Clinical trial NCT02220894
Conditions: Non-small Cell Lung Cancer
Keywords: PD-1 PD1 PD-L1 PDL1
Sponsor: Merck Sharp & Dohme LLC
Start date: 2014-10-30; Completion date: 2022-09-12
Enrollment: 1274 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
In this study, participants with programmed cell death ligand 1 (PD-L1)-positive non-small cell lung cancer (NSCLC) will be randomized to receive single agent pembrolizumab for up to 35 treatments or standard of care (SOC) platinum-based chemotherapy (carboplatin + paclitaxel or carboplatin + pemetrexed for 4 to 6 21-day cycles). Participants in the platinum-based chemotherapy arms with non-squamous tumor histologies may receive pemetrexed maintenance therapy after the 4 to 6 cycles of chemotherapy. The primary study hypothesis is that pembrolizumab prolongs overall survival (OS) compared to SOC chemotherapy.

Detailed description:
Pembrolizumab-treated participants, who attain a confirmed complete response (CR) or who stop trial treatment after 35 administrations of study medication for reasons other than disease progression or intolerability, may consider stopping trial treatment. These participants may be eligible for re-treatment with pembrolizumab monotherapy after they have experienced radiographic disease according to protocol-defined criteria. Response or progression in the Second Course Phase will not count towards the objective response rate (ORR) and progression free survival (PFS) endpoints in this trial.

The global study for MK-3475-042 enrolled 1274 participants. Of the 1274 total participants enrolled in the global study, 92 were also enrolled in the China extension study for MK-3475-042 (NCT03850444).

Arms: arm 1: Participants receive pembrolizumab 200 mg intravenous (IV) on Day 1 of every 21-day cycle (every 3 weeks, or Q3W) for up to 35 treatments. arm 2: Participants receive carboplatin target dose Area Under Curve (AUC) 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + paclitaxel 200 mg/m\^2 IV on Day 1 of every 21-day cycle (Q3W) for a maximum of 6 cycles OR carboplatin target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + pemetrexed 500 mg/m\^2 IV on Day 1 Q3W for a maximum of 6 cycles; participants with non-squamous histologies may go on to receive optional treatment with pemetrexed 500 mg/m\^2 IV on Day 1 Q3W.
Interventions: intervention 1: pembrolizumab intervention 2: carboplatin intervention 3: paclitaxel intervention 4: pemetrexed
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol documents:
Prot_SAP_001.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Randomized, Open Label, Phase III Study of 
Overall Survival Comparing Pembrolizumab 
(MK-3475) versus Platinum Based Chemotherapy 
in Treatment Naïve Subjects with PD-L1 Positive 
Advanced or Metastatic Non-Small Cell Lung 
Cancer (Keynote 042)
NCT02220894
24-Mar-2021


Product:  MK-3475 (SCH 900475)
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Protocol/Amendment No.: 042-08 
MK-3475-042-08 Final Protocol
24-Mar-2021
Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File
Binder (or equivalent).
TITLE:
A Randomized, Open Label, Phase III Study of Overall Survival Comparing Pembrolizumab 
(MK-3475) versus Platinum Based Chemotherapy in Treatment Naïve Subjects with PD-L1 
Positive Advanced or Metastatic Non-Small Cell Lung Cancer (Keynote 042)
IND NUMBER:  116833
EudraCT NUMBER:  2014-001473-14 
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 11
SUMMARY OF CHANGES................................................................................................ 13
1.0
TRIAL SUMMARY.................................................................................................. 14
2.0
TRIAL DESIGN........................................................................................................ 15
Trial Design ........................................................................................................... 15
Trial Diagram........................................................................................................ 18
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 18
Primary Objective(s) & Hypothesis(es).............................................................. 18
Secondary Objective(s) & Hypothesis(es)........................................................... 19
Exploratory Objectives......................................................................................... 20
4.0
BACKGROUND & RATIONALE.......................................................................... 21
Background ........................................................................................................... 21
Pharmaceutical and Therapeutic Background .................................................... 21
Completed Clinical Trials................................................................................... 23
Information on Other Trial-Related Therapy...................................................... 24
Rationale................................................................................................................ 25
Rationale for the Trial and Selected Subject Population .................................... 25
4.2.1.1
Benefit Risk ................................................................................................. 27
Rationale for Dose Selection/Regimen/Modification......................................... 28
Rationale for Endpoints ...................................................................................... 29
4.2.3.1
Efficacy Endpoints....................................................................................... 29
4.2.3.2
Planned Exploratory Biomarker Research................................................... 29
4.2.3.3
Future Biomedical Research........................................................................ 30
5.0
METHODOLOGY ................................................................................................... 31
Entry Criteria........................................................................................................ 31
Diagnosis/Condition for Entry into the Trial...................................................... 31
Subject Inclusion Criteria.................................................................................... 31
Subject Exclusion Criteria .................................................................................. 34
Trial Treatment(s) ................................................................................................ 36
Dose Selection/Modification .............................................................................. 37
5.2.1.1
Dose Selection (Preparation) ....................................................................... 37
 
