the US it is indicated for the treatment of advanced, unresectable or metastatic 
malignant melanoma in subjects with disease progression after prior treatment with 
ipilimumab and, for BRAF V600 mutation-positive patients, a BRAF inhibitor, while in the 
EU it is approved for the treatment of advanced (unresectable or metastatic) melanoma in 
adults. Pembrolizumab has also been granted approval in the US for the treatment of subjects 
with metastatic NSCLC whose tumors express PD-L1 as determined by an FDA-approved 
test and who have disease progression on or after platinum-containing chemotherapy.
An open-label Phase 1 trial (KEYNOTE-001) is being conducted to evaluate the safety and 
clinical activity of single-agent pembrolizumab. The dose escalation portion of this trial 
evaluated 3 dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks, in 
subjects with advanced solid tumors. All 3 dose levels were well tolerated and no DLTs were 
observed. Based on PK data showing a half-life of 21 days, the dosing frequency in the 
expansion cohort has been changed to Q3W [28].
In the same open-label multi-cohort Phase 1 trial (KEYNOTE-001), a total of 550 NSCLC 
subjects were treated with at least 1 dose of pembrolizumab in several dose expansion 
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cohorts. The initial data from 495 NSCLC subjects were published and reported. The ORR
was 19.4% (18.0% in the 394 previously-treated subjects and 24.8% in the 101 
previously-untreated subjects). The response rate was similar regardless of dose, schedule, 
and histologic analysis. Current or former smokers had a response rate of 22.5%, as 
compared with 10.3% among subjects who had never smoked cigarettes.
Subjects were required to submit a newly obtained tumor biopsy prior to initiating therapy 
with pembrolizumab to evaluate the tumors for expression of PD-L1. After evaluation of 
several methods for pathological assessment, in a training set, membranous PD-L1 
expression in at least 50% of tumor cells (TPS ≥50%) was selected as the cutoff point 
defining PD-L1 high. In a validation set of 313 subjects, the response rate was 45.2% in the 
73 subjects with a TPS of at least 50%, including 43.9% in previously-treated subjects and 
50.0% in previously-untreated subjects, values that numerically exceeded the response rate in 
the training group [29].
Pembrolizumab has been generally well tolerated. The most common treatment-related AEs 
were fatigue (19.4%), pruritus (10.7%), and decreased appetite (10.5%). Adverse events of 
Grade 3 or higher were reported in 47 of 495 subjects (9.5%). The only treatment-related 
AEs of an inflammatory or immune-mediated nature that occurred in more than 2% of 
patients were infusion-related reactions (in 15 patients [3.0%]), hypothyroidism (in 34 
patients [6.9%]), and pneumonitis (in 18 patients [3.6%]). One infusion reaction led to 
treatment discontinuation. All the patients with hypothyroidism were successfully treated 
with medical therapy [28].
Ongoing Clinical Trials
A number of clinical trials are exploring the value of pembrolizumab monotherapy compared 
to standard chemotherapy in a PD-L1-enriched population, both as second-line therapy 
(KEYNOTE-010) 
and 
first-line 
therapy 
(KEYNOTE-024 
and 
KEYNOTE-042). 
Pembrolizumab monotherapy compared to placebo is also being evaluated in patients with 
early-stage NSCLC after resection and completion of standard adjuvant therapy
(KEYNOTE-091).
Several ongoing trials are exploring different combinations of pembrolizumab with 
chemotherapy, targeted therapy and other immunotherapy. An ongoing Phase 1b/2 study 
(KEYNOTE-021) explored different chemotherapy combinations with pembrolizumab; 
preliminary data presented at ASCO 2015 suggest a manageable toxicity profile. In Cohort A 
of KEYNOTE-021, 25 subjects with NSCLC were treated with 4 cycles of carboplatin, 
paclitaxel, and pembrolizumab followed by maintenance pembrolizumab Q3W. There were
no DLTs or treatment-related deaths reported in Cohort A. Approximately 96% of patients 
experienced ≥1 treatment-related AE of any grade with the most common treatment-related 
AEs being alopecia, fatigue, and nausea. Overall, the toxicity profile from the combination 
was compatible with what would be expected with chemotherapy alone. The preliminary data 
using investigator-assessed response rate based on RECIST 1.1 was 25% in all comers and 
the responses were durable. In the exploratory analysis of 9 subjects with squamous cell 
NSCLC, the ORR was 55.6 % (95% CI: 21.2 to 86.3) with a disease control rate of 100%; 
median PFS and DOR were not reached. Responses were seen in both PD-L1 positive and 
PD-L1 negative patients. An ongoing Phase 1b/2 study (KEYNOTE-026) is exploring the 
combination of pembrolizumab with carboplatin and nab-paclitaxel. Preliminary safety 
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results from this trial show that the combination of carboplatin/nab-paclitaxel and 
pembrolizumab was safe and tolerable and the most common AEs were hematologic 
toxicities. Two of the initial 12 subjects treated in the Phase 1 portion of the study had a 
DLT: Grade 4 hyperglycemia and Grade 3 febrile neutropenia. The Phase 2 portion of the 
study is ongoing.
Information on Other Trial-Related Therapy
Platinum doublet chemotherapy is the SOC for the treatment of patients with good 
performance status (ECOG 0 or 1), advanced or metastatic, previously untreated squamous 
NSCLC. Treatments include cisplatin or carboplatin in combination with paclitaxel, 
gemcitabine, or docetaxel [30]. Multiple Phase 3 studies have demonstrated similar efficacy 
for most platinum doublets in NSCLC patients, Study ECOG 1594 being the most cited [31].
A meta-analysis of randomized controlled clinical trials compared chemotherapy regimens 
containing either cisplatin or carboplatin in combination with third generation antineoplastic 
agents including docetaxel, paclitaxel, and gemcitabine. Cisplatin-containing regimens were 
associated with a median survival of 9.1 months and a 1-year survival probability of 37%, 
while carboplatin-containing regimens were associated with a median survival of 8.4 months 
and a 1-year survival probability of 34%. The risk of death was higher with carboplatin 
compared with cisplatin, although the difference was not statistically significant (HR, 1.07;
95% CI: 0.99 to 1.15; p=0.10). These data support the interchangeable use of carboplatin or 
cisplatin in combination with SOC antineoplastic agents [32].
A randomized Phase 3 trial compared the efficacy and safety of nab-paclitaxel plus 
carboplatin with sb-paclitaxel plus carboplatin in advanced NSCLC. A total of 1,052 
untreated subjects with Stage IIIB to IV NSCLC were randomly assigned 1:1 to receive 100 
mg/m2 nab-paclitaxel weekly and carboplatin at AUC of 6 Q3W (nab-paclitaxel) or 200 
mg/m2 sb-paclitaxel plus carboplatin AUC 6 Q3W (sb-paclitaxel). The primary end point 
was ORR. The ORR in the nab-paclitaxel and sb-paclitaxel arms were 33% vs. 25%
respectively (response rate ratio, 1.313; 95% CI: 1.082 to 1.593). In subjects with squamous 
histology, the ORR was 41% vs. 24% (response rate ratio, 1.680; 95% CI: 1.271 to 2.221). 
However, there were no significant differences in PFS (median, 6.3 vs. 5.8 months; HR, 
0.902; 95% CI: 0.767 to 1.060; p=0.214) and OS (median, 12.1 vs. 11.2 months; HR, 0.922; 
95% CI: 0.797 to 1.066; p=0.271) in the nab-paclitaxel arm versus the sb-paclitaxel arm, 
respectively. Significantly less Grade 3 neuropathy, neutropenia, arthralgia, and myalgia 
occurred in the nab-paclitaxel arm, and less thrombocytopenia and anemia occurred in the sb-
paclitaxel arm [33].
Recently, an open-label, randomized, active controlled Phase 2 trial evaluated nab-paclitaxel
and carboplatin compared with gemcitabine and carboplatin as first-line therapy in locally 
advanced or metastatic squamous NSCLC. A total of 120 untreated advanced squamous 
NSCLC subjects were randomized at a 1:1 ratio to receive nab-paclitaxel (135 mg/m2, D1, 
D8, Q3W) plus carboplatin (AUC 5, D1, Q3W) or gemcitabine (1,250 mg/m2, D1, D8, Q3W) 
and carboplatin (AUC 5, D1, Q3W). The primary endpoint was ORR and the secondary
endpoints were PFS, OS, safety, and biomarkers associated with nab-paclitaxel. The 
preliminary results from this trial were presented at ASCO 2014. There were 110 cases 
evaluable for ORR (nab-paclitaxel, 54; gemcitabine, 56), 119 evaluable for OS (nab-
paclitaxel, 57; gemcitabine, 62) and 124 evaluable for safety (nab-paclitaxel, 59; 
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gemcitabine, 65), respectively. ORR was 46.3% (25/54) for the nab-paclitaxel arm and 
30.4% (17/56) for the gemcitabine arm respectively, p=0.085. The median PFS was 5.7 vs.
4.8 months (HR, 0.907; 95% CI: 0.588 to 1.399; p=0.657) in the nab-paclitaxel arm vs. the 
gemcitabine arm. Overall survival was not mature [34].
Recently, a large, randomized trial evaluated necitumumab, a second-generation, mAb
against EGFR in subjects with previously untreated Stage IV squamous NSCLC. In this
study, 1093 subjects were randomly assigned to receive necitumumab plus gemcitabine and 
cisplatin (n=545) or gemcitabine and cisplatin (n=548). The ORR was 31% in the 
necitumumab plus chemotherapy and 29% in the chemotherapy alone arms, respectively. The 
median PFS was 5.7 months (95% CI: 5.6 to 6.0) and 5.5 months (95% CI: 4.8 to 5.6) in the 
necitumumab plus chemotherapy and the chemotherapy alone arms, respectively. However, 
there was a statistically significant improvement in OS in the necitumumab plus 
chemotherapy arm with a median OS of 11·5 months (95% CI: 10·4 to 12·6) vs. 9·9 months 
(95% CI: 8·9 to 11·1); stratified HR, 0.84 (95% CI: 0·74 to 0·96; p=0·01). In the 
necitumumab plus chemotherapy arm, the number of subjects with at least 1 Grade 3 or 
worse AE was higher (388 [72%] of 538 subjects) than in the chemotherapy alone arm (333 
[62%] of 541 subjects), as was the incidence of SAEs (257 [48%] of 538 subjects vs. 203 
[38%] of 541 subjects). More subjects in the necitumumab plus chemotherapy arm than in 
the chemotherapy alone arm had Grade 3–4 hypomagnesaemia (47 [9%] of 538 subjects vs. 6
[1%] of 541 subjects) and Grade 3 rash (20 [4%] of 538 subjects vs. 1 [<1%] of 541 subjects) 
[35].
Rationale
Rationale for the Trial and Selected Subject Population
Lung cancer accounted for an estimated 13% of total cancer diagnoses, representing 1.8 
million new cases in 2012. Mortality from lung cancer in 2012 amounted to 1.6 million 
deaths globally: the leading cause of cancer death in men and the second leading cause in 
women [36]. NSCLC accounts for approximately 85% of all lung cancer cases, with 25% of 
these being squamous cell NSCLC.
Progress has been made in the clinical management of early-stage NSCLC by establishing 
comprehensive, multi-modality treatment regimens; however, the prognosis for advanced 
disease has not improved substantially. With an overall 5-year survival rate of 9% to 13%
[37]
the treatment of NSCLC remains a highly unmet medical need. Cytotoxic 
chemotherapies as single agents or in combination have served as the mainstay of treatment 
for decades with platinum-containing doublets conferring the greatest advances in overall 
survival gains.
Molecular profiling has, however, established a definite role for EGFR- and ALK-directed 
therapy in a subset of non-squamous NSCLC patients. The EGFR tyrosine kinase inhibitors 
gefitinib, erlotinib and afatinib have demonstrated marked superiority over chemotherapy in 
patients with activating EGFR mutations. In addition, agents that overcome resistance to 
initial therapy are also in development. Similarly, ALK inhibitors crizotinib and ceritinib 
have shown significant activity in ALK-rearranged NSCLC with more agents in 
development. Interestingly, the ALK inhibitors are also active in a rare subgroup of ROS-1 
rearranged NSCLC patients. However, these molecular aberrations are very uncommon in 
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patient with squamous cell NSCLC. Current guidelines do not recommend routine testing for 
EGFR and ALK in squamous cell NSCLC patients.
Compared to non-squamous NSCLC, the first-line treatment options for patients with 
squamous cell NSCLC are somewhat limited. Newer anti-metabolites like pemetrexed have
little or no activity in squamous cell patients and anti-angiogenic therapies like bevacizumab 
are not used due to toxicity concerns including major pulmonary hemorrhage. A 
platinum-based doublet with either a taxane or gemcitabine remains the mainstay first-line 
therapy for chemo-naïve and recurrent patients. Recently, necitumumab in combination with 
gemcitabine and cisplatin was approved by the FDA based on the trial outlined in Section 
4.1.4. The absolute benefit from addition of necitumumab to platinum doublet remains small 
and is not widely used yet due to toxicity concerns as well as the need to use cisplatin-based 
therapy. Newer chemotherapy combination options with better efficacy results and improved 
safety and tolerability outcome are needed in first-line therapy for Stage IV squamous cell 
NSCLC.
The current study will include patients with Stage IV squamous cell NSCLC as outlined in 
detail in the Section 5.1.2.
A platinum doublet with a taxane or gemcitabine is the most commonly used first-line 
therapy for chemo-naïve metastatic squamous NSCLC patients. Carboplatin with either 
paclitaxel or nab-paclitaxel is one of the accepted standard options for these patients. Based 
on preliminary safety and efficacy data from combination studies with pembrolizumab and 
other PD-L1 inhibitors, the current study will utilize the carboplatin and investigator’s choice 
of either paclitaxel or nab-paclitaxel at approved doses as the chemo-backbone in both arms
of the study.
Rationale for Dose Selection/Regimen/Modification
The planned dose of pembrolizumab for this trial is 200 mg Q3W. Based on the totality of 
data generated in the Keytruda development program, 200 mg Q3W is the appropriate dose 
of pembrolizumab across all indications and regardless of tumor type. As outlined below, this 
dose is justified by: 

Clinical data from eight randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg Q2W;

Clinical data showing meaningful improvement in benefit-risk including OS at 200 
mg Q3W across multiple indications; and