 
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5.2.1.2
Dose Modification (Escalation/Titration/Other).......................................... 38
5.2.1.2.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).......................................................................................... 38
Timing of Dose Administration.......................................................................... 42
Trial Blinding/Masking....................................................................................... 43
Randomization or Treatment Allocation............................................................ 43
Stratification.......................................................................................................... 43
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 44
Acceptable Concomitant Medications ................................................................ 44
Prohibited Concomitant Medications and/or Treatments ................................... 44
Rescue Medications & Supportive Care............................................................. 45
Supportive Care Guidelines ................................................................................ 45
Overview of Guidelines for Managing Suspected Pneumonitis From 
Pembrolizumab ................................................................................................... 46
Guidelines for Infusion Reactions....................................................................... 47
Diet/Activity/Other Considerations..................................................................... 48
Diet...................................................................................................................... 48
Contraception...................................................................................................... 48
Use in Pregnancy ................................................................................................ 49
Use in Nursing Women....................................................................................... 49
Subject Withdrawal/Discontinuation Criteria................................................... 49
Discontinuation From Treatment........................................................................ 50
Pembrolizumab End of Treatment Follow-up .................................................... 51
Subject Replacement Strategy............................................................................. 52
Beginning and End of the Trial ........................................................................... 52
Clinical Criteria for Early Trial Termination ................................................... 52
6.0
TRIAL FLOW CHART ........................................................................................... 53
Pembrolizumab Arm: Treatment and Follow-up Phase................................... 53
Standard of Care Arm: Treatment and Follow-up Phase ................................ 59
Second Course Treatment and Follow-up Phase for Pembrolizumab Arm.... 65
7.0
TRIAL PROCEDURES ........................................................................................... 68
Trial Procedures ................................................................................................... 68
Administrative Procedures.................................................................................. 68
 
 
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7.1.1.1
Informed Consent......................................................................................... 68
7.1.1.1.1
General Informed Consent.................................................................... 68
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 69
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 69
7.1.1.3
Subject Identification Card .......................................................................... 69
7.1.1.4
Medical History ........................................................................................... 69
7.1.1.5
Prior and Concomitant Medications Review............................................... 69
7.1.1.5.1
Prior Medications.................................................................................. 69
7.1.1.5.2
Concomitant Medications..................................................................... 69
7.1.1.6
Non-Small Cell Lung Cancer (NSCLC) Disease Details and Treatments .. 70
7.1.1.6.1
Disease Details...................................................................................... 70
7.1.1.6.2
Prior Treatment..................................................................................... 70
7.1.1.6.3
Subsequent Antineoplastic Therapy Status........................................... 70
7.1.1.7
Assignment of Screening Number............................................................... 70
7.1.1.8
Assignment of Randomization Number....................................................... 70
7.1.1.9
Trial Compliance (Medication/Diet/Activity/Other)................................... 70
Clinical Procedures/Assessments........................................................................ 71
7.1.2.1
Adverse Event (AE) Monitoring.................................................................. 71
7.1.2.2
Physical Exam.............................................................................................. 71
7.1.2.2.1
Full Physical Exam ............................................................................... 71
7.1.2.2.2
Directed Physical Exam........................................................................ 71
7.1.2.3
Vital Signs.................................................................................................... 72
7.1.2.4
Lead Electrocardiogram (ECG)................................................................... 72
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale ........... 72
7.1.2.6
Tumor Assessments and Imaging ................................................................ 72
7.1.2.7
Tumor Tissue Collection.............................................................................. 73
Laboratory Procedures/Assessments .................................................................. 74
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 74
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations........................................ 75
7.1.3.3
Molecular Testing ........................................................................................ 75
7.1.3.4
Future Biomedical Research........................................................................ 75
 
 
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Other Procedures................................................................................................. 75
7.1.4.1
Withdrawal/Discontinuation........................................................................ 75
7.1.4.1.1
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...................................................................................................... 76
7.1.5.2
Treatment Phase........................................................................................... 77
7.1.5.3
End of Treatment Visits............................................................................... 77
7.1.5.3.1
Discontinuation Visit............................................................................ 77
7.1.5.3.2
Safety Follow-up Visit.......................................................................... 77
7.1.5.3.3
Observation Visit .................................................................................. 78
7.1.5.4
Follow-up Phase........................................................................................... 78
7.1.5.4.1
Follow-up Visits ................................................................................... 78
7.1.5.4.2
Survival Follow-up ............................................................................... 79
7.1.5.5
Second Course Phase................................................................................... 79
7.1.5.6
Survival Status ............................................................................................. 80
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 ....................................... 82
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............ 85
Evaluating Adverse Events................................................................................. 85
Sponsor Responsibility for Reporting Adverse Events ...................................... 88
TRIAL GOVERNANCE AND OVERSIGHT................................................... 88
Scientific Advisory Committee........................................................................... 88
Trial Steering Committee.................................................................................... 88
Executive Oversight Committee......................................................................... 88
Data Monitoring Committee............................................................................... 88
 