Pharmacology data showing full target saturation in both systemic circulation 
(inferred from PK data) and tumor (inferred from physiologically-based PK analysis) 
at 200 mg Q3W.
Among the 8 randomized dose-comparison studies, a total of 2262 subjects were enrolled 
with melanoma and NSCLC, covering different disease settings (treatment-naïve, previously 
treated, PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and 
in combination with chemotherapy). Three studies compared 2 mg/kg Q3W vs. 10 mg/kg 
Q2W (KN001 B2, KN001 D, and KN021), and 3 studies compared 10 mg/kg Q3W vs. 10 
mg/kg Q2W (KN001 B3, KN001 F2, and KN006). All of these studies demonstrated flat 
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dose- and exposure-response relationships across the doses studied representing an 
approximate 5 to 7.5 fold difference in exposure. The 2 mg/kg (or 200 mg fixed-dose) Q3W 
provided similar responses to the highest doses studied. Subsequently, flat dose-/exposure-
response relationships were also observed in other tumor types including head and neck 
cancer, bladder cancer, gastric cancer, and classical Hodgkin Lymphoma, confirming 200 mg 
Q3W as the appropriate dose independent of the tumor type. These findings are consistent 
with the mechanism of action of pembrolizumab, which acts by interaction with immune 
cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KEYNOTE-001 evaluating TMDD conclusively demonstrated saturation of PD-1 in 
systemic circulation at doses much lower than 200 mg Q3W. Secondly, a 
physiologically-based PK analysis was conducted to predict tumor PD-1 saturation over a 
wide range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other subject covariates on exposure, has shown that fixed-dosing provides
similar control of PK variability as weight-based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose.
Supported by these PK characteristics, and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across all pembrolizumab protocols.
4.2.2.1
Rationale for the Use of Placebo
The use of saline placebo in combination with standard chemotherapy will ensure the 
objectivity 
of 
investigator-assessed 
progression 
as 
well 
as 
any 
decisions 
to 
interrupt/discontinue therapy. Since randomization and placebo use can be a perceived 
barrier to subject enrollment, crossover is allowed at time of documented disease 
progression. Due to positive interim results, subjects who are still on study intervention will 
be allowed to be unblinded, and subjects in the saline placebo arm will be allowed to 
discontinue saline placebo treatment and have the option of receiving pembrolizumab.
Rationale for Endpoints
4.2.3.1
Efficacy Endpoints
Primary: This trial has dual primary endpoints of PFS and OS. The trials will be considered 
positive if hypothesis test for either one of these primary endpoints is successful.
PFS is an acceptable measure of clinical benefit for a randomized Phase 3 trial that 
demonstrates superiority of a new antineoplastic therapy, especially if the magnitude of 
effect is large and the therapy has an acceptable risk-benefit profile. Furthermore, it is an 
endorsed regulatory endpoint for first-line NSCLC trials with recent FDA and EMA 
approvals including the EGFR inhibitors afatinib and erlotinib. PFS will be assessed per 
RECIST 1.1 by a blinded independent central imaging vendor that will be blinded to the 
treatment assignment to minimize any bias in the response assessments. In addition, final 
determination of radiologic PD will be based on the blinded independent central imaging 
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vendor assessment of progression, rather than local site investigator/radiology assessment. 
Expedited assessment by the blinded independent central imaging vendor in instances of 
suspected radiological progression identified at the site (verification of PD) will be 
communicated to the study team. The crossover arm as well as the approval of nivolumab
and pembrolizumab in the second-line setting will make subject crossover to a PD-1/PD-L1 
agent from the control group almost certain and may make the ability to measure OS reliably
challenging. However, OS is an important endpoint in the treatment of metastatic NSCLC 
and this trial will evaluate both PFS and OS as dual primary endpoints as outlined in detail in 
Section 8.0 Statistical Analysis Plan.
Secondary: ORR by RECIST 1.1 criteria as assessed by blinded independent central 
radiology review and DOR by RECIST 1.1 as assessed by blinded central radiologists’ 
review will serve as additional measures of efficacy. In a recent exploratory analysis of best 
RECIST response and survival in patients with metastatic squamous NSCLC treated with a 
PD-1 inhibitor, there was correlation between response and OS.
4.2.3.2
Immune-related RECIST (irRECIST)
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
with treatment of pembrolizumab. Immunotherapeutic agents such as pembrolizumab may 
produce antitumor effects by potentiating endogenous cancer-specific immune responses. 
The response patterns seen with such an approach may extend beyond the typical time course 
of responses seem with cytotoxic agents, and can manifest a clinical response after an initial 
increase in tumor burden or even the appearance of new lesions.
Standard RECIST 1.1 may, thus, not provide a complete response assessment of 
immunotherapeutic agents such as pembrolizumab. Based on an analysis of patients with 
melanoma enrolled in KEYNOTE-001, 7% of evaluable subjects experienced delayed or 
early tumor pseudo-progression. Of note, subjects who had progressive disease by RECIST 
1.1 but not by irRECIST had longer OS than subjects with progressive disease by both 
criteria. Additionally, the data suggest that RECIST 1.1 may underestimate the benefit of 
pembrolizumab in approximately 15% of subjects. These findings support the need to apply a 
modification to RECIST 1.1 that takes into account the unique patterns of atypical response 
in immunotherapy and enable treatment beyond initial radiographic progression. However, it 
is not clear whether the same pattern will be observed in combination with chemotherapy, 
hence RECIST 1.1 will remain the primary assessment method.
irRECIST is RECIST 1.1 adapted to account for the unique tumor response seen with 
immune-therapeutics as described in [38]. The assessment of unidimensional target lesions 
and response categories per irRECIST are identical to RECIST 1.1. However, MSD has 
implemented an adaptation related to new lesions, non-target and tumor burden assessment in 
order to confirm radiographic progression. irRECIST will be used by local site investigators 
to assess tumor response and progression, and make treatment decisions (see Section 
7.1.2.6.6 for details).
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4.2.3.3
Patient Reported Outcomes
EORTC QLQ-C30 and EORTC QLQLC13
The EORTC QLQ-C30 was developed to assess the quality of life of cancer subjects and is 
the most widely used cancer-specific HRQoL instrument. It contains 30 items and measures 
5 functional dimensions (physical, role, emotional, cognitive, and social), 3 symptom items 
(fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, sleep disturbance, appetite 
loss, constipation, diarrhea, and financial impact) and global health and quality of life. The 
global health and quality of life scale uses a 7-point scale scoring with anchors (1=very poor 
and 7=excellent); the other items are scored on a 4-point scale (1=not at all, 2=a little, 3= 
quite a bit, 4=very much).
The EORTC QLQ-LC13, a supplemental lung cancer-specific module used in combination 
with QLQ-C30, comprises multi-item and single-item measures of lung cancer-associated 
symptoms (cough, hemoptysis, dyspnea, and site specific pain) and treatment-related 
symptoms (sore mouth, dysphagia, peripheral neuropathy and alopecia) [39]. It is scored on a 
4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much) and has been translated and 
validated into more than 60 languages.
The EORTC QLQ-C30 and QLQ-LC13 are the most frequently utilized and reported patient-
reported outcome measures in lung cancer clinical trials. The reliability, validity and 
practicality of these instruments have been reported [39] [40].
EuroQol (EQ)-5D
The EuroQol-5D (EQ-5D) is a standardized instrument for use as a measure of health 
outcome. The EQ-5D will provide data for use in economic models and analyses including 
developing health utilities or QALYs. The 5 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 3-point scale from 1 (extreme problem) to 3 
(no problem). The EQ-5D also includes a graded (0 to 100) vertical visual analog scale on 
which the subject rates his or her general state of health at the time of the assessment. The 
EQ-5D will always be completed by subjects first before completing the EORTC QLQ-C30 
and EORTC QLQ-LC13.
4.2.3.4
Safety Endpoints
The safety objective of this study is to characterize the safety and tolerability of 
pembrolizumab
in combination with carboplatin and paclitaxel or nab-paclitaxel 
chemotherapy in subjects not previously systemically treated for squamous NSCLC. The 
safety analysis will be based on subjects who have toxicities as defined by the CTCAE,
version 4.0.
The attribution to drug, time-of-onset, duration of the event, its resolution, and any 
concomitant medications administered will be recorded. AEs will be analyzed including, but 
not limited to, all AEs, SAEs, fatal AEs, and laboratory changes. Furthermore, specific 
events will be collected and designated as ECIs as described in Section 7.2.3.2.
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The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study treatment or before the initiation of new anti-neoplastic treatment, 
whichever is earlier. All AEs that occur prior to the Safety Follow-up Visit should be 
recorded. Subjects with an AE of Grade >1 will be followed until the resolution of the AE to 
Grade 0-1 or until the beginning of a new anti-neoplastic therapy, whichever is earlier. SAEs 
that occur within 90 days following cessation of treatment or 30 days following cessation of 
treatment if the subject initiated new anti-neoplastic therapy, whichever is earlier, should be 
followed and recorded.
4.2.3.5
Planned Exploratory Biomarker Research
Introduction: Cancer immunotherapies represent an important and novel class of anti-tumor 
agents. However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating patients. Thus, to aid future patients, it is important to investigate the determinants 
of response or resistance to cancer immunotherapy as well as determinants of adverse events 
in 
the 
course 
of 
our 
clinical 
trials. 
These 
efforts 
will 
identify 
novel 
predictive/pharmacodynamic biomarkers and generate information that will better guide 
single agent and combination therapy with immuno-oncology drugs. To identify novel 
biomarkers, we will collect biospecimens (blood components, tumor material, etc.) to support 
analyses of cellular components (eg, protein, DNA, RNA, metabolites) and other circulating 
molecules. Investigations may include but are not limited to:
Germline (blood) genetic analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing): This research will evaluate whether genetic variation within a clinical 
trial population correlates with response to the treatment(s) under evaluation. If genetic 
variation is found to predict efficacy or AEs, the data might inform optimal use of therapies 
in the patient population. Furthermore, it is important to evaluate germline DNA variation 
across the genome in order to interpret tumor-specific DNA mutations. Finally, MSI may be 
evaluated as this is an important biomarker for some cancers (ie, colorectal cancer).
Genetic (DNA) analyses from tumor: The application of new technologies, such as next 
generation sequencing, has provided scientists the opportunity to identify tumor-specific 
DNA changes (ie, mutations, methylation status, MSI, etc.). Key molecular changes of 
interest to immune-oncology drug development include (for example) the mutational burden 
of tumors and the clonality of T cells in the tumor microenvironment. Increased mutational 
burden (sometimes referred to as a ‘hyper-mutated’ state) may generate neo-antigen 
presentation in the tumor microenvironment. To conduct this type of research, it is important 
to identify tumor-specific mutations that occur across all genes in the tumor genome. Thus, 
genome wide approaches may be used for this effort. Note that in order to understand tumor-
specific mutations; it is necessary to compare the tumor genome with the germline genome. 
MSI may also be evaluated as this is an important biomarker for some cancers (ie, colorectal 
cancer).
Tumor and blood RNA analyses: Both genome-wide and targeted mRNA expression 
profiling and sequencing in tumor tissue and in blood may be performed to define gene 
signatures that correlate to clinical response to treatment with pembrolizumab or other 
immunotherapies. Pembrolizumab induces a response in tumors that likely reflects an 
inflamed/ immune phenotype. Specific immune-related gene sets (such as those capturing 
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IFN-gamma transcriptional pathways) may be evaluated and new signatures may be 
identified. Individual genes related to the immune system may also be evaluated (eg, IL-10). 
MicroRNA profiling may also be pursued.
Proteomics and IHC using blood or tumor: Tumor and blood samples from this study may 
undergo proteomic analyses (eg, PD-L1 IHC). PD-L1 protein level in tumor sections,
assessed by IHC, has been shown to correlate with response to pembrolizumab in patients 
with NSCLC, and an IVD device has been developed for use with pembrolizumab in 
NSCLC. Preliminary data indicates that this association may also be true in additional cancer 
types (ie, TNBC, head and neck, and gastric). Additional tumor or blood-derived proteins 
may also correlate with response to pembrolizumab. Therefore, tumor tissue may be 
subjected to proteomic analyses using a variety of platforms that could include but are not 
limited to immunoassays, liquid chromatography/mass spectrometry. This approach could 
identify novel protein biomarkers that could aid in patient selection for pembrolizumab (MK-
3475) therapy.
Other blood-derived biomarkers:
In addition to expression on the tumor tissue, PD-L1 and other tumor-derived proteins can be 
shed from tumor and released into the blood. Assays such as enzyme-linked immunoassay 
measure such proteins in serum. Correlation of expression with response to pembrolizumab 
therapy may identify new approaches for predictive biomarkers in blood, representing a 
major advance from today’s reliance on assessing tumor biomarkers. This research would 
serve to develop such assays for future clinical use.
4.2.3.6
Future Biomedical Research
The Sponsor will conduct FBR on specimens for which consent was provided during this 
study.  This research may include genetic analyses (DNA), gene expression profiling (RNA), 
proteomics, metabolomics (serum, plasma) and/or the measurement of other analytes, 
depending on which specimens are consented for FBR.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure that subjects receive the correct dose of the 
correct drug/vaccine at the correct time.  The details of FBR are presented in Section 12.2 -
Collection and Management of Specimens for Future Biomedical Research.  Additional 
informational material for institutional review boards/ethics committees (IRBs/ERCs) and 
investigational site staff is provided in Section 12.3.
Benefit/Risk
Subjects in clinical trials generally cannot expect to receive direct benefit from 
treatment/vaccination during participation, as clinical trials are designed to provide 
information about the safety and effectiveness of an investigational medicine.
As described in Sections
4.1.2.
and 4.1.3 (preliminary) study results show that 
pembrolizumab in combination with chemotherapy have significant clinical activity as 
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first-line therapy in patients with advanced NSCLC. Considering the high unmet medical 
need for new and tolerable treatment options in patients with Stage IV squamous NSCLC, 
the anti-tumor activity and the favorable safety profiles, the existing data suggests that a 
combination of PD-1 blockade with chemotherapy is a promising therapeutic strategy and the 
benefit-risk assessment for patients included into this trial is considered to be favorable.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying IB and informed consent documents.
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male/Female subjects with squamous NSCLC who have not received prior systemic 
chemotherapy treatment for their metastatic NSCLC and who are at least 18 years of age will 
be enrolled in this trial.
Subject Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant meets all of the 
following criteria:
1. Have a histologically or cytologically confirmed diagnosis of Stage IV (M1a or M1b-
AJCC 7th edition) squamous NSCLC. Patients with mixed histology (example 
adenosquamous) are allowed if there is squamous component in the specimen.
2. Have measurable disease based on RECIST 1.1 as determined by the local site 
investigator/radiology assessment. Target lesions situated in a previously irradiated 
area are considered measurable if progression has been demonstrated in such lesions.
3. Have not received prior systemic treatment for their metastatic NSCLC. Subjects who 
received adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant 
therapy was completed at least 12 months prior to the development of metastatic 
disease.
4. Have provided tumor tissue from locations not radiated prior to biopsy; formalin-
fixed specimens after the subject has been diagnosed with metastatic disease will be 
preferred for determination of PD-L1 status prior to randomization. Biopsies obtained 
prior to receipt of adjuvant/neoadjuvant chemotherapy will be permitted if recent 
biopsy is not feasible.
5. Be ≥18 years of age on day of providing documented informed consent.
6. Have a life expectancy of at least 3 months.
7. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group 
(ECOG) Performance Status.
8. Have adequate organ function as indicated by the following laboratory values (Table 1):
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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
≥9.0 g/dL or ≥5.6 mmol/L– 4 weeks without transfusions
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
Serum total bilirubin
≤1.5xULN OR
Direct bilirubin ≤ULN for subjects with total bilirubin levels 
>1.5xULN
AST (SGOT) and ALT (SGPT)
≤2.5xULN OR
≤5xULN for subjects with liver metastases
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
Activated Partial Thromboplastin Time 
(aPTT) or Partial Thromboplastin Time (PTT)
≤1.5 × ULN unless subject is receiving anticoagulant therapy as 
long as PT or aPTT is within therapeutic range of intended use 
of anticoagulants
a. Creatinine Clearance should be calculated per institutional standard
9. If female of childbearing potential (Section 5.7.2), have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication. If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.
10. If female of childbearing potential (Section 5.7.2), be willing to use an adequate 
method of contraception as outlined in Section 5.7.2-Contraception, for the course of 
the study through 120 days after the last dose of pembrolizumab or 180 days after the 
last dose of chemotherapy, whichever is longer.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
11. If male subject with a female partner(s) of child-bearing potential, must agree to use 
an adequate method of contraception as outlined in Section 5.7.2-Contraception, 
starting with the first dose of chemotherapy through 95 days after the last dose of 
chemotherapy. If male subject with a pregnant partner(s), must agree to use a condom
starting with the first dose of chemotherapy through 95 days after the last dose of 
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chemotherapy; no additional method of contraception is required for the pregnant 
partner.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
12. Subject (or legally acceptable representative) has provided documented informed 
consent/assent for the trial. The subject may also provide consent/assent for Future 
Biomedical Research. However, the subject may participate in the main trial without 
participating in Future Biomedical Research.
Subject Exclusion Criteria
The participant must be excluded from the study if the participant meets any of the following 
criteria:
1. Has non-squamous histology NSCLC. Mixed tumors will be categorized by the 
predominant cell type. If small cell elements are present, the subject is ineligible. For 
non-small cell histology, if there is any squamous element present (example 
adenosquamous), the subject is eligible; the squamous element does not have to be 
predominant.
2. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks prior to administration of pembrolizumab.
3. Before the first dose of trial treatment:
a) Has received prior systemic cytotoxic chemotherapy for metastatic disease.
b) Has received other targeted or biological antineoplastic therapy (eg, erlotinib, 
crizotinib, cetuximab) for metastatic disease.
c) Had major surgery (<3 weeks prior to first dose).
4. Received radiation therapy to the lung that is >30 Gy within 6 months of the first 
dose of trial treatment.
5. Completed palliative radiotherapy within 7 days of the first dose of trial treatment.
6. Is expected to require any other form of antineoplastic therapy while on study.
7. Has received a live-virus vaccination within 30 days of planned treatment start. 
Seasonal flu vaccines that do not contain live virus are permitted.
8. Has a known history of prior malignancy except if the subject 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 the study. 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, in situ cervical cancer, or other in situ cancers.
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9. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate 
provided they are clinically stable for at least 2 weeks and, have no evidence of new 
or enlarging brain metastases and also are off steroids 3 days prior to dosing with 
study medication. Stable brain metastases by this definition should be established 
prior to the first dose of study medication. Subjects with asymptomatic brain 
metastases (ie, no neurological symptoms, no requirements for corticosteroids, and no 
lesion >1.5 cm) may participate but will require regular imaging of the brain as a site 
of disease.
10. Has pre-existing peripheral neuropathy that is ≥Grade 2 by Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.
11. Previously had a severe hypersensitivity reaction to treatment with another 
monoclonal antibody.
12. Has a known sensitivity to any component of carboplatin or paclitaxel or nab-
paclitaxel.
13. Has active autoimmune disease that has required systemic treatment in past 2 years 
(ie, with use of disease-modifying agents, corticosteroids or immunosuppressive 
drugs). 
Replacement 
therapy 
(eg, 
thyroxine, 
insulin, 
or 
physiologic 
corticosteroid-replacement therapy for adrenal or pituitary insufficiency, etc.) is not 
considered a form of systemic treatment.
14. Is on chronic systemic steroids. Subjects with asthma who require intermittent use of 
bronchodilators, inhaled steroids, or local steroid injections would not be excluded 
from the study.
15. Had prior treatment with any other anti-PD-1, PD-L1, or PD-L2 agent or an antibody
or a small molecule targeting other immuno-regulatory receptors or mechanisms. Has 
participated in any other pembrolizumab
trial and has been treated with 
pembrolizumab.
Examples of such antibodies include (but are not limited to) antibodies against IDO, 
PD-L1, IL-2R, GITR.
16. Has an active infection requiring therapy.
17. Has known history of human immunodeficiency virus (HIV) (known HIV 1/2 
antibodies positive).
18. 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.
19. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the subject’s participation 
for the full duration of the study, or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator.
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20. Has known psychiatric or substance abuse disorder that would interfere with 
cooperation with the requirements of the trial.
21. Is, at the time of providing documented 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).
22. 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.
23. Removed.
Trial Treatment(s)
Trial treatment should begin on the day of randomization or as close as possible to the date 
on which treatment is allocated. The 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 Treatment
Arm 
Name
Arm 
Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/Treat-
ment Period/
Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Arm 1
Experi-
mental
Pembrolizumab
Biological/
Vaccine
Solution for 
Infusion
25 mg/mL
200 mg
IV 
Infusion
Q3W for up to 
35 cycles
Test 
Product
IMP
Provided 
centrally 
by the 
Sponsor
Arm 1
Experi-
mental
Paclitaxel
Drug
Per 
Approved 
Product 
Label
Per 
Approved 
Product 
Label
200 mg/m2
IV 
Infusion
Q3W for up to 
4 cycles
Back-
ground 
Treatment
NIMP/
AxMP
Provided 
centrally 
by the 
Sponsor 
or locally 
sourced
Arm 1
Experi-
mental
Nab-paclitaxel
Drug
Per 
Approved 
Product 
Label
Per 
Approved 
Product 
Label
100 mg/m2
IV 
Infusion
Q1W for up to 
4 cycles
Back-
ground 
Treatment
NIMP/
AxMP
Provided 
centrally 
by the 
Sponsor 
or locally 
sourced
Arm 1
Experi-
mental
Carboplatin
Drug
Per 
Approved 
Product 
Label
Per 
Approved 
Product 
Label
AUC 6 
mg/mL/
min
IV 
Infusion
Q3W for up to 
4 cycles
Back-
ground 
Treatment
NIMP/
AxMP
Provided 
centrally 
by the 
Sponsor 
or locally 
sourced
Arm 2
Placebo
Comp-
arator
Saline Placebo
Drug
Solution of 
Infusion
NA
NA
IV 
Infusion
Q3W for up to 
35 cycles
Placebo
IMP
Locally 
sourced
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Arm 
Name
Arm 
Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/Treat-
ment Period/
Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Arm 2
Placebo
Comp-
arator
Paclitaxel
Drug
Per 
Approved 
Product 
Label
Per 
Approved 
Product 
Label
200 mg/m2
IV 
Infusion
Q3W for up to 
4 cycles
Back-
ground 
Treatment
NIMP/
AxMP
Provided 
centrally 
by the 
Sponsor 
or locally 
sourced
Arm 2
Placebo
Comp-
arator
Nab-paclitaxel
Drug
Per 
Approved 
Product 
Label
Per 
Approved 
Product 
Label
100 mg/m2
IV 
Infusion
Q1W for up to 
4 cycles
Back-
ground 
Treatment
NIMP/
AxMP
Provided 
centrally 
by the 
Sponsor 
or locally 
sourced
Arm 2
Placebo
Comp-
arator
Carboplatin
Drug
Per 
Approved 
Product 
Label
Per 
Approved 
Product 
Label
AUC 6 
mg/mL/
min
IV 
Infusion
Q3W for up to 
4 cycles
Back-
ground 
Treatment
NIMP/
AxMP
Provided 
centrally 
by the 
Sponsor 
or locally 
sourced
AUC=area under the curve; EEA=European Economic Area; IMP=investigational medicinal product; IV=intravenous; NIMP/AxMP=noninvestigational/auxiliary 
medicinal product; Q1W=once every week; Q3W=once every 3 weeks.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country 
differences with respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
In this protocol, placebo for pembrolizumab is diluent alone (normal saline); diluent is used for blinding purposes and does not contain active ingredients.
Other current or former names or aliases for pembrolizumab are as follows: MK-3475.
Pembrolizumab/saline placebo to be administered prior to chemotherapy.
Investigator’s choice of either paclitaxel or nab-paclitaxel.
Carboplatin daily dose should not exceed 900 mg.
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All supplies indicated in Table 2 above will be provided centrally by the Sponsor or locally 
by the trial site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the trial site, subsidiary or 
designee every attempt will be made to source these supplies from a single lot/batch number. 
The trial site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
5.2.1.1
Dose Selection (Preparation)
Pembrolizumab: the dose amount required to prepare the pembrolizumab infusion solution 
will be based on a fixed dose of 200 mg. Details on the dose calculation, preparation and 
administration are provided in the Pharmacy Manual.
Standard chemotherapeutic agents (carboplatin and paclitaxel or nab-paclitaxel) will be 
prepared and administered as per the approved product label.
5.2.1.2
Dose Modification (Escalation/Titration/Other)
If appropriate, the investigator may attribute each toxicity event to carboplatin, paclitaxel or 
nab-paclitaxel or pembrolizumab alone or to the combination and use a stepwise dose 
reduction. Dose modifications must be based on the maximum toxicity experienced during a 
cycle. Treatment-related toxicity must resolve to Grade ≤1 or baseline prior to resuming the 
subsequent cycle, with the exception of alopecia, Grade 2 fatigue, endocrine-related AEs 
requiring treatment or hormone replacement, which may be Grade ≤2. Dose modifications 
and toxicity management guidelines for immune-related AEs associated with pembrolizumab 
are outlined in Section 5.2.1.2.2 and Table 3 below. If a dose reduction for toxicity occurs 
with any agent, the dose may not be re-escalated. Subjects can have a maximum of 2 dose 
modifications (if applicable) to each of the components of study therapy throughout the 
course of the study for toxicities. If a subject experiences several toxicities and there are 
conflicting recommendations, the most conservative dose adjustment recommended should 
be followed (dose reduction appropriate to the most severe toxicity). Subjects who require a 
third dose modification to any particular component will have that agent discontinued.
If a dose reduction for toxicity occurs with any agent, the dose may not be re-escalated. 
Subjects can have a maximum of 2 dose modifications (if applicable) to each of the 
components of study therapy throughout the course of the study for toxicities. If a subject 
experiences several toxicities and there are conflicting recommendations, the most 
conservative dose adjustment recommended should be followed (dose reduction appropriate 
to the most severe toxicity). Subjects who require a third dose modification to any particular 
component will have that agent discontinued.
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Pembrolizumab dose reductions are not permitted. Pembrolizumab treatment may be 
interrupted or discontinued due to toxicity.
Reduction of one chemotherapy agent and not the other agent is appropriate if, in the opinion 
of the investigator, the toxicity is clearly related to one of the treatments. If, in the opinion of 
the investigator, the toxicity is related to the combination of both chemotherapy agents, both 
drugs should be reduced according to recommended dose modifications. If the toxicity is 
related to the combination of 3 agents, all 3 agents should be reduced (if applicable), 
interrupted, or discontinued according to the recommended dose modifications.
Subjects may have chemotherapy discontinued and continue on pembrolizumab/saline 
placebo alone. Similarly subjects may discontinue pembrolizumab/saline placebo and 
continue on chemotherapy alone during the first 4 cycles if appropriate.
Chemotherapy may be interrupted for a maximum of 6 weeks; pembrolizumab may be 
interrupted for a maximum of 12 weeks.
The CTCAE, version 4.0 must be used to grade the severity of AEs. All dose modifications 
should be based on the AE requiring the greatest dose modification.
Carboplatin and Paclitaxel or Nab-paclitaxel Chemotherapy Regimen
Refer to approved product labels for dose modifications regarding this regimen.
Immune-Related 
Events 
and 
Dose 
Modification 
(Withhold, 
Treat, 
Discontinue
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation. Based on the severity of irAEs, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids.
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 3.
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Table 3
Dose Modifications and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if 
the irAEs are not controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid dose 
is not ≤10 mg/day within 12 weeks of the last treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 after 
corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 

Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper

Add prophylactic antibiotics 
for opportunistic infections

Monitor participants for signs and symptoms of 
pneumonitis

Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment
Recurrent Grade 2 
or Grade 3 or 4 
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold

Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper

Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood 
or mucus in stool with or without fever) and of 
bowel perforation (ie, peritoneal signs and ileus)

Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis

Participants with diarrhea/colitis should be advised 
to drink liberal quantities of clear fluids. If 
sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST / ALT 
Elevation or 
Increased 
Bilirubin
Grade 2 a
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 b or 4 c
Permanently 
discontinue

Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure
Withhold d

Initiate insulin replacement 
therapy for participants with 
T1DM

Administer anti-
hyperglycemic in 
participants with 
hyperglycemia

Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold

Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated

Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue d
Hyperthyroidism 
Grade 2
Continue

Treat with non-selective 
beta-blockers (eg, 
propranolol) or thionamides 
as appropriate

Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
Permanently 
discontinue d
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidism
Grade 2-4
Continue

Initiate thyroid replacement 
hormones (eg, 
levothyroxine or 
liothyronine) per standard 
of care

Monitor for signs and symptoms of thyroid 
disorders
Nephritis and 
renal dysfunction
Grade 2
Withhold

Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by 
taper

Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Asymptomatic 
cardiac enzyme 
elevation with 
clinical suspicion of 
myocarditis (which 
was previously 
myocarditis Grade 1 
using CTCAE v4.0)
Withhold

Based on severity of AE 
administer corticosteroids

Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
Exfoliative 
Dermatologic 
Conditions
Suspected SJS, 
TEN, or DRESS
Withhold

Based on severity of AE 
administer corticosteroids

Ensure adequate evaluation to confirm etiology or 
exclude other causes
Confirmed SJS, 
TEN, or DRESS
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
All Other irAEs
Persistent Grade 2
Withhold

Based on severity of AE 
administer corticosteroids

Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold or 
discontinue e
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 
1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal.
b
AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal;
bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline if baseline abnormal.
c
AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal.
d
The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
e
Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis).
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Dose Modification and Toxicity Management of Infusion Reactions Related to 
Pembrolizumab Monotherapy, Coformulations, or IO Combinations
Pembrolizumab monotherapy, coformulations, or IO combinations 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 monotherapy, coformulations, or IO 
combinations associated infusion reactions are provided in Table 4.
Table 4
Pembrolizumab Monotherapy, Coformulations or IO Combinations 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 
participant is deemed medically stable 
in the opinion of the investigator
None
Grade 2
Requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment (eg, 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 h
Stop Infusion
Additional appropriate medical 
therapy may include but is not limited 
to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the 
participant is deemed medically stable 
in the opinion of the investigator.
If symptoms resolve within 1 hour of 
stopping drug infusion, the infusion 
may be restarted at 50% of the original 
infusion rate (eg, from 100 mL/h to 
50 mL/h). Otherwise dosing will be 
held until symptoms resolve and the 
participant should be premedicated for 
the next scheduled dose.
Participants who develop Grade 2 
toxicity despite adequate 
premedication should be permanently 
discontinued from further study 
intervention.
Participant may be premedicated 
1.5 h (±30 min) prior to infusion of 
study intervention with:
Diphenhydramine 50 mg PO (or 
equivalent dose of antihistamine).
Acetaminophen 500 to 1000 mg 
PO (or equivalent dose of 
analgesic).
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NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
Grade 3 or 4
Grade 3:
Prolonged (ie, not 
rapidly responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms after 
initial improvement; 
hospitalization 
indicated for other 
clinical sequelae (eg, 
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 
participant is deemed medically stable 
in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine 
should be used immediately.
Participant is permanently 
discontinued from further study 
intervention.
No subsequent dosing
h=hour; IV=intravenous; CTCAE=Common Terminology Criteria for Adverse Events; NCI=National Cancer Institute; 
NSAIDs=nonsteroidal anti-inflammatory drugs.
Note:  Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the 
period of drug administration.
For further information, please refer to the CTCAE v5.0 at http://ctep.cancer.gov.
Other Allowed Dose Interruption for Pembrolizumab Monotherapy, Coformulations, 
or IO Combinations
Pembrolizumab monotherapy, coformulations, or IO combinations may be interrupted for 
situations other than treatment-related AEs such as medical or surgical events and/or 
unforeseen circumstances not related to study intervention. However, study intervention is to 
be restarted within 3 weeks of the originally scheduled dose and within 42 days of the 
previously administered dose, unless otherwise discussed with the Sponsor. The reason for 
study intervention interruption is to be documented in the participant’s study record.
Timing of Dose Administration
Subjects will receive blinded pembrolizumab 200 mg (D1) or saline placebo (D1) together 
with paclitaxel 200mg/m2 (D1) OR nab-paclitaxel 100mg/m2 (D1, D8, D15) + carboplatin 
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AUC 6 (D1) Q3W for 4 cycles followed by blinded pembrolizumab 200 mg (D1) or saline 
placebo (D1) Q3W until progression/completion. Because of positive interim results, subjects
will be unblinded and will be allowed to discontinue treatment with saline placebo.
Pembrolizumab or saline will be administered prior to chemotherapy.
Trial treatment should be administered on Day 1 of each cycle after all procedures / 
assessments have been completed. Trial treatment can be administered +/- 3 days of the 
targeted Day 1 for each cycle, except Cycle 1 where treatment can only be administered + 3 
days of the targeted day 1.
All trial treatments will be administered on an out-patient basis.
For subjects who experience disease progression, investigators may elect to interrupt 
treatment by deferring the decision to continue/discontinue treatment in the trial until 
confirmation of disease progression per RECIST 1.1 at least 28 days from the date of 
imaging demonstrating disease progression confirmed through blinded independent central
imaging vendor review. Subjects for whom PD is not confirmed on subsequent imaging may 
resume treatment. Please see Section 5.8 for other exceptions.
5.2.2.1
Pembrolizumab/Saline Placebo
Pembrolizumab/saline placebo will be administered as a 30-minute IV infusion Q3W. 
Pembrolizumab/saline placebo will be administered prior to chemotherapy. Sites should 
make every effort to target infusion timing to be as close to 30-minutes as possible. However, 
given the variability of infusion pumps from site to site, a window of -5 minutes and +10 
minutes is permitted (ie, infusion time is 30-minutes: -5 min/+10 min).
The Pharmacy Manual contains specific instructions for pembrolizumab reconstitution, 
preparation of the infusion fluid, and administration.
5.2.2.2
Paclitaxel
Paclitaxel 200 mg/m2 will be administered as an IV infusion over 3 hours Q3W for 4 cycles
as per local practice and labels. All subjects should be pre-medicated with oral or IV steroids
and anti-histamines according to the approved product label and/or standard practice. 
Additional pre-medications should be administered as per standard practice. Paclitaxel 
should be completely administered before initiating carboplatin dose.
5.2.2.3
Nab-paclitaxel
Nab-paclitaxel will be administered at 100 mg/m2 as an IV infusion over 30 minutes for 4 
cycles as per local practice and labels. Subjects will be dosed on Day 1, 8 and 15 of each 
Q3W cycle. Nab-paclitaxel should be completely administered before initiating carboplatin 
dose.
5.2.2.4
Carboplatin
Carboplatin AUC 6 mg/mL/min will be administered as an IV infusion over 15-60 minutes 
Q3W for 4 cycles immediately after paclitaxel or nab-paclitaxel as per local practice and 
labels. The carboplatin dose should be calculated using Calvert formula (see below). 
Carboplatin dose should not exceed 900 mg.
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Calvert Formula:
Total Dose (mg) = (target AUC) x (CrCl + 25)
The estimated GFR used in the Calvert formula should not exceed 125 mL/min
Maximum carboplatin dose (mg) = target AUC 6 (mg•min/mL) x (125 + 25) = 6 x 150 
mL/min = 900 mg
5.2.2.5
Antiemetic Therapy
Antiemetic therapy should follow MASCC guidelines (http://www.mascc.org/antiemetic-
guidelines/) and should, for the first 4 cycles, include a 5-HT3 receptor antagonist, 
dexamethasone (or equivalent), and/or aprepitant as per the MASCC guidelines. If aprepitant 
is not locally available, the Sponsor will provide supplies.
Trial Blinding 
This is a double-blinded trial; therefore, the subject, the investigator, and Sponsor personnel 
or delegate(s) who are involved in the treatment administration or clinical evaluation of the 
subjects are unaware of the group assignments. The chemotherapy agents will be open-label. 
The Sponsor, investigator and subject will not know whether the treatment administered 
contains pembrolizumab or saline placebo. The study site’s unblinded pharmacist will obtain 
each subject’s study identification number and study drug assignment from the IVRS/IWRS 
and prepare the solutions for infusion. The unblinded pharmacist will provide the 
investigative staff with ready-to-use blinded pembrolizumab/saline infusion solutions, 
packaged identically in order to maintain the blinding, for administration at scheduled 
infusion visits.
Because of positive interim results, this study is being unblinded so that subjects assigned to 
the placebo arm (Arm 2) may discontinue treatment with normal saline placebo and have the 
option of receiving pembrolizumab if there is documented progressive disease by central 
radiological review. Thus, the subject, investigator, and Sponsor personnel or delegate(s) 
who are involved in the treatment administration or clinical evaluation of the subjects will be 
made aware of the group assignments.
See Section 7.1.4.2, Blinding/Unblinding, for a description of the method of unblinding a 
subject during the trial, should such action be warranted.
Randomization or Treatment Allocation
Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS).
There are 2 treatment arms.  
Subjects will be assigned randomly in a 1:1 ratio to pembrolizumab and chemotherapy or
saline placebo and chemotherapy, respectively. The choice of paclitaxel or nab-paclitaxel
treatment will be determined prior to randomization and documented in the IVRS/IWRS.
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Stratification
Treatment allocation/randomization will be stratified according to the following factors:
1) PD-L1 expression: TPS ≥1% vs. <1%. PD-L1 non-evaluable subjects will be included 
with the TPS <1% group.
2) Choice of taxane chemotherapy: paclitaxel vs. nab-paclitaxel.
3) Geographic region of the enrolling site (East Asia vs. non-East Asia).
Concomitant Medications/Vaccinations (Allowed & Prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the CRF including all 
prescription, 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.
Palliative and supportive care is permitted during the course of the trial for underlying 
medical conditions and management of symptoms. Surgery or radiotherapy for tumor control 
is not permitted during the study; however, radiotherapy or procedures for symptom 
management is allowed.
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.
Colony-Stimulating Factors
Routine use of CSFs is not permitted. American Society of Clinical Oncology guidelines for 
use of CSFs should be followed [41].
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening, 
Treatment, Crossover, and Second Course Phases of this trial:

Antineoplastic systemic chemotherapy or biological therapy not specified in this 
protocol.
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
Immunotherapy not specified in this protocol.

Chemotherapy not specified in this protocol.

Investigational agents other than pembrolizumab.

Radiation therapy; radiotherapy for symptom management is allowed with Sponsor’s 
approval.

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chickenpox, yellow fever, nasal seasonal flu, 
nasal H1N1 flu, rabies, BCG, and typhoid.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
immune-related adverse Event (as listed in Section 5.6) or for use as a pre-medication 
for chemotherapeutic agents specified in the protocol or as a pre-medication prior to a 
CT scan for subjects with contrast allergy or for use for COPD exacerbation requiring 
steroid for recovery. Replacement doses of steroids (for example, prednisone 10 mg 
daily) are permitted while on study.
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
treatment. Subjects may receive other medications that the investigator deems to be 
medically necessary.
The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
Rescue Medications & Supportive Care
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 below. Where appropriate, these guidelines 
include the use of oral or IV treatment with corticosteroids as well as additional anti-
inflammatory agents if symptoms do not improve with administration of corticosteroids. 
Note that several courses of steroid tapering may be necessary as symptoms may worsen 
when the steroid dose is decreased. For each disorder, attempts should be made to rule out 
other causes such as metastatic disease or bacterial or viral infection, which might require 
additional supportive care. The treatment guidelines are intended to be applied when the 
investigator determines the events to be related to pembrolizumab.
Note: If after the evaluation the event is determined not to be related, the investigator does 
not need to follow the treatment guidance (as outlined below). Refer to Table 3 in 
Section 5.2.1 for guidelines regarding dose modification and supportive care.
Diet/Activity/Other Considerations
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea, or vomiting.
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Contraception
Pembrolizumab may have adverse effects on a fetus in utero.
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).
Female subjects will be considered of non-reproductive potential if they are either: 
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women <45 years of age a high FSH level in the postmenopausal 
range may be used to confirm a post-menopausal state in women not using hormonal 
contraception or hormonal replacement therapy. In the absence of 12 months of
amenorrhea, a single FSH measurement is insufficient.); 
OR 
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy, or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR 
(3) has a congenital or acquired condition that prevents childbearing.
Female subjects of childbearing potential must agree to avoid becoming pregnant while 
receiving study intervention and for 120 days after the last dose of pembrolizumab or 180 
days after the last dose of chemotherapy, whichever is longer, and male subjects of 
reproductive potential must agree to avoid impregnating a partner while receiving 
chemotherapy through 95 days after the last dose of chemotherapy, by complying with one of 
the following:
(1) practice abstinence† from heterosexual activity; 
OR 
(2) use (or have their partner use) acceptable contraception during heterosexual activity.
Acceptable methods of contraception are‡:
Single method (one of the following is acceptable):
•
intrauterine device (IUD)
•
vasectomy of a female subject’s male partner 
•
contraceptive rod implanted into the skin
Combination method (requires use of two of the following):
•
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)
•
cervical cap with spermicide (nulliparous women only)
•
contraceptive sponge (nulliparous women only)
•
male condom or female condom (cannot be used together)
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•
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle 
and if considered acceptable by local regulatory agencies and ERCs/IRBs. Periodic 
abstinence (eg, calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and 
withdrawal are not acceptable methods of contraception.
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then 
it does not qualify as an acceptable method of contraception for subjects participating at 
sites in this country/region.
Subjects should be informed that taking the study intervention may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in 
the study, female subjects of childbearing potential must adhere to the contraception 
requirement (described above) from the day of study intervention initiation (or 14 days prior 
to the initiation of study intervention for oral contraception) throughout the study period up 
to 120 days after the last dose of pembrolizumab or 180 days after the last dose of 
chemotherapy, whichever is longer and male subjects of reproductive potential must adhere 
to the contraception requirement (described above) starting with the first dose of 
chemotherapy through 95 days after the last dose of chemotherapy. If there is any question 
that a subject of childbearing or reproductive potential will not reliably comply with the 
requirements for contraception, that subject should not be entered into the study.
Use in Pregnancy
If a female subject inadvertently becomes pregnant while on treatment in this study, the 
subject will immediately be removed from the study. The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated. The outcome of the pregnancy will be reported to the Sponsor without delay and 
within 24 hours if the outcome is a serious adverse experience (eg, death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn). The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the Sponsor.
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.
In this trial, a subject may discontinue from treatment but continue to participate in the 
regularly scheduled activities, as long as the subject does not withdraw consent.
Discontinuation from the treatment is permanent except for 1) a subject who discontinued 
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treatment for CR or 2) a subject who discontinued after receiving the maximum 35 
pembrolizumab/saline placebo treatment. These last 2 categories of subjects may be allowed 
to begin treatment again if deemed medically appropriate in the second course phase (re-
treatment).
A subject must be discontinued from the trial for the following reasons:

The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.

The subject is lost to follow-up.
A subject must be discontinued from trial treatment but continue to be followed for any of 
the following reasons:

Unacceptable adverse experiences as described in Section 5.2.1.2.

Completed a total of 35 treatments of pembrolizumab/saline placebo. Subjects are 
allowed to discontinue saline placebo.

Documented disease progression.
Note: If a subject has PD verified by central radiological review using RECIST 1.1, 
the subject may be unblinded. If a subject was receiving saline placebo and meets all
crossover criteria defined in Section 7.1.5.6, he/she will have the opportunity to 
crossover to receive open-label pembrolizumab monotherapy. If a subject was 
receiving pembrolizumab and is deemed to be clinically benefiting despite 
radiological progression they will have the opportunity to continue open-label 
pembrolizumab monotherapy. If a subject has unconfirmed PD and is clinically 
stable, it is at the discretion of the investigator to continue treating the subject with 
the assigned treatment per protocol until PD is confirmed at least 28 days from the 
date of the scan suggesting PD.
Clinical Stability is defined as:
o
Absence of symptoms and signs indicating clinically significant progression of 
disease (including worsening of laboratory values) indicating disease progression.
o
No decline in ECOG performance status.
o
Absence of rapid progression of disease or progressive tumor at critical 
anatomical sites (eg, cord compression) requiring urgent alternative medical 
intervention.

Intercurrent illness that prevents further administration of treatment.

Investigator’s decision to withdraw the subject from treatment.

The subject has a confirmed positive serum pregnancy test.

Noncompliance with trial treatment or procedure requirements.