 
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8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 89
Statistical Analysis Plan Summary ..................................................................... 89
Efficacy Analyses ............................................................................................... 91
Safety Analyses................................................................................................... 92
Multiplicity Adjustment...................................................................................... 92
Power and Sample Size....................................................................................... 93
Interim Analysis.................................................................................................. 94
Statistical Analysis Plan ....................................................................................... 94
Responsibility for Analyses/In-House Blinding ................................................. 94
Hypotheses/Estimation ....................................................................................... 95
Analysis Endpoints ............................................................................................. 95
8.2.3.1
Efficacy Endpoints....................................................................................... 95
8.2.3.2
Safety Endpoints.......................................................................................... 96
Analysis Population ............................................................................................ 96
8.2.4.1
Efficacy Analysis Population....................................................................... 96
8.2.4.2
Safety Analysis Populations ........................................................................ 96
Statistical Methods.............................................................................................. 97
8.2.5.1
Statistical Methods for Efficacy Analyses................................................... 97
8.2.5.1.1
Overall Survival (OS) ........................................................................... 97
8.2.5.1.2
Progression-Free Survival (PFS) .......................................................... 98
8.2.5.1.3
Objective Response Rate (ORR).......................................................... 99
8.2.5.1.4
Exploratory Analyses............................................................................ 99
8.2.5.2
Statistical Methods for Safety Analyses ...................................................... 99
8.2.5.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses..................................................................................................... 101
Multiplicity ....................................................................................................... 101
Sample Size and Power Calculation ................................................................. 103
Subgroup Analyses and Effect of Baseline Factors.......................................... 104
Interim Analyses ............................................................................................... 104
Compliance (Medication Adherence)............................................................... 108
Extent of Exposure............................................................................................ 108
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 108
 
 
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Investigational Product ...................................................................................... 108
Packaging and Labeling Information ............................................................... 109
Clinical Supplies Disclosure............................................................................... 109
Storage and Handling Requirements................................................................ 109
Returns and Reconciliation................................................................................ 109
Standard Policies................................................................................................. 109
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 110
Confidentiality..................................................................................................... 110
Confidentiality of Data ..................................................................................... 110
Confidentiality of Subject Records................................................................... 110
Confidentiality of Investigator Information...................................................... 110
Confidentiality of IRB/IEC Information........................................................... 111
Compliance with Financial Disclosure Requirements..................................... 111
Compliance with Law, Audit and Debarment ................................................. 111
Compliance with Trial Registration and Results Posting Requirements...... 113
Quality Management System............................................................................. 114
Data Management............................................................................................... 114
Publications ......................................................................................................... 114
11.0
LIST OF REFERENCES....................................................................................... 116
12.0
APPENDICES......................................................................................................... 123
Merck Code of Conduct for Clinical Trials...................................................... 123
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 125
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 131
ECOG Performance Status................................................................................ 140
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............. 141
Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 Criteria 
for Evaluating Response in Solid Tumors........................................................ 142
List of Abbreviations .......................................................................................... 143
13.0
SIGNATURES......................................................................................................... 145
Sponsor's Representative ................................................................................... 145
 
 
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Investigator.......................................................................................................... 145
 
 
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LIST OF TABLES
Table 1
Adequate Organ Function Lab Values ................................................................ 32
Table 2
Trial Treatment.................................................................................................... 37
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations................................................................... 39
Table 4
Pembrolizumab Infusion Reaction Treatment Guidelines .................................. 47
Table 5
Laboratory Tests.................................................................................................. 74
Table 6
Evaluating Adverse Events ................................................................................. 86
Table 7
Analysis Strategy for Key Efficacy Endpoints.................................................... 91
Table 8
Summary of Interim and Final Analysis Strategy............................................... 94
Table 9
Censoring Rules for Primary and Sensitivity Analyses of PFS .......................... 99
Table 10
Analysis Strategy for Safety Parameters........................................................... 101
Table 11
Decision Guidance for the Primary OS Hypotheses at the Interim Analyses 
and Final Analysis under a Hypothetical Scenario ........................................... 107
Table 12
Product Descriptions ......................................................................................... 108
 