Administrative reasons.
If a subject attains CR verified by central radiological review, has been treated for at least 8 
cycles of study treatment, and has at least 2 cycles of study treatment beyond the date when 
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the initial CR was declared OR the subject has received the maximum administrations of 
pembrolizumab/saline placebo as outlined above, the subject and investigator may consider 
stopping therapy 
with pembrolizumab/saline placebo. Subjects who discontinue 
pembrolizumab/saline placebo and then experience radiographic PD by local investigator’s 
assessment according to irRECIST may be eligible for re-treatment with pembrolizumab in 
the Second Course Phase at the discretion of the investigator as described in Section 7.1.5.5.
Chemotherapy will be discontinued when a subject has received the maximum number of 4 
cycles as outlined in the protocol.
The End of Treatment and Follow-up visit procedures are listed in Section 6.0 - 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 AE monitoring even if the subject started new 
antineoplastic treatment (SAEs will be collected for up to 90 days following cessation of 
Sponsor’s product, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, 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.
This study will be considered complete in terms of primary endpoint following the final 
analysis of PFS and OS, after the pre-specified number of PFS and OS events.
Subject Replacement Strategy
A subject who discontinues from the trial will not be replaced.
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent.  The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study, if available.
Clinical Criteria for Early Trial Termination
The clinical trial may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the trial population as 
a whole is unacceptable.  In addition, 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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6.0 TRIAL FLOW CHART
Initial Treatment Phase
Initial Treatment Phase – Cycles 1-4
Details regarding procedures listed in this table are outlined in Section 7.
Screening 
Phase
Treatment Cycles (3-Week Cycles)
Treatment Cycle
Screening 
(Visit 1)
1
1
1
2
2
2
3
3
3
4
4
4
Day (in Cycle)
1
8
15
1
8
15
1
8
15
1
8
15
Scheduling Window (Days):1
-28 to -1
+3
± 1
± 1
± 3
± 1
± 1
± 3
± 1
± 1
± 3
± 1
± 1
Administrative Procedures
Informed Consent 
X
Informed Consent for Future Biomedical Research 
(optional)
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior and Concomitant Medications
X
X
X
X
X
NSCLC Disease Details and Prior Treatment
X
Call IVRS
X
X2
X2
X2
X2
X2
X2
X2
X2
X2
X2
X2
Clinical Procedures / Assessments
Review Adverse Events 
X
X3
X3
X
X3
X3
X
X3
X3
X
X3
X3
Full Physical Examination
X
Directed Physical Examination
X
X
X
X
Vital Signs and Weight 
X4
X
X3
X3
X
X3
X3
X
X3
X3
X
X3
X3
12-Lead ECG
X
ECOG Performance Status
X5
X
X
X
X
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Screening 
Phase
Treatment Cycles (3-Week Cycles)
Treatment Cycle
Screening 
(Visit 1)
1
1
1
2
2
2
3
3
3
4
4
4
Day (in Cycle)
1
8
15
1
8
15
1
8
15
1
8
15
Scheduling Window (Days):1
-28 to -1
+3
± 1
± 1
± 3
± 1
± 1
± 3
± 1
± 1
± 3
± 1
± 1
Laboratory Procedures / Assessments: Analysis Performed by Local Laboratory
Pregnancy Test - Urine or Serum β-HCG 6
X
X
X
X
X
PT/INR and aPTT/PTT 
X5
CBC with Differential 7
X5
X3,8
X2,8
X
X3,8
X3,8
X
X3,8
X3,8
X
X3,8
X3,8
Comprehensive Chemistry Panel5,7
X5
X
X
X
Urinalysis7
X5
T3 or FT3, FT4 and TSH 7,9
X5
X
X
Analysis Performed by Central Laboratory
Blood for Genetic Analysis10
X
Blood for RNA Analyses
X
X
Blood for Plasma Biomarker Analyses
X
X
Blood for Serum Biomarker Analyses
X
X
Tumor Tissue Collection
Tumor Tissue Collection 
X
Efficacy Measurements
Tumor Imaging 
X
X11
Study Drug Administration
Carboplatin
X
X
X
X
Paclitaxel 
X
X
X
X
Nab-paclitaxel12
X
X
X
X
X
X
X
X
X
X
X
X
Pembrolizumab or Saline Placebo13
X
X
X
X
Patient Reported Outcomes (PRO)14
EuroQol (EQ)-5D1
X
X
X
X
EORTC QLQ-C30
X
X
X
X
EORTC QLQ-LC13
X
X
X
X
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Screening 
Phase
Treatment Cycles (3-Week Cycles)
Treatment Cycle
Screening 
(Visit 1)
1
1
1
2
2
2
3
3
3
4
4
4
Day (in Cycle)
1
8
15
1
8
15
1
8
15
1
8
15
Scheduling Window (Days):1
-28 to -1
+3
± 1
± 1
± 3
± 1
± 1
± 3
± 1
± 1
± 3
± 1
± 1
1.
In general, the window for each visit is ± 3 days unless otherwise noted. If treatment cycles are adjusted all procedures except imaging will be completed according to the 
cycle number and not weeks on treatment, imaging will not be adjusted for delays in treatment cycles and will be performed per calendar schedule.
2.
On Cycle 1, Day 1, call to obtain allocation number. At subsequent visits, call to ensure visits are captured in the IVRS system.
3.
Visit Day 8 and Day 15 procedures only apply to subjects receiving nab-paclitaxel.
4.
Height will be measured only at Visit 1.
5.
ECOG and laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment.
6.
For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose of each cycle of trial treatment. A serum test can be 
considered if urine is not appropriate.
7.
After Cycle 1, lab samples can be collected up to 3 days prior to Day 1 of subsequent cycles.
8.
If subject received nab-paclitaxel, labs are drawn in conjunction with each dose of nab-paclitaxel on Day 8 and Day 15 of each Q3W cycle.
9.
Subjects may be dosed in subsequent cycles after Cycle 1, Day 1 while thyroid function tests are pending.
10. This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. If there is either a documented law or regulation 
prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes, then this sample will not be collected at that site. If the sample is 
collected, leftover extracted DNA will be stored for FBR if the participant (or their legally acceptable representative) provides documented informed consent for FBR. If the 
planned genetic analysis is not approved, but FBR is approved and consent is given, this sample will be collected for the purpose of FBR.
11. Imaging is performed at Week 6 (± 7 days),  Week 12 (± 7 days), and Week 18 (± 7 days) then every 9 weeks (63 days ± 7 days) for the first 45 weeks in the treatment period. 
Refer to imaging manual for additional details.
12. Dosing for nab-paclitaxel is on Day 1, Day 8, and Day 15 of each Q3W.
13. Subjects assigned to the placebo arm (Arm 2) may discontinue treatment with saline placebo and have the option of receiving pembrolizumab if there is documented 
progressive disease by central radiological review.
14. PROs (EQ-5D, EORTC QLQ-C30, and EORTC QLQ-LC13) are completed at Cycles 1 through 7 and then every third cycle (every 9 weeks) while on treatment up to 48 
weeks.
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Initial Treatment Phase – Cycles 5 and Beyond
Details regarding procedures listed in this table are outlined in Section 7.
Treatment Cycles (3-Week Cycles)
End of Treatment
Post Treatment
Treatment Cycle
5
6 to 17
18 to 35
Discon
Safety Follow-
up
Follow-up Visits
Survival Follow-up1
Scheduling Window (Days):2
± 3
± 3
± 3
At Time of 
Discon± 3 
days
30 Days Post 
Dose+ 7 days
6 Weeks Post 
Safety Follow-up± 
3 days
Every 12 Weeks± 7 
days
Prior and Concomitant Medications
X
X
X
X
X
X
X
Subsequent antineoplastic therapy status
X
X
X
X
Survival Status3
X
Clinical Procedures / Assessments
Review Adverse Events 
X
X
X
X
X
X4
Full Physical Exam
X
Directed Physical Examination
X
X
X
Vital Signs and Weight5
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
Laboratory Procedures / Assessments: Analysis Performed by Local Laboratory
Pregnancy Test - Urine or Serum β-HCG 
X6
CBC with Differential 7
X
X
X
X
X
Comprehensive Chemistry Panel7
X
X
X
X
X
Urinalysis7
X8
X8
X
T3 or FT3, FT4 and TSH 7,9
X10
X10
X
Analysis Performed by Central Laboratory
Blood for RNA Analyses
X
X
Blood for Plasma Biomarker Analyses
X
Blood for Serum Biomarker Analyses
X
Efficacy Measurements
Tumor Imaging 
X11
X11 
X12
X13
X13,14
Study Drug Administration
Pembrolizumab or Saline Placebo15
X
X
X
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Treatment Cycles (3-Week Cycles)
End of Treatment
Post Treatment
Treatment Cycle
5
6 to 17
18 to 35
Discon
Safety Follow-
up
Follow-up Visits
Survival Follow-up1
Scheduling Window (Days):2
± 3
± 3
± 3
At Time of 
Discon± 3 
days
30 Days Post 
Dose+ 7 days
6 Weeks Post 
Safety Follow-up± 
3 days
Every 12 Weeks± 7 
days
Patient Reported Outcomes (PRO)16
EuroQol (EQ)-5D
X
X
X
X
EORTC QLQ-C30
X
X
X
X
EORTC QLQ-LC13
X
X
X
X
1.
After documented disease progression, or the start of new anticancer therapy; contacts are every 12 weeks by telephone.
2.
In general, the window for each visit is ± 3 days unless otherwise noted.
3.
After documented local site assessed disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks by telephone. Updated survival 
status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all participants who do not/will not have a scheduled study visit 
or study contact during the Sponsor-defined time period will be contacted for their survival status (excluding participants that have a death event previously recorded).
4.
Serious adverse events must be reported up to 90 days following cessation of treatment or 30 days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier.
5.
Height will be measured only at Visit 1.
6.
For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose of each cycle of trial treatment. A serum test can be 
considered if urine is not appropriate.
7.
After Cycle 1, lab samples can be collected up to 3 days prior to Day 1 of subsequent cycles.
8.
To be repeated every 6 cycles beginning with Cycle 6.
9.
Subjects may be dosed in subsequent cycles after Cycle 1, Day 1 while thyroid function tests are pending.
10. To be repeated every other cycle beginning with Cycle 6.
11. Imaging is performed at Week 6 (± 7 days), Week 12 (± 7 days), and Week 18 (± 7 days) then every 9 weeks (63 days ± 7 days) for the first 45 weeks in the treatment period. 
Refer to imaging manual for additional details.
12. Imaging performed every 12 weeks (84 days ± 7 days) subsequently. Refer to imaging manual for additional details.
13. If a previous scan was obtained within 4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation is not mandatory. Follow-up scans to be performed 
every 12 weeks (84 ± 7 days), refer to Section 7.1.2.6.3.
14. In subjects who discontinue trial treatment, tumor imaging should be performed at the time of treatment discontinuation (± 4 week window).
15. Subjects assigned to the placebo arm (Arm 2) may discontinue treatment with saline placebo and have the option of receiving pembrolizumab if there is documented 
progressive disease by central radiological review.
16. PROs (EQ-5D, EORTC QLQ-C30, and EORTC QLQ-LC13) are completed at Cycles 1 through 7 and then every third cycle (every 9 weeks) while on treatment up to 48 
weeks. All PROs are also completed at treatment discontinuation visit and 30-day safety follow-up visit.
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Second Course Phase (Retreatment)
Details regarding the procedures listed in this table are outlined in Section 7.0. Second course retreatment subjects may receive up to 
17 cycles (approximately 1 year) of pembrolizumab therapy.
Trial Period:
Treatment Cycles (3-Week Cycles)
End of 
Treatment
Post-Treatment
Treatment Cycle/Title:
1
2
3
4
To be Repeated 
Beyond 6 Cycles 
Discon
Safety 
Follow-up1
Follow-
Up Visits
Survival 
Follow-
up1
5
6
Scheduling Window (Days)2:
+3
± 3
± 3
± 3
± 3
± 3
At Time 
of 
Discon± 3 
days
30 Days 
Post 
Discon + 7 
days
6 Weeks 
Post 
Safety 
Follow-
up± 3 
days
Every 
12 
Weeks± 
7 days
Administrative Procedures
Eligibility Criteria
X
Concomitant Medication Review
X
X
X
X
X
X
X
X
Subsequent antineoplastic therapy status
X
X
X
X
Survival Status3
X
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
Full Physical Examination
X
Directed Physical Examination
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
Laboratory Procedures/Assessments: analysis performed 
by LOCAL laboratory
Pregnancy Test – Serum or Urine
X4
Hematology5
X6
X
X
X
X
X
X
X
Chemistry Panel5
X6
X
X
X
X
X
X
X
Urinalysis5
X6
X
X8
T3 or FT3, FT4, TSH5,7
X6
X
X9
X
Efficacy Measurements
Tumor Imaging
X10
X11
X11
X
X11
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Trial Period:
Treatment Cycles (3-Week Cycles)
End of 
Treatment
Post-Treatment
Treatment Cycle/Title:
1
2
3
4
To be Repeated 
Beyond 6 Cycles 
Discon
Safety 
Follow-up1
Follow-
Up Visits
Survival 
Follow-
up1
5
6
Scheduling Window (Days)2:
+3
± 3
± 3
± 3
± 3
± 3
At Time 
of 
Discon± 3 
days
30 Days 
Post 
Discon + 7 
days
6 Weeks 
Post 
Safety 
Follow-
up± 3 
days
Every 
12 
Weeks± 
7 days
Study Drug Administration
Pembrolizumab 
X
X
X
X
X
X
1. After documented disease progression, or the start of new anticancer therapy; contacts are every 12 weeks by telephone.
2.
In general, the window for each visit is ± 3 days unless otherwise noted.
3.
After documented local site assessed disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks by telephone. Updated survival 
status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all participants who do not/will not have a scheduled study 
visit or study contact during the Sponsor-defined time period will be contacted for their survival status (excluding participants that have a death event previously recorded).
4.
For women of reproductive potential, a serum pregnancy test should be performed within 72 hours prior to first dose of each cycle of trial treatment. A urine test can be 
considered if serum is not appropriate.
5.
After Cycle 1, lab samples can be collected up to 3 days prior to the scheduled time point.
6.
Laboratory tests for determining eligibility for retreatment are to be performed within 10 days prior to the first retreatment dose of pembrolizumab.
7.
Subjects may be dosed in subsequent cycles after Cycle 1, Day 1 while thyroid function tests are pending.
8.
To be repeated every 6 cycles beginning with Cycle 6.
9. To be repeated every other cycle beginning with Cycle 6.
10. A scan must be performed within 28 days prior to restarting treatment with pembrolizumab.
11. Imaging performed every 12 weeks (84 ± 7 days) from the date of re-treatment.
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Crossover Phase
Applicable for subjects who are unblinded after verification for PD by blinded independent central radiological review and eligible 
and qualified for the crossover phase. Details regarding the procedures listed in this table are outlined in Section 7.0. Crossover 
subjects may receive up to 35 cycles (approximately 2 years) of pembrolizumab therapy.
Scr 
Phase
Treatment Cycles1
End of Treatment Phase
Follow-
up 
Phase2
Survival 
Follow-
up3
Treatment Cycle / Scheduled 
Time
Scr 
(Visit 
1)
14
2
3
4
5
6
7
8
9
10
11
12
13
14 
through 
35
Discontinuation 
Visit5
Safety 
Follow-up 
Visit 6
Follow-
up Visit 
3 and 
Beyond
Survival 
Follow-
up Visit 
1 and 
Beyond
Scheduling Window (Days):
-28 to 
-1
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At Study Drug 
Discontinuation±3
30 Days 
From Last 
Dose+7
Every 3 
Months 
After Visit 
2± 3
Every 3 
Months  
± 7
Administrative Procedures
Prior and Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subsequent antineoplastic 
therapy status
X
X
X
X
Survival Status7
X
Clinical Procedures / Assessments
Review Adverse Events 8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Full Physical Examination
X
X
X
X
Directed Physical Examination
X
X
X
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
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Procedures / Assessments: analysis performed by local laboratory9
CBC with Differential
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PT/INR and aPTT/PTT 
X
X
Comprehensive Chemistry 
Panel
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X10
X
X
T3 or FT3, FT4 and TSH11
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test – Serum or 
Urine
X
X12
Efficacy Measurements
Tumor Imaging13
X
X
X
X
X
X
X
X
X14
Study Drug Administration
Pembrolizumab15
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Scr 
Phase
Treatment Cycles1
End of Treatment Phase
Follow-
up 
Phase2
Survival 
Follow-
up3
Treatment Cycle / Scheduled 
Time
Scr 
(Visit 
1)
14
2
3
4
5
6
7
8
9
10
11
12
13
14 
through 
35
Discontinuation 
Visit5
Safety 
Follow-up 
Visit 6
Follow-
up Visit 
3 and 
Beyond
Survival 
Follow-
up Visit 
1 and 
Beyond
Scheduling Window (Days):
-28 to 
-1
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At Study Drug 
Discontinuation±3
30 Days 
From Last 
Dose+7
Every 3 
Months 
After Visit 
2± 3
Every 3 
Months  
± 7
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 ± 3 days). 
If treatment cycles are adjusted all procedures except imaging will be completed according to the cycle number and not weeks on treatment, imaging will be performed every 12 weeks (84 days ± 7 
days) from the first dose of trial treatment regardless of any treatment delays.
2.
Subjects who stop pembrolizumab after 35 trial treatments and have achieved PR and/or SD OR have achieved a CR (see Section 5.8) will move to the Follow-up Phase of the study. Follow-up Visit 1 
should take place 3 months after the last dose of trial treatment. Follow-up Visit 2 should take place 6 months after the last dose of trial treatment and additional Follow-up visits should take place every 
3 months thereafter. Subjects who experience disease progression (and do not continue into the Second Course Phase) or start a new antineoplastic therapy will move directly into Survival Follow-up. 
For subject convenience, all follow-up assessments may occur during the same visit as the imaging studies are obtained. Subjects with an AE of Grade >1 will be further followed until the resolution of 
the AE to Grade 0-1 or until start of a new antineoplastic therapy, whichever is earlier.
3.
Once the subject stops the imaging assessments for this protocol (eg, for PD or starting a new antineoplastic therapy), the subject moves into the Survival Follow-up Phase and should be contacted by 
telephone every 3 months to assess for survival status. Post-study treatments and the subject’s response to them will also be collected.
4.
Screening procedures may be completed during these 30 days. All procedures and assessments completed at the time of withdrawal from the main study may be used as appropriate for the start of the 
Crossover Phase of the study. If subjects continue into the Crossover phase, Safety follow-up is not required.
5.
The Discontinuation Visit should occur at the time study drug is discontinued for any reason. If the Discontinuation Visit occurs 30 days from the last dose of study treatment, at the time of the
mandatory Safety Follow-up Visit, procedures do not need to be repeated.
6.
The mandatory Safety Follow-up Visit for all subjects should be conducted approximately 30 days after the last dose of trial treatment or before the initiation of new antineoplastic treatment, whichever 
is earlier. 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 is earlier. Subjects who are 
eligible for treatment with pembrolizumab during the Second Course Phase may have up to 3 Safety Follow-up Visits, one after the Treatment Phase, Crossover Phase, and the Second Course Phase. If 
the Discontinuation Visit occurs approximately 30 days (+/- 3 days) from last dose trial treatment the same procedures do not need to be repeated for the Safety Follow-up Visit.
7.
After documented local site assessed disease progression, or the start of new anticancer therapy; contacts are approximately every 12 weeks by telephone. Updated survival status may be requested by 
the Sponsor at any time during the course of the study. Upon Sponsor notification, all participants who do not/will not have a scheduled study visit or study contact during the Sponsor-defined time 
period will be contacted for their survival status (excluding participants that have a death event previously recorded).
8.
Once a subject discontinues study treatment, report all SAEs (related and unrelated to trial treatment), occurring within 90 days following cessation of treatment or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier. After this time, report only SAEs that are considered related to trial treatment.
9.
Laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment. After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point. 
Laboratory results must be known prior to dosing. Urinalysis: perform every 6 cycles after Cycle 14. T3 or FT3, FT4, and TSH: perform every 2 cycles after Cycle 14; thyroid function tests will be 
performed by a central lab only if the local laboratory is unable to perform this service. See Section 7.1.3 for details regarding laboratory tests.
10.
Urinalysis is performed every 6 cycles after Cycle 13. Urinalysis is not required at Cycle 14.
11.
Subjects may be dosed in subsequent cycles after Cycle 1, Day 1 while thyroid function tests are pending.
12.
For women of reproductive potential, a serum pregnancy test should be performed within 72 hours prior to first dose of each cycle of trial treatment. A urine test can be considered if serum is not 
appropriate.
13.
Blinded independent central review verifying progressive disease is: 1) required for crossover, without exception, and 2) is based on RECIST 1.1. Tumor response assessment is required every 12 weeks 
(84 days±7 days) until the subject starts a new anticancer therapy. Refer to imaging manual for additional details. Assessment of disease response or progression will be determined by the investigator. 
The treating physician will record a physician-assessed tumor response and the criteria used, ie, immune-related RECIST or standard RECIST 1.1 on the discontinuation form.
14.
Tumor imaging is not needed for subjects who start a new anticancer therapy regimen.
15.
Pembrolizumab can be administered for up to 35 cycles.
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7.0 TRIAL PROCEDURES
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place. 
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. 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 participant’s or the participant’s legally acceptable representative’s dated 
signature.
Specifics about the study and the study population are to be included in the study informed 
consent form.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
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Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial. The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency. The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides documented informed consent. At the time of treatment allocation/randomization, 
site personnel will add the treatment/randomization number to the Subject Identification 
Card.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
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. Details regarding the subject’s 
lung cancer will be recorded separately and not listed as medical history.
The investigator or qualified designee will obtain prior and current details regarding the 
subject’s lung cancer.
7.1.1.5
Prior and Concomitant Medications Review
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 
during the screening period (Day -30 through Day -1 of trial treatment start). Prior anticancer
therapy for NSCLC will be recorded separately and not listed as a prior medication.
The investigator or qualified designee will review and record all prior anti-cancer treatments
including systemic treatments, radiation, and surgeries, regardless of the time prior to first
dose of trial treatment.
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Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial. All medications related to reportable SAEs should be recorded as defined in 
Section 7.2.
7.1.1.6
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.
7.1.1.7
Assignment of Treatment/Randomization Number
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the subject for all procedures 
occurring after treatment allocation/randomization.  Once a treatment/randomization number 
is assigned to a subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment plan for greater than 12 weeks between
pembrolizumab doses for non-drug-related or administrative reasons (see Section 5.2.1.2 for
drug-related modifications) require consultation between the investigator and the Sponsor 
and written documentation of the collaborative decision on subject management.
Trial medications will be administered by site and/or institution staff per local SOPs and
guidelines. The total volume of pembrolizumab infused will be compared to the total volume
prepared to determine compliance to each dose of pembrolizumab administered.
The instructions for preparing and administering pembrolizumab will be provided in the
Pharmacy Manual.
Clinical Procedures/Assessments
7.1.2.1
Adverse Event (AE) Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated. Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE, version 4.0 (see Section 12.5). Toxicities 
will be characterized in terms including seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment.
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An irAE may be defined as an AE 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 AE immune related. 
Immunological, serological, and histological (biopsy) data should be used to support the 
diagnosis of an immune-related toxicity.
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs.
7.1.2.2
Physical Exam
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 time points for full physical exam are described in Section 6.0 - Trial Flow 
Chart. After the first dose of trial treatment new clinically significant abnormal findings 
should be recorded as AEs.
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.
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 ECGs may be performed as clinically necessary.
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (see Section 12.6) at 
screening, prior to each cycle of trial treatment, and during the Follow -up period as specified 
in the Trial Flow Chart.
7.1.2.6
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the central imaging vendor can be 
found in the Site Imaging Manual. Tumor imaging should be acquired by CT (strongly 
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preferred) and should include the chest, abdomen and pelvis. MRI should be used when CT 
is contraindicated or for imaging in the brain. The same imaging technique regarding 
modality and use of contrast should be used in a subject throughout the trial to optimize the 
visualization of existing and new tumor burden.
Local site investigator/radiology assessment based on RECIST 1.1 will be used to determine 
subject eligibility. Although RECIST 1.1 references a maximum of 5 target lesions in total 
and 2 per organ, MSD allows maximum of 10 target lesions in total and 5 per organ. All 
scheduled images for all study subjects from the sites will be submitted to the central 
imaging vendor. In addition, additional imaging (including other modalities) that are 
obtained at unscheduled time points to determine disease progression, as well as imaging 
obtained for other reasons but captures radiologic progression, should be submitted to the 
central imaging vendor.
The central imaging vendor will verify PD following local site investigator-assessed first 
radiologic evidence of PD. Expedited verification of radiologic PD by the central imaging 
vendor will be communicated to the study site and Sponsor (see Section 7.1.2.6.2). The 
expedited central verification of PD should be requested only when the subject is a candidate 
for crossover and may occur either at the first instance of PD by RECIST 1.1 or the 
confirmation scan ≥ 4 weeks later to confirm PD by irRECIST.
Initial Tumor Imaging
Initial tumor imaging at screening must be performed within 28 days prior to the date of 
randomization. The site study team must review screening images to confirm the subject has 
measurable disease per RECIST 1.1. The screening images must be submitted to the central 
imaging vendor for retrospective confirmation of eligibility.
Scans performed as part of routine clinical management are acceptable for use as screening 
tumor imaging if they are of diagnostic quality and performed within 28 days prior to the 
date of randomization and can be assessed by the central imaging vendor.
Subjects with previously treated brain metastases may participate provided they have stable 
brain metastases, ie, without evidence of progression by imaging during screening; 
(confirmed by MRI if MRI was used at prior imaging, or confirmed by CT imaging if CT 
was used at prior imaging). Any neurologic symptoms must have returned to baseline and 
subjects must have no clinical evidence of new or enlarging brain metastases, and have not 
used steroids for brain metastases for at least 3 days prior to trial initiation as per local site 
assessment. This exception does not include carcinomatous meningitis, as subjects with 
carcinomatous meningitis are excluded regardless of clinical stability.
Tumor Imaging During the Trial
The imaging assessment should be performed at Week 6 (42 ± 7 days), Week 12 (84 ± 7 
days), and Week 18 (126 ± 7 days) from the date of randomization. Subsequent tumor 
imaging should be performed every 9 weeks (63 days ±7 days) or more frequently if 
clinically indicated. After 45 weeks, subjects who remain on treatment will have imaging 
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performed every 12 weeks (84 days ±7 days). Imaging timing should follow calendar days 
and should not be adjusted for delays in cycle starts. Imaging should continue to be 
performed until disease progression verified by central imaging vendor (unless the local site 
investigator elects to continue treatment and follow irRECIST), the start of new anticancer 
therapy, withdrawal of consent, or death, whichever is earlier. All supplemental imaging 
must be submitted to the central imaging vendor.
Per RECIST 1.1, partial and complete response should be confirmed by a repeat tumor 
imaging assessment not less than 4 weeks from the date the response was first documented. 
The tumor imaging for confirmation of response may be performed at the earliest 4 weeks 
after the first indication of response, or at the next scheduled scan (ie, 6, 9, or 12 weeks 
later), whichever is clinically indicated. Subjects will then return to regular scheduled 
imaging, starting with the next scheduled imaging time point. Subjects who obtain a 
confirmation scan do not need to undergo the next scheduled tumor imaging if it is <4 weeks 
later; tumor imaging may resume at the subsequent scheduled imaging time point.
Per irRECIST (Section 7.1.2.6.6), disease progression should be confirmed by the site at least 
4 weeks after central verification of site-assessed first radiologic evidence of PD in clinically 
stable subjects. Subjects who have unconfirmed disease progression may continue on 
treatment at the discretion of the site investigator until progression is confirmed by the site 
provided they have met the conditions detailed in Section 7.1.2.6.6. Subjects who obtain a 
confirmation scan do not need to undergo the next scheduled tumor imaging if it is <4 weeks 
later; tumor imaging may resume at the subsequent scheduled imaging time point if clinically 
stable. Subjects who have confirmed disease progression as assessed by the site will 
discontinue the treatment. An exception is detailed in Section 7.1.2.6.6.
End of Treatment and Follow-up of Tumor Imaging
In subjects who discontinue trial treatment, tumor imaging should be performed at the time 
of treatment discontinuation (± 4 week window). If a previous scan was obtained within 4 
weeks prior to the date of discontinuation, then a scan at treatment discontinuation is not 
mandatory. In subjects who discontinue trial treatment due to documented disease 
progression, this is the final required tumor imaging.
In subjects who discontinue trial treatment without documented disease progression, tumor 
imaging using the same imaging schedule used while on treatment (every 9 weeks in Year 1 
or 12 weeks after Year 1) to monitor disease status until (1) the start of new anticancer 
therapy, (2) disease progression, (3) death, or (4) the end of the study, whichever is earlier, 
should be used.
Second Course (Retreatment) Tumor Imaging
A scan must be performed within 28 days prior to restarting treatment with pembrolizumab. 
Local reading (investigator assessment with site radiology reading) will be used to determine 
eligibility. Imaging should be submitted to the central imaging vendor for retrospective 
verification.
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The first on-study imaging assessment should be performed at 12 weeks (84 days ±7 days) 
after the restart of treatment. Subsequent tumor imaging should be performed every 12 weeks 
(84 days ±7 days) or more frequently if clinically indicated.
Per RECIST 1.1, partial or complete response should be confirmed by a repeat tumor 
imaging assessment not less than 4 weeks from the date the response was first documented. 
The tumor imaging for confirmation of response may be performed at the earliest 4 weeks 
after the first indication of response, or at the next scheduled scan, whichever is clinically 
indicated. Subjects will then return to regular scheduled imaging every 12 weeks (84 days ±7 
days), starting with the next scheduled imaging time point. Subjects who obtain a 
confirmation scan do not need to undergo scheduled tumor imaging if it is <4 weeks later and 
may wait until the next scheduled imaging time point.
Per irRECIST (Section 7.1.2.6.6), if tumor imaging shows initial PD, tumor assessment 
should be repeated ≥4 weeks later in order to confirm PD with the option of continuing 
treatment while awaiting radiologic confirmation of progression. Subjects who obtain a 
confirmation scan do not need to undergo scheduled tumor imaging if it is <4 weeks later and 
may wait until the next scheduled imaging time point if clinically stable.
Imaging should continue to be performed until disease progression, the start of new 
anticancer therapy, withdrawal of consent, death, or notification by the Sponsor, whichever is 
earlier. Disease progression may be confirmed at least 4 weeks after the first tumor imaging 
indicating progressive disease in clinically stable subjects.
In subjects who discontinue trial treatment, tumor imaging should be performed at the time 
of treatment discontinuation (± 4 week window). If a previous scan was obtained within 4 
weeks prior to the date of discontinuation, then a scan at treatment discontinuation isn’t 
mandatory. In subjects who discontinue trial treatment due to documented disease 
progression, this is the final required tumor imaging.
In subjects who discontinue trial treatment without documented disease progression, every 
effort should be made to continue monitoring their disease status by radiologic imaging every 
12 weeks (84 days ± 7 days) until (1) the start of new anticancer therapy, (2) disease 
progression, (3) death, or (4) the end of the study, whichever is earlier.
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be applied by the central imaging vendor as the primary measure for 
assessment of tumor response, date of disease progression, and as a basis for all protocol 
guidelines related to disease status (eg, discontinuation of study therapy). Initial tumor 
imaging showing site-assessed PD should be submitted to the central imaging vendor 
immediately. The site will be notified via email if the central imaging vendor verifies PD 
using RECIST 1.1. Figure 2 illustrates the imaging flow involving verification of PD for 
clinically stable subjects.
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irRECIST Assessment of Disease
irRECIST is RECIST 1.1 adapted as described below to account for the unique tumor 
response seen with immunotherapeutic drugs. irRECIST will be used by site 
investigator/local radiology review to assess tumor response and progression, and make 
treatment decisions. This data will be collected in the clinical database. Treatment efficacy 
based on irRECIST as assessed by central imaging vendor review will be evaluated 
retrospectively.
When feasible, subjects should not be discontinued until progression is confirmed by the 
local site investigator/radiology assessment. This allowance to continue treatment despite 
initial radiologic PD takes into account the observation that some subjects can have a 
transient tumor flare in the first few months after the start of immunotherapy, and then 
experience subsequent disease response. Subjects who are deemed clinically unstable are not 
required to have repeat tumor imaging for confirmation of PD. Tumor flare includes any of 
the following scenarios:
•
Worsening of existing target lesion(s)
•
Worsening of existing non-target lesion(s)
•
Development of new lesions(s)
In subjects who have initial evidence of radiological PD by RECIST 1.1 as verified by the 
central imaging vendor, it is at the discretion of the local site investigator whether to continue 
a subject on study treatment until repeat imaging is obtained (using irRECIST for subject 
management, see Table 5 and Figure 2). This clinical judgment decision by the site should be 
based on the subject’s overall clinical condition, including performance status, clinical 
symptoms, and laboratory data. Subjects may receive study treatment and tumor assessment 
should be repeated ≥4 weeks later in order to confirm PD by irRECIST per site assessment. 
Clinical stability is defined as the following: 
1) Absence of symptoms and signs indicating clinically significant progression of disease, 
including worsening of laboratory values
2) No decline in ECOG performance status
3) Absence of rapid PD
4) Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention
Any subject deemed clinically unstable should be discontinued from trial treatment at site-
assessed first radiologic evidence of PD and is not required to have repeat imaging for PD 
confirmation.
In determining whether or not the tumor burden has increased or decreased per irRECIST, 
the local site investigator should consider all target and non-target lesions as well as any 
incremental new lesion(s).
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PD is not confirmed at repeat imaging if ALL of the following occur by irRECIST:
•
Target lesion sum of diameters is <20% or there is less than a 5-mm absolute increase 
compared to the nadir
•
Non-target disease resulting in initial PD is stable or qualitatively improved
•
New lesion resulting in initial PD is stable or qualitatively improved
•
No incremental new lesion(s) since last evaluation
•
No incremental new non-target lesion progression since last evaluation
If repeat imaging does not confirm PD per irRECIST as assessed by the local site 
investigator and the subject continues to be clinically stable, study treatment and tumor 
imaging may continue per study schedule.
PD is confirmed at repeat imaging if ANY of the following occur by irRECIST:
•
Target lesion sum of diameters remains ≥20 % and there is at least a 5-mm absolute 
increase compared to the nadir
•
Non-target disease resulting in initial PD is qualitatively worse
•
New lesion resulting in initial PD is qualitatively worse
•
Additional new lesion(s) since last evaluation
•
Additional new non-target lesion progression since last evaluation
If repeat imaging confirms PD due to any of the scenarios listed above, subject will be 
discontinued from study therapy.
NOTE: If a subject has confirmed radiographic progression (ie, 2 scans at least 4 weeks apart 
demonstrating PD) per irRECIST, but the subject is achieving a clinically meaningful 
benefit, and there is no further increase in the tumor burden at the confirmatory tumor 
imaging, an exception to continue treatment may be considered following consultation with 
the Sponsor. In this case, if treatment is continued, tumor imaging should continue to be 
performed following the intervals outlined in Section 6.0 Trial Flow Chart and be submitted 
to the central imaging vendor.
Additional details about irRECIST are referenced in the Merck TIP Sheet for RECIST 1 1 
and irRECIST.
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Table 5
Imaging and Treatment after First Radiologic Evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD by 
RECIST 1.1 which 
has been verified 
by the central 
imaging vendor
Repeat imaging at 
>4 weeks at site to 
confirm PD
May continue study 
treatment at the local 
site investigator’s 
discretion while 
awaiting confirmatory 
tumor imaging by site
by irRECIST
Repeat imaging at >4 
weeks to confirm PD 
per physician 
discretion only
Discontinue treatment
Repeat tumor 
imaging confirms 
PD by irRECIST at 
the local site
No additional 
imaging required
Discontinue treatment
(exception is possible 
upon consultation with 
Sponsor)
No additional 
imaging required
N/A
Repeat tumor 
imaging shows SD, 
PR, or CR by 
irRECIST by the 
local site
Continue regularly 
scheduled imaging 
assessments 
Continue study 
treatment at the local 
site investigator’s 
discretion
Continue regularly 
scheduled imaging 
assessments
May restart study 
treatment if condition 
has improved and/or 
clinically stable per 
investigator’s discretion. 
Next tumor imaging
should occur according 
to the regular imaging 
schedule outlined in the 
protocol
Figure 2
Imaging and Treatment for Clinically Stable Subjects After First Radiologic 
Evidence of PD Assessed by the Site
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7.1.2.7
Tumor Tissue Collection: PD-L1 Status
Participation in this trial will be dependent upon supplying tumor tissue for PD-L1 testing 
from locations not radiated prior to biopsy; formalin-fixed specimens after the subject has 
been diagnosed with metastatic disease will be preferred for determination of PD-L1 status 
prior to randomization. Biopsies obtained prior to receipt of adjuvant/neoadjuvant 
chemotherapy will be permitted if recent biopsy is not feasible. Subjects whose submitted 
tissue is non-evaluable for PD-L1 status can still be eligible to participate in the study.
All subjects should submit either a newly obtained core or excisional biopsy or archival 
tissue (FNA is not adequate for both archival and new tissue samples) to a central lab for 
characterization of PD-L1 status prior to treatment allocation.
Note: Submission of formalin-fixed paraffin-embedded tumor tissue sample blocks are 
preferred; if submitting unstained slides, the slides should be freshly cut and submitted to the 
testing laboratory within 14 days from the site slide section date, otherwise a new specimen 
will be requested.
If the sample is determined to be non-evaluable prior to testing by the central laboratory, a 
new sample should be submitted if available. This may include additional cut slides that are 
outside of the 14-day window noted above.
Individual subject PD-L1 status will not be disclosed to investigative sites and study subjects. 
Analyses by PD-L1 biomarker status will be limited and documented.
If the subject (or their legally acceptable representative) provides documented informed 
consent for FBR, any leftover samples that would ordinarily be discarded at the end of the 
main study will be retained for FBR.
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the Procedure 
Manual.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Table 6.
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Table 6
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-human chorionic 
gonadotropin (β-hCG)a
Hemoglobin
Alkaline phosphatase
Glucose
PT (INR)d
Platelet count
Alanine aminotransferase (ALT)
Protein
aPTT/PTT d
White Blood Cell -
WBC (total and 
differential)
Aspartate aminotransferase (AST)
Specific gravity 
Total triiodothyronine (T3)e
Red Blood Cell 
Count
Carbon dioxide (CO2 or 
Bicarbonate) b
Microscopic exam 
if abnormal results 
are noted 
Free thyroxine (FT4)
Absolute 
Neutrophil Count
Calcium
Urine pregnancy 
testa
Thyroid stimulating hormone 
(TSH)
Absolute 
Lymphocyte Count
Chloride
Follicle Stimulating Hormone 
(FSH)f
Creatinine
Blood for correlative studies
Glucose
Blood for genetics
Lactate Dehydrogenase
Phosphorus
Potassium
Sodium
Total Bilirubin
Direct Bilirubin if total bilirubin is 
elevated above the upper limit of 
normal
Total protein
Blood Urea Nitrogen
Uric acid
Ureac
a.
Perform on women of childbearing potential only. Urine pregnancy test is preferred. If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required.
b. If these tests are not done as part of standard of care in your region then these tests do not need to be 
performed.
c.
Blood Urea Nitrogen is preferred; if not available urea may be tested.
d. Coagulation factors (PT/INR and aPTT/PTT) should be tested as part of the screening procedures for all 
subjects. Any subject receiving anticoagulant therapy should have coagulation factors monitored closely 
throughout the trial.
e.
Total T3 is preferred; if not available free T3 may be tested.
f.
As needed, FSH to be performed at Screening to confirm post-menopausal status.
Laboratory tests for screening 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 3 days 
prior to Day 1 of subsequent cycles.
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Results must be reviewed by the investigator or qualified designee and found to be 
acceptable prior to each dose of trial treatment. Unresolved abnormal labs that are 
drug-related AEs should be followed until resolution. Labs do not need to be repeated after 
the end of treatment if labs are within the normal range.
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations
Pembrolizumab
The accumulation of robust PK and ADA data has allowed for the adequate characterization 
of the clinical pharmacology of pembrolizumab across indications. Therefore, the collection 
of PK and ADA samples for pembrolizumab are being discontinued. Blood samples for PK 
and ADA that have already been collected may be stored. Analysis will be performed only if 
required.
Exploratory drug-drug interaction analysis
The potential of drug interaction between biologics such as pembrolizumab and small 
molecule drugs is negligible. Therefore, collection of samples for the assessment of PK of 
paclitaxel and nab-paclitaxel is being discontinued. Blood samples for PK that have already 
been collected may be stored. Analysis will be performed only if required.
7.1.3.3
Patient-Reported Outcomes (PROs)
The EuroQol (EQ)-5D, EORTC QLQ-C30, and EORTC QLQ-LC13 questionnaires will be 
administered by trained study site personnel and completed electronically by the subjects 
themselves.
It is strongly recommended that ePROs are administered prior to drug administration, AE
evaluation, and disease status notification. The ePROs are completed in the following order: 
EuroQol e(EQ)-5D first, then EORTC eQLQ-C30, and lastly the EORTC eQLQ-LC13 at the 
time points specified in the Trial Flow Charts and briefly summarized below.
PROs (EQ-5D, EORTC QLQ-C30, and EORTC QLQ-LC13) are completed at Cycles 1 
through 7 and then every third cycle (every 9 weeks) while on treatment up to 48 weeks. All 
PROs are also completed at the treatment discontinuation visit and the 30-day safety follow-
up visit.
7.1.3.4
Blood for RNA Analyses and Biomarker Analyses (plasma, serum)
Blood for RNA analyses should be collected pre-dose on Day 1 of Cycles 1, 2, and 5, or at 
the time of discontinuation. Blood for biomarker analyses (plasma, serum) should be 
collected pre-dose on Day 1 of Cycles 1, 2, or at the time of discontinuation. Detailed 
instructions with specific time points per sample are provided in the Procedures Manual. Any 
leftover samples will be stored for FBR if the participant (or their legally acceptable 
representative) provides documented informed consent for FBR.
7.1.3.5
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Procedure Manual.
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7.1.3.6
Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of Future Biomedical Research:
DNA for future research.
•
Leftover RNA
•
Leftover plasma and serum from biomarker analyses
•
Leftover main study tumor
Other Procedures
7.1.4.1
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from treatment prior to completion of the treatment
regimen should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the end of treatment visit should be performed at the time of discontinuation.  
Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events. Subjects who a) attain a CR or b) complete 35 administrations of 
pembrolizumab (approximately 2 years) may discontinue treatment with the option of 
restarting treatment if they meet the criteria specified in Section 7.1.5.5. After discontinuing 
treatment following assessment of CR or 35 administrations of pembrolizumab, these 
subjects should return to the site for a Safety Follow-up Visit (described in Section 7.1.5.3) 
and then proceed with assessments (described in Section 7.1.5.3).
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the 
investigator 
will 
contact 
the 
Sponsor 
using 
the 
designated 
mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
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7.1.4.2
Blinding/Unblinding
When the investigator or sub-investigator needs to identify the drug used by a subject and the 
dosage administered in case of emergency e.g., the occurrence of serious adverse 
experiences, he/she will contact the emergency unblinding call center by telephone and make 
a request for emergency unblinding.  As requested by the investigator or sub-investigator the 
emergency unblinding call center will provide the information to him/her promptly and 
report unblinding to the sponsor.  The emergency unblinding call center will make a record 
promptly however, the investigator or sub-investigator must enter the toxicity grade of the 
adverse experiences observed,   their relation to study drug, the reason thereof, etc., in the 
medical chart etc., before unblinding is performed. Subjects whose treatment assignment has 
been unblinded must be discontinued from study drug.
Additionally, the investigator must go into the IVRS system and perform the unblind in the 
IVRS system to update drug disposition.  In the event that the emergency unblinding call 
center is not available for a given site in this trial, IVRS/IWRS should be used for emergency 
unblinding in the event that this is required for subject safety.
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., 
date, reason and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible. Only the principal investigator or 
delegate and the respective subject’s code should be unblinded. Trial site personnel and 
Sponsor personnel directly associated with the conduct of the trial should not be unblinded.
Subjects whose treatment assignment has been unblinded (by the investigator, Merck 
subsidiary, or through the emergency unblinding call center) must be discontinued from 
study drug.
7.1.4.3
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:
•
Laboratory equipment – as required for inclusion labs and trial assessments
•
Imaging equipment – as required for study objectives
See protocol-specified guidance in the Administrative Binder, Procedures Manual, and Site 
Imaging Manual.
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
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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 28 days prior to randomization, potential subjects will be evaluated to
determine that they fulfill the entry requirements as set forth in Section 5.1. Screening
procedures may be repeated after consultation with the Sponsor.
Documented informed consent must be obtained prior to performing any protocol-specific
procedure. Results of a test performed prior to the subject providing documented informed
consent as part of routine clinical management are acceptable in lieu of a screening test if 
performed within the specified time frame. Screening procedures are to be completed within 
28 days prior to the first dose of trial treatment except for the following:

Laboratory tests are to be performed within 10 days prior to the first dose of trial 
treatment.

For women of reproductive potential, a urine pregnancy test will be performed within 
72 hours prior to first dose of trial treatment. If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test, performed by the local study site 
laboratory, will be required.

Tumor imaging must be performed within 28 days prior to randomization.
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria.
Results from assessments performed during the initial screening period are acceptable in lieu
of repeating a screening test if performed within the specified time frame and the results meet
the inclusion/exclusion criteria.
7.1.5.2
Treatment Period Visit
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-Trial
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 will be followed for 
disease status. If the subject experienced a CR, PR, or SD during the Treatment Phase on
pembrolizumab, and then experiences PD at any time during the follow-up period, he/she 
will be eligible to receive up to 12 months of therapy with pembrolizumab in the Second 
Course Phase according to the criteria in Section 7.1.5.5. After the Second Course Phase, 
subjects should be followed for up to 2 years, with no option of retreatment with
pembrolizumab on study.
Subjects who discontinue trial treatment for a reason other than disease progression will still 
be considered on-study and should continue with regularly scheduled assessments (also refer 
to Section 7.1.2.6.3), including collecting subject information on the start of new 
antineoplastic therapy, disease progression, and death.
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Safety Follow-up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the
last dose of trial treatment or before the initiation of a new antineoplastic treatment,
whichever is earlier. 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 is earlier. Subjects who are eligible per the requirements in Section 7.1.5.5 for
treatment with pembrolizumab during the Second Course Phase may have up to 3 safety
follow- up visits, after the Treatment Phase, after the Crossover Phase, and after the Second 
Course Phase.
Follow-up Visits
Follow-up visit requirements are outlined in Section 6.0 - Trial Flow Chart.
Survival Follow-up
Subjects who experience confirmed disease progression or start a new anticancer therapy, 
will move into Survival Follow-Up Phase and should be contacted by telephone 
approximately every 12 weeks to assess for survival status until death, withdrawal of 
consent, or the end of the study, whichever is earlier. Post-study treatments and the subject’s 
response to them will also be collected.
7.1.5.4
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 eDMC 
review, IA, and/or final analysis. Upon Sponsor notification, all participants who do not/will 
not have a scheduled study visit or study contact during the Sponsor-defined time period will 
be contacted for their survival status (excluding participants who have a previously-recorded 
death event in the collection tool).
7.1.5.5
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 pembrolizumab or who crossed over to 
pembrolizumab from placebo may be eligible to receive pembrolizumab in the Second 
Course Phase of this study for up to 17 cycles if the subject:

Stopped their initial treatment with pembrolizumab/placebo after attaining a 
confirmed CR by central review, were treated for at least 8 cycles with 
pembrolizumab/placebo, 
and 
received 
at 
least 
2
treatments 
with
pembrolizumab/placebo beyond the date when the initial CR was declared.
OR

Had SD, PR, or CR and stopped pembrolizumab treatment after 35 treatments for 
reasons other than disease progression or intolerability.
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AND

Experienced an investigator-determined confirmed radiographic disease progression 
according to irRECIST after stopping their initial treatment with pembrolizumab due 
to achievement of a confirmed CR.

Did not receive any other systemic anticancer therapy since the last dose of 
pembrolizumab. (Local treatment such as radiation or surgery as anticancer therapy is 
allowed; Sponsor consultation must be obtained and subjects should have recovered 
completely from side effects of local procedures. In subjects with brain metastases, 
neurological stability must be documented before initiating pembrolizumab.)

Continues to meet Inclusion Criteria 7, 8, and 9.

Does not meet Exclusion Criteria 2, 3, 4, 6-8, 11, 13, 14, and/or 22.
An objective response or progression of disease that occurs during the Second Course Phase 
for a subject will not be counted as an event for the primary analysis of either endpoint in this 
trial.
7.1.5.6
Crossover Phase
Subjects who are unblinded after verification for PD by blinded independent central 
radiological review, will have the opportunity to receive pembrolizumab monotherapy in the 
crossover phase. Subjects who permanently discontinue chemotherapy due to an AE, 
withdraw consent, or for any reason other than progressive disease, will not be eligible for 
crossover. Subjects who are unblinded will be allowed to crossover after documented PD by 
blinded independent central radiological review. Crossover subjects must not initiate 
treatment with pembrolizumab any earlier than 21 days after their last dose of chemotherapy 
regardless of the time of progression.
Crossover Qualifications:
Subjects who received placebo will be considered for crossover to pembrolizumab after
documented progressive disease based on RECIST 1.1. verified by central imaging vendor
review. Crossover is optional and is at the discretion of the investigator (with the Sponsor’s 
agreement). Subjects who meet the following criteria are eligible for crossover:

Documentation of PD by central imaging vendor assessment.

AEs (except alopecia and peripheral neuropathy) due to therapy must have improved 
to CTCAE version 4.0) ≤Grade 1.

If a subject is unstable as a result of a new or progressing brain metastasis(es), the
subject will not be eligible for crossover.

ECOG performance status 0-1.

Subject has not received any other systemic anticancer therapies other than the
chemotherapy administered during the treatment phase.

If required, completed palliative radiotherapy (30 Gy or less) ≥7 days before the first
dose of crossover trial treatment.
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
Subject has adequate organ function as indicated by the laboratory values in Section
5.1.2.
7.1.5.7
Crossover Assessments and Procedures
Crossover subjects must not initiate treatment with pembrolizumab any earlier than 21 days
after their last dose of chemotherapy regardless of the time of progression. The subject will
then start the crossover phase as outlined in the Crossover Flow Chart in Section 6.3. 
Screening procedures need to be completed within 28 days of confirmed PD (or up to 42 
days from last dose if recovering from an adverse event). All procedures and assessments 
completed at the time of withdrawal from the main study may be used as appropriate for the 
start of the Crossover Phase of the study. The tumor imaging used to determine PD can be 
used as the new baseline imaging for the Crossover Phase if 1) it occurred 30 days prior to 
receiving the first dose of pembrolizumab monotherapy and 2) no study treatment was 
received between the imaging and the first dose of pembrolizumab monotherapy, otherwise a 
new baseline image must be performed prior to pembrolizumab monotherapy treatment. 
Subjects who crossover and then achieve a CR per RECIST 1.1 have the option to hold 
pembrolizumab while continuing in the trial. Additional details are provided in Section 
7.1.5.5.
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 
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not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 30 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any 
protocol-specified procedure or intervention.  If the subject requires a blood draw, fresh 
tumor biopsy etc., the subject is first required to provide consent to the main study and AEs 
will be captured according to guidelines for standard AE reporting.
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for pembrolizumab by ≥1000 mg (5 times the dose). No specific information is 
available on the treatment of overdose of pembrolizumab. In the event of overdose, 
pembrolizumab should be discontinued and the subject should be observed closely for signs 
of toxicity.  Appropriate supportive treatment should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee), including the pregnancy of a male participant’s female 
partner, that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
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The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, 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.
Immediate Reporting of Adverse Events to the Sponsor
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to Table 7 for additional details regarding each of the above criteria.
For the time period beginning when the participant provides documented informed consent 
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 
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media or paper. Electronic reporting procedures can be found in the EDC data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent)
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor.
All subjects with serious adverse events must be followed up for outcome.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI)  and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 30 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints 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.
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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 an SAE 
within 24 hours of determination that the event is not progression of the cancer under study.
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each adverse event causality to the combination regimen or to a 
single agent of the combination.  In general, causality attribution should be assigned to the 
combination regimen (i.e., to all agents in the regimen). However, causality attribution may 
be assigned to a single agent if in the investigator’s opinion, there is sufficient data to support 
full attribution of the adverse experience to the single agent.
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Table 7
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor’s 
Product
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor’s 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology 
or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to their best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an 
associated AE.)
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Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
TRIAL GOVERNANCE AND OVERSIGHT
Scientific Advisory Committee
This trial was developed in collaboration with a Scientific Advisory Committee (SAC).  The 
SAC comprises both Sponsor and non-Sponsor scientific experts who provide input with 
respect to trial design, interpretation of trial results and subsequent peer-reviewed scientific 
publications.
Executive Oversight Committee
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management.  The EOC will receive and decide upon any recommendations made by the 
DMC regarding the trial.
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (DMC) will monitor the interim data from this trial.  The voting 
members of the committee are external to the Sponsor.  The members of the DMC must not 
be involved with the trial in any other way (e.g., they cannot be trial investigators) and must 
have no competing interests that could affect their roles with respect to the trial. 
The DMC will make recommendations to the EOC regarding steps to ensure both subject 
safety and the continued ethical integrity of the trial.  Also, the DMC will review interim trial 
results, consider the overall risk and benefit to trial participants (see Section 8.7 - Interim 
Analyses) and recommend to the EOC if the trial should continue in accordance with the 
protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the trial governance structure; and requirements for and proper documentation of 
DMC reports, minutes, and recommendations will be described in 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.
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8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, changes are made to primary and/or key secondary hypotheses, or the 
statistical methods related to those hypotheses, then the protocol will be amended (consistent 
with ICH Guideline E-9). Changes to exploratory or other non-confirmatory analyses made 
after the protocol has been finalized, but prior to the conduct of any analysis, will be 
documented in a sSAP as needed and referenced in the CSR for the study. Separate analysis 
plans (ie, separate documents from the sSAP) may be developed for PK/modeling analysis, 
biomarker analysis, and genetic data analysis. Post hoc exploratory analyses will be clearly 
identified in the CSR.
Statistical Analysis Plan Summary
Key elements of the SAP are summarized below; the comprehensive plan is provided in 
Sections 8.2 through 8.11.
Study Design Overview
A Phase III Study of Carboplatin-Paclitaxel/Nab-Paclitaxel Chemotherapy 
with or without Pembrolizumab (MK-3475) in First Line Metastatic 
Squamous Non-small Cell Lung Cancer Subjects (KEYNOTE-407)
Treatment Assignment
Subjects will be randomized in a 1:1 ratio to receive pembrolizumab or saline 
placebo in combination with carboplatin and a taxane (investigators choice of 
paclitaxel or nab-paclitaxel). Stratification factors are in Section 5.4. This is a 
randomized double-blinded study.
Analysis Populations
Efficacy: Intention-to-treat (ITT)
Safety: All-subjects-as-treated (ASaT)
Dual Primary
Endpoints/Hypotheses
1)
PFS per RECIST 1.1 assessed by a blinded independent central
imaging vendor
2)
OS
Statistical Methods for
Key
Efficacy Analyses
The dual primary hypotheses on PFS and OS will be evaluated by comparing
pembrolizumab to saline placebo in combination with carboplatin and a taxane 
using a stratified Log-rank test. The HR will be estimated using a stratified
Cox regression model. Event rates over time will be estimated within each 
treatment group using the Kaplan-Meier method. The stratified Miettinen and 
Nurminen method with sample size weights will be used for analysis of ORR.
Statistical Methods for
Key Safety Analyses
The analysis of safety results will follow a tiered approach. There are no Tier 
1 safety parameters in this trial. All safety parameters are considered either 
Tier 2 or Tier 3. Tier 2 parameters will be assessed via point estimates with 
95% CIs provided for between-group comparisons; only point estimates by 
treatment group are provided for Tier 3 safety parameters. The between-
treatment difference will be analyzed using the Miettinen and Nurminen 
method.
In the primary safety comparison, subjects who crossover to pembrolizumab 
are censored at time of crossover (ie, AEs occurring during treatment with 
pembrolizumab are excluded for control-arm subjects). An exploratory safety 
analysis will be conducted for the crossover population including all safety 
events starting from the date of the first dose of pembrolizumab.
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Interim Analyses
There are 4 analyses planned for this study: 3 IAs and one final analysis.
Results from the first 3 IAs will be reviewed by an eDMC. Details are
provided in Section 8.7.
IA1
o
Timing: To be performed after ~200 subjects have ~28 
weeks of follow-up
o
Purpose: To demonstrate superiority of pembrolizumab in 
combination with carboplatin and a taxane in ORR
IA2
o
Timing: To be performed after a target number of PFS 
events (~332) is observed
o
Purpose: 1) To demonstrate superiority of pembrolizumab in 
combination with carboplatin and a taxane in PFS; 2) To 
demonstrate superiority of pembrolizumab in combination 
with carboplatin and a taxane in OS
IA3
o
Timing: To be performed after a target number of PFS events
(~415) is observed
o
Purpose: 1) To demonstrate superiority of pembrolizumab in 
combination with carboplatin and a taxane in PFS; 2) To 
demonstrate superiority of pembrolizumab in combination 
with carboplatin and a taxane in OS
Because of positive interim results for both PFS and OS, subsequent 
analyses will be conducted and reviewed by the Sponsor and may be 
performed at the planned time of final analysis, or as needed.
Multiplicity
The study uses the graphical method of Maurer and Bretz [42] to control
multiplicity for multiple hypotheses as well as IAs. According to this
approach, study hypotheses may be tested more than once, and when a 
particular null hypothesis is rejected, the alpha allocated to that hypothesis can 
be reallocated to other hypothesis tests. The overall type I error is controlled at 
0.025 (one-sided) for the hypothesis testing of ORR, PFS, and OS. The pre-
allocated alpha is 0.005, 0.01, and 0.01 for ORR, PFS, and OS, respectively. 
ORR may be tested at 0.005 or at 0.025 (if both PFS and OS are positive, 
using the p-value from IA1). PFS may be tested at 0.01 or at 0.015 (if ORR is 
positive but OS is not positive), or at 0.02 (if OS is positive but ORR is not 
positive) or at 0.025 (if both OS and ORR are positive). OS may be tested at 
0.01 or at 0.02 (if PFS is positive but ORR is not positive) or 0.025 (if both 
PFS and ORR are positive). A Lan-DeMets O'Brien-Fleming approximation 
spending function will be used for the calculation of efficacy bounds for PFS 
and OS.
Sample Size and Power
The final analysis occurs after ~361 deaths are observed unless the trial is 
terminated early. With 361 deaths, the study has 92% power for detecting an
HR of 0.7 at 0.025 (one-sided), ~90% power for detecting an HR of 0.7 at 0.02 
(one-sided), and ~85% power for detecting an HR of 0.7 at 0.01 (one-sided).
The planned sample size is approximately 560 subjects assuming ~15.5
months of enrollment.
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Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The Sponsor will generate the randomized allocation schedule(s) for study treatment 
assignment for this protocol, and the randomization will be implemented in IVRS.
This trial is double-blinded with a crossover phase. At the time of documented progression, 
subjects will have treatment assignment unblinded and be able to continue therapy in the 
Crossover Phase (please refer to Section 2.1 - Trial Design for details). In addition, 
independent central radiologist(s) will perform the central imaging review without 
knowledge of treatment assignment.
An eDMC will be convened to review accumulating safety data to provide an opportunity to 
terminate the study early if there are concerns regarding safety. The eDMC will also review 
the unblinded efficacy results at the planned IAs. The eDMC responsibilities and review 
schedules will be outlined in the eDMC charter. The recommendation of the eDMC will be 
communicated to an EOC of the Sponsor. In the event of a recommendation to halt the trial 
early due to safety concerns, the Sponsor will communicate this to the appropriate regulatory 
agencies. If the eDMC recommends modifications to the design of the protocol or 
discontinuation of the study, the EOC may be unblinded to results at the treatment level in 
order to act on these recommendations.
A limited number of additional Sponsor personnel may be unblinded, if required, in order to 
act on the recommendations of the eDMC. The extent to which individuals are unblinded to 
the results will be documented. Additional logistical details, revisions to the above plan, and 
data monitoring guidance will be provided in the eDMC Charter.
Positive interim results for both PFS and OS were observed. Thus, a limited number of 
Sponsor personnel have been unblinded to support regulatory filing. The extent to which
individuals were unblinded to the results has been documented.
See Appendix 12.7 for country-specific information.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0.
Analysis Endpoints
Efficacy Endpoints
Dual Primary
PFS – RECIST 1.1 assessed by a blinded independent central imaging vendor
PFS is defined as the time from randomization to the first documented disease progression 
per RECIST 1.1 based on blinded independent central imaging vendor review or death due to 
any cause, whichever is earlier. See Section 8.6.1 for the censoring rules.
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Overall Survival
OS is defined as the time from randomization to death due to any cause. Subjects without
documented death at the time of analysis will be censored at the date of the last known 
contact.
Secondary
ORR – RECIST 1.1 assessed by a blinded independent central imaging vendor
ORR is defined as the proportion of subjects who have a CR or a PR. Responses are based on 
confirmed assessments by the blinded independent central imaging vendor review per 
RECIST 1.1.
DOR – RECIST 1.1 assessed by a blinded independent central imaging vendor
For subjects who demonstrated CR or PR, DOR is defined as the time from the 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 using RECIST 1.1 based
on blinded independent radiologist review.
Safety Endpoints
Safety measurements are described in Section 4.2.3.4.
Analysis Populations
Efficacy Analysis Populations
The intention-to-treat (ITT) population will serve as the population for the primary efficacy 
analyses. All randomized subjects will be included in this population. Subjects will be 
included in the treatment group to which they are randomized.
See Appendix 12.7 for country-specific information.
Safety Analysis Populations
The all-subjects-as-treated (ASaT) population will be used for the analysis of safety data in 
this study. The ASaT population consists of all randomized subjects who received at least 1
dose of study treatment. Subjects will be included in the treatment group corresponding to 
the study treatment they actually received for the analysis of safety data using the ASaT 
population. For most subjects this will be the treatment group to which they are randomized. 
Subjects who take incorrect study treatment for the entire treatment period will be included in 
the treatment group corresponding to the study treatment actually received. Any subject who 
receives the incorrect study medication for 1 cycle but receives the correct treatment for all 
other cycles will be analyzed according to the subject’s randomized treatment group and a 
narrative will be provided for any events that occur during the cycle for which the subject 
was incorrectly dosed.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
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Extension Study
Chinese subjects randomized and treated in the extension study will not be included in the 
above primary safety analysis population. The Chinese ASaT population as well as the entire 
ASaT population consisting of the primary safety population and subjects randomized and 
treated will be analyzed per local regulatory requirements.
Statistical Methods
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the sSAP.
Efficacy results that will be deemed to be statistically significant after consideration of the 
Type I error control strategy are described in Section 8.8 - Multiplicity. Nominal p-values 
will be computed for other efficacy analyses, but should be interpreted with caution due to 
potential issues of multiplicity.
All statistical tests, unless otherwise specified, will be stratified for treatment and 
stratification factors.
8.6.1.1
Progression-Free Survival (PFS)
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. The treatment difference in PFS will be assessed by the stratified log-rank 
test (based on the stratification factors defined in Section 5.4). A stratified Cox proportional 
hazard model with Efron's method of tie handling will be used to assess the magnitude of the 
treatment difference (ie, HR) between the treatment arms. The HR and its 95% CI from the 
stratified Cox model with Efron's method of tie handling and with a single-treatment 
covariate will be reported. The stratification factors used for randomization (see Section 5.4)
will be applied to both the stratified log-rank test and the stratified Cox model.
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. For the primary analysis, for the subjects who have PD, the true date of disease 
progression will be approximated by the date of the first assessment at which PD is 
objectively documented per RECIST 1.1 by a blinded independent central imaging vendor, 
regardless of discontinuation of study drug. Death is always considered as a confirmed PD 
event. Sensitivity analyses will be performed for comparison of PFS based on investigator's 
assessment.
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 by a blinded 
independent central imaging vendor, we will perform 2 sensitivity analyses with a different
set of censoring rules. The first sensitivity analysis is the same as the primary analysis except 
that it censors at the last disease assessment without PD when PD or death is documented 
after more than 1 missed disease assessment. The second sensitivity analysis is the same as 
the primary analysis except that it considers discontinuation of treatment or initiation of an 
anticancer therapy subsequent to discontinuation of study-specified treatments, whichever is 
later, to be a PD event for subjects without documented PD or death. The censoring rules for 
primary and sensitivity analyses are summarized in Table 8. In case there is an imbalance 
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between the treatment groups on disease assessment schedules or censoring patterns, we will 
perform an additional PFS sensitivity analysis using time from randomization to scheduled 
tumor assessment time instead of actual tumor assessment.
Table 8
Censoring Rules for Primary and Sensitivity Analyses of PFS
Situation
Primary Analysis
Sensitivity Analysis 1
Sensitivity Analysis 2
No PD and no death; 
new anticancer therapy
is not initiated
Censored at last disease 
assessment
Censored at last disease 
assessment
Censored at last disease 
assessment if still on study 
therapy; progressed at 
treatment discontinuation 
otherwise
No PD and no death; 
new anticancer therapy
is initiated
Censored at last disease 
assessment before new 
anticancer therapy
Censored at last disease 
assessment before new 
anticancer therapy
Progressed at date of new 
anticancer therapy
PD or death 
documented after ≤1 
missed disease 
assessment
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or death
PD or death 
documented 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
In case the proportional hazards assumption is not valid, supportive analyses using the 
Restricted Mean Survival Time method may be conducted for PFS to account for the possible 
non-proportional hazards effect.
An exploratory analysis of PFS2, defined as the time from randomization to subsequent 
disease progression after initiation of new anticancer therapy, or death from any cause, 
whichever is earlier, may be carried out. Patients alive and for whom a disease progression 
following initiation of new anticancer therapy has not been observed will be censored at the 
last time the subject was known to be alive and without disease progression.
Further details of sensitivity analyses will be described in sSAP as needed.
8.6.1.2
Overall Survival (OS)
The non-parametric Kaplan-Meier method will be used to estimate survival curves. The 
treatment difference in survival will be assessed by the stratified log-rank test (based on the 
stratification factor defined in Section 5.4). A stratified Cox proportional hazard model with 
Efron's method of tie handling will be used to assess the magnitude of the treatment 
difference (ie, HR). The HR and its 95% CI from the stratified Cox model with a 
single-treatment covariate will be reported. The stratification factors used for randomization 
(see Section 5.4) will be applied to both the stratified log-rank test and the stratified Cox 
model. The Restricted Mean Survival Time method may be conducted for OS to account for 
the possible non-proportional hazards effect and to estimate the absolute benefit of 
experimental treatment. A cure-rate model may be applied to estimate the long-term effect.
Since subjects in the control arm are allowed to switch to pembrolizumab monotherapy after 
progressive disease, adjustment for the effect of crossover on OS may be performed based on 
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recognized methods, eg, a 2-stage method or the Rank Preserving Structural Failure Time 
model, based on an examination of the appropriateness of the data to the assumptions 
required by the methods.
Further details of sensitivity analyses will be described in sSAP as needed.
8.6.1.3
Objective response rate (ORR) and Duration of Response (DOR)
The stratified Miettinen and Nurminen method will be used for the comparison of ORR 
between the 2 treatment groups. The difference in ORR and its 95% CI from the stratified 
Miettinen and Nurminen method with strata weighting by sample size with a single-treatment 
covariate will be reported. The stratification factors used for randomization (see Section 5.4) 
will be applied to the analysis.
If sample size permits, DOR will be summarized descriptively using Kaplan-Meier medians 
and quartiles. Only the subset of subjects who show a CR or PR will be included in this 
analysis.
8.6.1.4
Analysis Strategy for Key Efficacy Endpoints
Table 9 summarizes the primary analysis approach for primary and key secondary efficacy 
endpoints. Sensitivity analysis methods are described above for each endpoint as applicable.
The strategy to address multiplicity issues with regard to multiple efficacy endpoints, and IAs 
is described in Section 8.7 - Interim Analyses and in Section 8.8 - Multiplicity.
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Table 9
Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
(Description, Time Point) 
Statistical Method†
Analysis 
Population
Missing Data Approach
Dual Primary Endpoints
PFS per RECIST 1.1 by blinded 
independent central imaging 
vendor
Test: Stratified Log-rank test 
to assess the treatment 
difference
Estimation: Stratified Cox 
model with Efron’s tie 
handling method to assess the 
magnitude of treatment 
difference
ITT
Primary censoring rule
Sensitivity analysis 1
Sensitivity analysis 2
OS
Test: Stratified Log-rank test 
to assess the treatment 
difference
Estimation: Stratified Cox 
model with Efron’s tie 
handling method to assess the 
magnitude of treatment 
difference
ITT
Model based
(censored at the last date the 
subject was known to be 
alive)
Key Secondary Endpoints
ORR per RECIST 1.1 by blinded 
independent central imaging 
vendor
Test and Estimation: Stratified 
Miettinen and Nurminen
method with sample size 
weights††
ITT
Subjects without assessments 
are considered non-responders 
and conservatively included in 
the denominator
DOR per RECIST 1.1 by blinded 
independent central imaging 
vendor
Descriptive statistics for range 
and Kaplan-Meier estimate of 
median
Patients in ITT
population with an 
objective response
  † Statistical models are described in further detail in the text. For stratified analyses, the stratification factors used for 
randomization (Section 5.4) will be applied to the analysis.
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, and vital signs.
Adverse Events
AEs will be coded using the standard MedDRA and grouped by system organ class. AEs will 
be graded by the investigator according to the CTCAE, version 4.0.
Tiered Approach
The analysis of safety results will follow a tiered approach (Table 10). The tiers differ with 
respect to the analyses that will be performed. “Tier 1” safety endpoints that will be subject 
to inferential testing for statistical significance with p-values and 95% CIs provided for 
between-group comparisons. For this protocol, there are no Tier 1 events. Other safety 
parameters will be considered “Tier 2” or “Tier 3”. Tier 2 parameters will be assessed via 
point estimates with 95% CIs provided for between-group comparisons; only point estimates 
by treatment group are provided for Tier 3 safety parameters.
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Adverse experiences (specific terms as well as system organ class terms) that are not pre-
specified as Tier 1 endpoints will be classified as belonging to Tier 2 or Tier 3, based on the 
number of events observed. Membership in Tier 2 requires that at least 4 subjects in any 
treatment group exhibit the event; all other adverse experiences and predefined limits of 
change will belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% CI for the between-group 
difference in percent incidence will always include zero when treatment groups of equal size 
each have less than 4 events and thus would add little to the interpretation of potentially 
meaningful differences. Because many 95% CIs may be provided without adjustment for 
multiplicity, the CIs 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 values and vital signs, 
which 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, the broad clinical and laboratory AE categories consisting of the percentage of 
subjects with any AE, any drug-related AE, any Grade 3-5 AE, any serious AE, any AE that
is both drug-related and Grade 3-5, any AE which is both serious and drug-related, a dose 
modification due to AE, a discontinuation due to an AE, and death will be considered Tier 2 
endpoints. The 95% CIs (Tier 2) will be provided for between- treatment differences in the 
percentage of subjects with events; these analyses will be performed using the unstratified
Miettinen and Nurminen method (1985), an unconditional, asymptotic method.
Table 10
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint†
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE
X
X
Any Serious AE 
X
X
Any Grade 3-5 AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Any Grade 3-5 and Drug-Related AE
X
X 
Dose Modification due to AE
X
X
Discontinuation due to AE
X
X
Death
Specific AEs, SOCs, or PDLCs‡ (incidence ≥4 of subjects in 
one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs‡ (incidence <4 of subjects in 
all of the treatment groups)
X
Change from Baseline Results (Labs, ECGs, Vital Signs)
X
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Summaries of Demographic and Baseline Characteristics 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 reasons 
for discontinuation will be displayed. Demographic variables (eg, age, gender) and baseline 
characteristics will be summarized by treatment either by descriptive statistics or categorical 
tables.
Interim Analyses
There are 3 planned IAs in addition to the final analysis for this study. Details on the 
boundaries for establishing statistical significance with regard to efficacy are discussed 
further in Section 8.8. The trial will continue until the number of deaths (see Section 8.9) is 
approximately equal to the targeted number for the final analysis irrespective of the outcome 
from the IAs.
The analyses planned, endpoints evaluated, and drivers of timing are summarized in Table 11.
Table 11
Summary of Interim and Final Analyses Strategy
Analyses 
Key 
Endpoints
Timing
Estimated Time after 
First Participant 
Randomized
Primary Purpose of 
Analysis
IA1
ORR
~ 200 subjects are 
followed for ~ 28 weeks so 
that each patient has at 
least 4 tumor assessments
~ 15 months 
Demonstrate ORR 
superiority
IA2
PFS
OS
~ 332 PFS events have 
been observed
~ 20 months 
Demonstrate PFS 
superiority
Demonstrate OS 
superiority
IA3
PFS
OS
~ 415 PFS events have 
been observed
~ 25 months
Demonstrate PFS 
superiority
Demonstrate OS 
superiority
Final 
Analysis
OS
~ 361 deaths have occurred
~ 31 months
Demonstrate OS 
superiority
Because of positive results in the China extension for both PFS and OS observed at the IA, 
subsequent analyses may be performed at the planned time of final analysis, or as needed.
Multiplicity
The study uses the graphical method of Maurer and Bretz [42] to control multiplicity for 
multiple hypotheses as well as IAs. According to this approach, study hypotheses may be 
tested more than once, and when a particular null hypothesis is rejected, the alpha allocated 
to that hypothesis can be reallocated to other hypothesis tests. Figure 3 shows the initial one-
sided alpha allocation for each hypothesis in the ellipse representing the hypothesis. The 
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weights for reallocation from each hypothesis to the others are represented in the boxes on 
the lines connecting hypotheses.
Figure 3
Type I Error Reallocation Strategy Following Closed Testing Principle
ORR=objective response rate; OS=overall survival; PFS=progression-free survival.
Note: If both PFS and OS null hypotheses are rejected, the reallocation strategy allows re-testing of ORR at alpha=0.025 based on the p-
value at IA1.
Objective Response Rate
The study allocates alpha=0.005, one-sided, to test ORR, and ORR is tested only at IA1. 
However, if the test does not reach statistical significance at IA1, the p-value from IA1 can 
be compared to an updated alpha-level if the null hypotheses for both PFS and OS are 
rejected at a later time. Power at the possible alpha-levels as well as the approximate 
treatment difference required to reach the bound (ORR difference) are shown in Table 12, 
assuming underlying 25% and 50% response rates in the control and experimental groups, 
respectively. 
Table 12
Possible Alpha-levels and Approximate ORR Difference Required to 
Demonstrate Efficacy for ORR at IA1
Alpha
ORR difference
Power
0.005
~ 0.18
0.84
0.025
~ 0.13
0.94
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Progression-free Survival
The initial alpha-level for testing PFS is 0.01. If the null hypothesis for ORR is rejected, 
Table 12 shows that its alpha=0.005 is fully reallocated to PFS hypothesis testing. If the null 
hypothesis for OS is rejected, then alpha=0.01 is essentially fully reallocated to PFS 
hypothesis testing. Thus, the PFS null hypothesis may be tested at alpha=0.01, alpha=0.015 
(if the ORR null hypothesis is rejected but not the OS null hypothesis), alpha=0.02 (if the OS 
null hypothesis is rejected but not the ORR null hypothesis), or alpha=0.025 (if both the ORR 
and OS null hypotheses are rejected). Table 13 shows the boundary properties for each of 
these alpha-levels for the IAs, which were derived using a Lan-DeMets O'Brien-Fleming 
spending function. Note that the final row indicates the total power to reject the null 
hypothesis for PFS at each alpha-level. If the actual number of events at the PFS analyses 
differ from those specified in the table, the bounds will be adjusted using the Lan-DeMets 
O'Brien-Fleming spending function accordingly. Also note that if the OS null hypothesis is 
rejected at an IA or final analysis, each PFS IA and final analysis test may be compared to its 
updated bounds considering the alpha reallocation from the OS hypothesis.
Table 13
Efficacy Boundaries and Properties for Progression-free Survival Analyses
Analysis
Value
=0.01
=0.015
=0.02
=0.025
IA2: 80%*
N: 560
Events: 332
Month: 20
Z
-2.6539
-2.4817
-2.3536
-2.2504
p (1-sided) §
0.004
0.0065
0.0093
0.0122
HR at bound
0.7473
0.7616
0.7723
0.7811
P(Cross) if HR=1†
0.004
0.0065
0.0093
0.0122
P(Cross) if HR=0.7#
0.7243
0.7787
0.8148
0.8411
IA3: 100%*
N: 560
Events: 415
Month:25
Z
-2.3737
-2.2244
-2.1138
-2.025
p (1-sided) §
0.0088
0.0131
0.0173
0.0214
HR at bound
0.7921
0.8038
0.8126
0.8197
P(Cross) if HR=1†
0.01
0.015
0.02
0.025
P(Cross) if HR=0.7#
0.9
0.9243
0.9392
0.9494
*Percentage of expected number of events at final analysis required at interim analysis.
§p (1-sided) is the nominal alpha for testing.
HR at bound is the approximate HR required to reach an efficacy bound.
†P(Cross if HR=1) is the cumulative probability of crossing a bound under the null hypothesis.
#P(Cross if HR=0.7) is the cumulative probability of crossing a bound under the alternative hypothesis.
Overall Survival
The OS hypothesis may be tested at alpha=0.01 (initially allocated alpha), alpha=0.02 (if the 
PFS but not the ORR null hypothesis is rejected), or alpha=0.025 (if both the ORR and PFS 
null hypotheses are rejected). Table 14 demonstrates the bounds and boundary properties for 
OS hypothesis testing derived using a Lan-DeMets O'Brien-Fleming spending function. If 
the actual number of OS events at the IA and final analyses differs from those specified in 
the table, the bounds will be adjusted using the Lan-DeMets O'Brien-Fleming spending 
function accordingly.
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Table 14
Efficacy Boundaries and Properties for Overall Survival Analyses
Analysis
Value
=0.01
=0.02
=0.025
IA2: 59%*
N: 560
Events: 212
Month: 20
Z 
-3.1648
-2.8202
-2.702
p (1-sided) §
0.0008
0.0024
0.0034
HR at bound
0.6474
0.6788
0.6899
P(Cross) if HR=1†
0.0008
0.0024
0.0034
P(Cross) if HR=0.7 #
0.2849
0.4115
0.458
IA3: 79%*
N: 560
Events: 286
Month: 25
Z 
-2.6914
-2.3992
-2.2995
p (1-sided) §
0.0036
0.0082
0.0107
HR at bound 
0.7274
0.7530
0.7619
P(Cross) if HR=1†
0.0038
0.009
0.0117
P(Cross) if HR=0.7#
0.6312
0.7362
0.7684
Final 
N: 560
Events: 361
Month: 31
Z 
-2.3742
-2.116
-2.028
p (1-sided) §
0.0088
0.0172
0.0213
HR at bound 
0.7789
0.8003
0.8078
P(Cross) if HR=1†
0.01
0.02
0.025
P(Cross) if HR=0.7 #
0.85
0.9034
0.9181
*Percentage of expected number of events at final analysis required at interim analysis.
§p (1-sided) is the nominal α for testing.
HR at bound is the approximate HR required to reach an efficacy bound.
†P(Cross if HR=1) is the cumulative probability of crossing a bound under the null hypothesis.
#P(Cross if HR=0.7) is the cumulative probability of crossing a bound under the alternative hypothesis.
Sample Size and Power Calculations
With ~200 subjects, the study has ~84% power for detecting a 25% difference in ORR (50% 
vs. 25%) or ~97% power for detecting a 30% difference in ORR (50% vs. 20%) at initially 
assigned 0.005 (one-sided) significance level. The study has ~94% power for detecting a 
25% difference in ORR (50% vs. 25%) or ~99% power for detecting a 30% difference in 
ORR (50% vs. 20% ) at 0.025 (one-sided) significance level.
With 415 PFS events, the study has ~90% power for detecting an HR of 0.7 at 
initially-assigned 0.01 (one-sided) significance level, ~92% power for detecting an HR of 0.7 
at 0.015 (one-sided) significance level, ~94% power for detecting an HR of 0.7 at 0.02 (one-
sided) significance level, and ~95% power for detecting an HR of 0.7 at 0.025 (one-sided) 
significance level.
With 361 deaths, the study has ~85% power for detecting an HR of 0.7 at 0.01 (one-sided)
significance level, ~90% power for detecting an HR of 0.7 at 0.02 (one-sided) significance 
level, and ~92% power for detecting an HR of 0.7 at 0.025 (one-sided) significance level.
The planned sample size is approximately 560 subjects assuming: (1) the enrollment period 
is 15.5 months and the ramp-up period of enrollment is 7 months; (2) median PFS is 6 
months in the control group and the true HR is 0.7; (3) median OS is 12 months in the control 
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group and the true HR is 0.7; (4) the annual dropout rate is 3% for PFS and 1% for OS; (5) 
the number of events and alpha levels of IAs and final analysis are as specified in Section 8.7 
and Section 8.8.
See Appendix 12.7 for country-specific information.
Subgroup Analyses and Effect of Baseline Factors
To determine whether the treatment effect is consistent across various subgroups, the 
between-group treatment effect for OS, PFS, and ORR (with a nominal 95% CI) will be 
estimated and plotted within each category of the following classification variables:
•
Age category (<65, ≥65 years)
•
ECOG Performance Scale (0, 1)
•
Sex (female, male)
•
Race (white, non-white)
•
Geographic region of enrolling site (East Asia, non-East Asia)
•
Smoking status (never, former/ current)
•
Brain metastasis status at baseline (yes, no)
•
PD-L1 expression (TPS <1%, 50%>TPS ≥1%, or TPS ≥50%) 
•
Taxane chemotherapy (paclitaxel, nab-paclitaxel)
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles.
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 15.
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
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Table 15
Product Descriptions
Product Name & 
Potency
Dosage Form
Source/Additional Information
Pembrolizumab
(MK-
3475) 100 mg / 4 mL
Solution for Infusion
Provided centrally by the Sponsor.
Nab-Paclitaxel 
100mg
vial
Powder for Infusion
Provided centrally by the Sponsor 
or locally by the trial site, 
subsidiary, or designee. 
Carboplatin 10 mg/mL, 
60 mL
Solution for Infusion
Provided centrally by the Sponsor 
or locally by the trial site, 
subsidiary, or designee. 
Paclitaxel 6 mg/mL, 16.7 
mL
Solution for Infusion
Provided centrally by the Sponsor 
or locally by the trial site, 
subsidiary, or designee. 
All supplies indicated in Table 15 will be provided per the “Source/Additional Information” 
column depending on local country operational requirements.
Any commercially available product not included in Table 15 will be provided by the trial 
site, subsidiary or designee. Every attempt should be made to source these supplies from a 
single lot/batch number. The trial site is responsible for recording the lot number, 
manufacturer, and expiry date for any locally purchased product as per local guidelines 
unless otherwise instructed by the Sponsor.
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
All supplies will be provided open label. Pembrolizumab will be provided as non-kitted 
single vials or as single/multi vials in a kit box. The other products will be provided as a kit 
with a single vial.
Clinical Supplies Disclosure
This trial is blinded but provided open label; therefore, an unblinded pharmacist or qualified 
trial site personnel will be used to blind supplies. Treatment identity (name, strength or 
potency) is included in the label text; random code/disclosure envelopes or lists are not 
provided.
The emergency unblinding call center will use the treatment/randomization schedule for the 
trial to unblind subjects and to unmask treatment identity. In the event that the emergency 
unblinding call center is not available for a given site in this trial, the central electronic 
treatment allocation/randomization system (IVRS/IWRS) should be used in order to unblind 
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subjects and to unmask treatment/vaccine identity. The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
Treatment identification information is to be unmasked ONLY if necessary for the welfare of 
the subject.  Every effort should be made not to unblind the subject unless necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., 
date, reason and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.  Only the principal investigator or 
delegate and the respective subject’s code should be unblinded.  Trial site personnel and 
Sponsor personnel directly associated with the conduct of the trial should not be unblinded to 
treatment assignment. Subjects whose treatment assignment has been unblinded (by the 
investigator, Merck subsidiary, or through the emergency unblinding call center) must be 
discontinued from study drug.
Section 5.8 outlines the criteria for allowing subjects who are discontinued from treatment to 
continue to be monitored in the trial.
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.   Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Standard Policies
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
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10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
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If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice:
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/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.
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The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
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.
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According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Merck, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements.  Merck entries are not limited to FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.    
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
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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 
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.
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The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
11.0 LIST OF REFERENCES
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[5]
Patnaik A, Kang SP, Tolcher AW, Rasco DW, Papadopoulos KP, Beeram M, et al.  
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antibody) in patients with advanced solid tumors.
[6]
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Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J 
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Chapman PB, Hauschild A, Robert C, Hannen JB, Ascierto P, Larkin J, et al. 
Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N 
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Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, et al. Ipilimumab 
plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 
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Sasaki A, Tanaka F, Mimori K, Inoue H, Kai S, Shibata K, et al. Prognostic value of 
tumor-infiltrating FOXP3+ regulatory T cells in patients with hepatocellular 
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[10]
Shen Z, Zhou S, Wang Y, Li R, Zhong C, Liang C, et al. Higher intratumoral
infiltrated Foxp3+ Treg numbers and Foxp3+/CD8+ ratio are associated with 
adverse prognosis in resectable gastric cancer. J Cancer Res Clin Oncol 
2010;136:1585-95.
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[11]
Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll 
or Hyde. Cancer Metastasis Rev 2007;26(3-4):373-400.
[12]
Usubütün A, Ayhan A, Uygur MC, Özen H, Toklu C, Ruacan S. Prognostic factors 
in renal cell carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81.
[13]
Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged 
survival of a patient affected by pancreatic adenocarcinoma with massive 
lymphocyte and dendritic cell infiltration after interleukin-2 immunotherapy. Report 
of a case. Tumori 2008;94(3):426-30.
[14]
Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: 
molecular biology. Int J Clin Oncol 2010;15(6):544-51.
[15]
Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J 
Cutan Pathol 2010;37(Suppl 1):48-53.
[16]
Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet Oncol. 
2009 Sep;10(9):840-1.
[17]
Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic 
implications of type and density of tumour-infiltrating lymphocytes in gastric 
cancer. Br J Cancer 2008;99(10):1704-11.
[18]
Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of 
regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes 
correlates with poor prognosis in renal cell carcinoma. BJU Int 2011;107(9):1500-6.
[19]
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.
[20]
Chew V, Tow C, Teo M, Wong HL, Chan J, Gehring A, et al. Inflammatory tumor 
microenvironment is associated with superior survival in hepatocellular carcinoma 
patients. J Hepatol 2010;52:370-9.
[21]
Pölcher M, Braun M, Friedrichs N, Rudlowski C, Bercht E, Fimmers R, et al. 
Foxp3(+) cell infiltration and granzyme B(+)/Foxp3(+) cell ratio are associated with 
outcome in neoadjuvant chemotherapy-treated ovarian carcinoma. Cancer Immunol 
Immunother 2010;59(6):909-19.
[22]
Oble DA, Loewe R, Yu P, Mihm MC Jr. Focus on TILs: prognostic significance of 
tumor infiltrating lymphocytes in human melanoma. Cancer Immun. 2009 Apr 
2;9:3.
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[23]
Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma V-M. Prognostic 
value of tumour-infiltrating lymphocytes (TILs) in colorectal cancer. J Pathol 
1997;182(3):318-24.
[24]
Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. 
Adoptive cell transfer therapy following non-myeloablative but lymphodepleting 
chemotherapy for the treatment of patients with refractory metastatic melanoma. J 
Clin Oncol 2005;23(10):2346-57.
[25]
Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. 
Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-
1. N Engl J Med 2008;358(25):2698-703.
[26]
Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor 
inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-
containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A 
2001;98(24):13866-71.
[27]
Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev 
Immunol 2005;23:515-48.
[28]
KEYTRUDA (pembrolizumab) Investigator's Brochure, Edition Number 10, 31-
AUG-2015.
[29]
Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. 
Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015 
May 21;372(21):2018-28.
[30]
Peters S, Adjei AA, Gridelli C, Reck M, Kerr K, Felip E, et al. Metastatic non-
small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, 
treatment and follow-up. Annals Oncol 2012;23(Supplement 7):vii56-vii64.
[31]
Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. 
Comparison of four chemotherapy regimens for advanced non-small-cell lung 
cancer. N Engl J Med 2002;346:92-8.
[32]
Ardizzoni A, Boni L, Tiseo M, Fossella FV, Schiller JH, Paesmans M, et al. 
Cisplatin- versus carboplatin-based chemotherapy in first-line treatment of advanced 
non-small-cell lung cancer: an individual patient data meta-analysis. J Natl Cancer 
Inst. 2007 Jun 6;99(11):847-57.
[33]
Socinski MA, Bondarenko I, Karaseva NA, Makhson AM, Vynnychenko I, 
Okamoto I, et al. Weekly nab-Paclitaxel in Combination With Carboplatin Versus 
Solvent-Based Paclitaxel Plus Carboplatin as First-Line Therapy in Patients With 
Advanced Non-Small-Cell Lung Cancer: Final Results of a Phase III Trial. J Clin 
Oncol 2012;30:2055-62.
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[34]
Yang JJ, Huang C, Chen GY, Song Y, Cheng Y, Yan HH, et al. A randomized 
phase II clinical trial of nab-paclitaxel and carboplatin compared with gemcitabine 
and carboplatin as first-line therapy in locally advanced or metastatic squamous cell 
carcinoma of lung. BMC Cancer. 2014 Sep 20;14:684.
[35]
Thatcher N, Hirsch FR, Luft AV, Szczesna A, Ciuleanu TE, Dediu M, et al. 
Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone 
as first-line therapy in patients with stage IV squamous non-small-cell lung cancer 
(SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2015 
Jul;16(7):763-74.
[36]
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer 
statistics, 2012. CA Cancer J Clin. 2015 Mar;65(2):87-108.
[37]
Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, et al. 
International Association for the Study of Lung Cancer International Staging
Committee; Participating Institutions. The IASLC Lung Cancer Staging Project: 
proposals for the revision of the TNM stage groupings in  the forthcoming (seventh) 
edition of the TNM Classification of malignant tumours. J Thorac Oncol. 2007 
Aug;2(8):706-14. Erratum in: J Thorac Oncol. 2007 Oct;2(10):985.
[38]
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. 
Developing a common language for tumor response to immunotherapy: immune-
related response criteria using unidimensional measurements. Clin Cancer Res. 
2013 Jul 15;19(14):3936-43.
[39]
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 1994;30A(5):635-42.
[40]
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.
[41]
Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, et al. 
2006 update of recommendations for the use of white blood cell growth factors: an 
evidence-based clinical practice guideline. J Clin Oncol 2006;24(19):3187-205.
[42]
Maurer W and Bretz F. Multiple testing in group sequential trials using graphical 
approaches. Stat Biopharm Res 2013;5(4):311-20.
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12.0 APPENDICES
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I.
Introduction
A. Purpose
MSD, 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 participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and 
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD 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 that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities 
and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, 
sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to 
successfully conduct the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts 
to raise awareness of clinical trial opportunities in various communities. MSD will seek to engage 
underrepresented groups and those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to those who will ultimately 
use the products under investigation.
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3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. 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 such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). 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. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants 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.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
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D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
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Collection and Management of Specimens for Future Biomedical Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research3,4
The specimens consented and/or collected in this study as outlined in Section 7.1.3.6 will be 
used in various experiments to understand:  

The biology of how drugs/vaccines work

Biomarkers responsible for how a drug/vaccine enters and is removed by the body

Other pathways with which drug/vaccines may interact

The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations with 
the greatest need.  All specimens will be used by the Sponsor or those working for or with 
the Sponsor.
3. Summary of Procedures for Future Biomedical Research3,4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate.  Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA.  If delayed, present consent at next possible Participant Visit.  Consent 
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forms signed by the subject will be kept at the clinical trial site under secure storage 
for regulatory reasons.  
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.  
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of subject consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other trial purposes.
4. Confidential Participant Information for Future Biomedical Research3,4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants’ 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 participant 
characteristics like sex, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the future biomedical research 
specimens.  This first code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this first unique code will be held at the study site.  No personal identifiers 
will appear on the specimen tube.  
5. Biorepository Specimen Usage3,4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices.  Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3,4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR.  Participants may withdraw consent at any time by contacting the study 
investigator.  If medical records for the main trial are still available, the investigator will 
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contact 
the 
Sponsor 
using 
the 
designated 
mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only.  If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and be destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable.  It is the responsibility of the 
investigator to inform the participant of completion the withdrawal and/or destruction, if 
applicable.  Any analyses in progress at the time of request for withdrawal/destruction or 
already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed. 
7. Retention of Specimens3,4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study.  Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3,4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3,4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
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rapidly report this information to doctors and participants.  Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3,4
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3,4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent. 
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused. 
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National 
Cancer 
Institute 
[Internet]: 
Available 
from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding 
Categories. Available from http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/definitions-for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-
genomic-data-and-sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, Scope 
and Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry 
Pharmacogenomics 
Working 
Group 
[Internet]: 
Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-
pwg.org/
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff
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List of Abbreviations
Abbreviation/Term
Definition
1L
first line
5-HT3
5-hydroxytryptamine 3
ADA
anti-drug antibodies
AE
adverse event
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
ASaT
all-subjects-as-treated
AST
aspartate aminotransferase
AUC
area under the curve
β-HCG
beta human chorionic gonadotropin
BSC
best supportive care
CBC
complete blood count
CD
cluster of differentiation
CI
confidence interval
CNS
central nervous system
COPD
chronic obstructive pulmonary disease
CR
complete response
CrCl
calculated creatinine clearance
CRF
Case Report Form
CSF
colony-stimulating factor
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Toxicity Criteria for Adverse Events
CTLA-4
cytotoxic T lymphocyte antigen-4
DLT
dose-limiting toxicity
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DOR
duration of response
ECG
electrocardiogram
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eDMC
external Data Monitoring Committee
EGFR
epidermal growth factor receptor
EMA
European Medicines Agency
EOC
Executive Oversight Committee
ERC
Ethics Review Committee
EU
European Union
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GFR
glomerular filtration rate
Hb
hemoglobin
HBV
hepatitis B
HCV
hepatitis C
HIV
human immunodeficiency virus
HR
hazard ratio
IA
interim analysis
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Abbreviation/Term
Definition
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use
IFN
interferon
Ig
immunoglobulin
IHC
immunohistochemistry
IL
interleukin
INR
international normalized ratio
IO
immuno-oncology
irAE
immune-related adverse event
IRB
Institutional Review Board
irRECIST
immune-related Response Evaluation Criteria in Solid Tumors
ITT
intent-to-treat
IV
intravenous(ly)
IVD
in vitro diagnostics
IVRS
interactive voice response system
IWRS
interactive web response system
kg
kilogram
LDH
lactate dehydrogenase
mAb
monoclonal antibody
MASCC
Multinational Association of Supportive Care in Cancer
mcL
microliters
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
mg/kg
milligram per kilogram
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
MTD
maximum tolerated dose
NA or N/A
not applicable
nab-paclitaxel
nano particle albumin-bound paclitaxel
NCI
National Cancer Institute
NSCLC
non-small cell lung cancer
ORR
overall response rate
OS
overall survival
OTC
over-the-counter
PD
progressive disease
PD-1
programmed cell death 1
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PET
positron emission tomography
PFS
progression-free survival
PFS2
second progression-free survival
PK
pharmacokinetic(s)
PR
partial response
PRO
patient-reported outcome
PT
prothrombin time
RCC
renal cell carcinoma
RECIST 1.1
Response Evaluation Criteria in Solid Tumors, version 1.1
RNA
ribonucleic acid
RR
response rate
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Abbreviation/Term
Definition
Q2W
once every 2 weeks
Q3W
once every 3 weeks
SAE
serious adverse event
SAP
Statistical Analysis Plan
sb-paclitaxel
solvent-based paclitaxel
SFU
survival follow-up
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SNP
single-nucleotide polymorphism
SOC
standard of care
sSAP
supplemental SAP
TIL
tumor-infiltrating lymphocyte
TMDD
target-mediated drug disposition
TNBC
triple-negative breast cancer
TPS
Tumor Proportion Score
Treg
regulatory T cell
TSH
thyroid stimulating hormone
TTP
time-to-progression
ULN
upper limit of normal
US
United States
WHO
World Health Organization
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Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
The descriptions and grading scales found in the revised NCI CTCAE, version 4.0 will be 
utilized for AE reporting. (http://ctep.cancer.gov/reporting/ctc.html).
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ECOG Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(e.g., light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% of 
waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.:  Oken, 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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Country-specific Information: Extension Study in China
Section 2.1 Trial Design
After the enrollment period of the global study is completed, subjects from China will 
continue to be enrolled in the extension study, until the target number of 120 Chinese 
subjects is reached, to collect additional efficacy and safety data in Chinese subjects in order 
to support future local registration in China. The extension study will be identical to the 
global study (eg, inclusion and exclusion criteria, study endpoints, primary and secondary 
objectives, study procedures), with the exception of an additional sSAP for Chinese subjects. 
The extension study will be unblinded so that subjects assigned to the placebo arm (Arm 2) 
may discontinue treatment with normal saline placebo and have the option of receiving 
pembrolizumab if there is documented PD by central radiological review.
Details of the analysis will be provided in a separate China-specific sSAP document.
Section 8.2 Responsibility for Analyses/In-House Blinding
For all Chinese subjects, including subjects randomized in the global study and the extension 
study, subject-level treatment randomization information will be blinded to the 
statistician(s)/programmer(s) responsible for the China extension study analysis until the 
extension study database lock is achieved. The extent to which individuals are unblinded to 
the results will be limited. Blinded and unblinded members will be clearly documented.
Section 8.5.1 Efficacy Analysis Populations
Any subject enrolled in the extension study in China after global enrollment is completed,
will be excluded from the ITT population. After enrollment for the global study is completed, 
the study will continue to randomize subjects in China until the sample size for the Chinese 
subjects reaches approximately 120 Chinese subjects. Chinese subjects randomized in the 
extension study will not be included in the above primary efficacy analysis population. The 
Chinese ITT population as well as the entire ITT population consisting of the primary 
efficacy population and subjects randomized in the extension will be analyzed separately per 
local regulatory requirement.
Section 8.9 Sample Size and Power Calculations
After enrollment for the global study is completed, the study will continue to randomize 
subjects in a 1:1 ratio into the pembrolizumab + chemotherapy arm or saline placebo + 
chemotherapy arm in China until the sample size for Chinese subjects reaches approximately 
120, to evaluate the consistency of efficacy and safety in the Chinese subpopulation 
compared to the global population. Chinese subjects randomized after completion of 
enrollment in the global study will not be included in the analysis of the global study.
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13.0 SIGNATURES
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – TRIAL PROCEDURES (Assessing and Recording Adverse 
Events).  I also agree to handle all clinical supplies provided by the Sponsor and collect and 
handle all clinical specimens in accordance with the protocol.  I understand that information 
that identifies me will be used and disclosed as described in the protocol, and that such 
information may be transferred to countries that do not have laws protecting such 
information.  Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
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