 
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LIST OF FIGURES
          
Figure 1
Trial Diagram...................................................................................................... 18
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
MK-3475-042-08
24-MAR-2021
To add language regarding the enrollment of subjects in a pembrolizumab extension study 
upon study completion.
MK-3475-042-07
(China Specific)
09-JAN-2018
To enable flexibility of survival status activities and ensure that current, complete survival 
data are available at the time of database locks. To update the SAP based on minimal follow-
up duration and desired trial power in subjects with TPS≥1%, and the reallocation to the 
remaining unspent alpha after the first interim analysis
MK-3475-042-06
09-JAN-2018
To enable flexibility of survival status activities and ensure that current, complete survival 
data are available at the time of database locks. To update the SAP based on minimal follow-
up duration and desired trial power in subjects with TPS≥1%, and the reallocation to the 
remaining unspent alpha after the first interim analysis
MK-3475-042-05
(China Specific)
01-JUN-2017
To update the number of events and timing of analysis based upon update to SAP, and 
clarify that subjects from China randomized after completion of enrollment in the global 
study will not be included in the analyses of the global study
MK-3475-042-04
(China Specific)
21-DEC-2016
To extend the enrollment period beyond the global study to achieve required exposure and 
number of events to investigate efficacy and safety in subjects with 1L NSCLC enrolled in 
China.
MK-3475-042-03
12-APR-2017
To align TPS cutpoint terminology, and to update the SAP based on primary, secondary, and 
exploratory objectives/hypotheses updates.
MK-3475-042-02
21-DEC-2015
Changes were made based on new safety and efficacy data that has become available, and to 
clarify relevant sections of the protocol.
 
 
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Document
Date of Issue
Overall Rationale
MK-3475-042-01
(Sweden Specific)
28-AUG-2014
To comply with regulatory requirements by the MPA in Sweden, the Benefit and Risk 
section was added.
Original Protocol 
18-JUN-2014
Not applicable.
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Amendment: 08
Overall Rationale for the Amendment: To add language regarding the enrollment of subjects in a pembrolizumab extension study 
upon study completion.
Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
5.2.1.2.1
Immune-Related Events 
and Dose Modification 
(Withhold, 
Treat, 
Discontinue)
A section entitled “Immune-Related Events and 
Dose 
Modification 
(Withhold, 
Treat, 
Discontinue)” was added.
Table 3 (Dose Modification and Toxicity 
Management Guidelines for Immune-related 
Adverse 
Events 
Associated 
with 
Pembrolizumab) was updated.
To align with the pembrolizumab 
labeling update.
5.10
Beginning and End of 
the Trial
Added language to state that upon study 
completion, subjects are discontinued and may 
be enrolled in a pembrolizumab extension 
study, if available.
Subjects may be enrolled in a 
pembrolizumab 
extension 
study 
upon study completion.
Throughout
Throughout
Made typographical corrections and minor 
administrative edits.
To correct typographical errors and 
clarify intended meaning.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
No additional changes.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
OS Study of Pembrolizumab (MK-3475) vs. SOC in Treatment Naïve Subjects with 
PD-L1 Positive Advanced or Metastatic NSCLC (Keynote 042)
Trial Phase
Phase III
Clinical Indication
PD-L1 positive (TPS≥1%), previously untreated advanced or metastatic non-small 
cell lung cancer (NSCLC)
Trial Type
Interventional
Type of control
Active control without placebo
Route of 
administration
Intravenous
Trial Blinding
Unblinded Open-label
Treatment Groups
Pembrolizumab (MK-3475) 200 mg intravenous (IV) every 3 weeks (Q3W)
OR
SOC:  investigator’s choice of one of the following:
--Carboplatin AUC 5 or 6 + paclitaxel 200 mg/m2 Q3W for a         maximum of 6 
cycles, followed by optional pemetrexed 500 mg/m2 for subjects with non-squamous 
histologies
--Carboplatin AUC 5 or 6 + pemetrexed 500 mg/m2 Q3W for a maximum of 6 cycles, 
followed by optional pemetrexed 500 mg/m2 for subjects with non-squamous 
histologies
Number of trial 
subjects
Global Study: Approximately 1240 subjects will be enrolled.
Estimated duration of 
trial
Global Study: The sponsor estimates that the trial will require approximately 3.5 years
from the time the first subject signs the informed consent until the last subject’s last 
visit.
Duration of 
Participation
Each subject will participate in the trial for approximately 2.5 years from the time the 
subject signs the Informed Consent Form (ICF) through the final contact. After a 
Screening Phase of up to 42 days, each subject will receive treatment based on the arm to 
which they have been randomized. Treatment on study will continue until disease 
progression, unacceptable adverse event(s), intercurrent illness that prevents further 
administration of treatment, investigator’s decision to withdraw the subject, 
noncompliance with trial treatment or procedures requirements, the subject receives 35 
treatments of study medication (pembrolizumab
arm only), or administrative 
reasons. Subjects on the pembrolizumab arm who attain a complete response may consider 
stopping trial treatment if they meet criteria for holding therapy. Subjects receiving 
pembrolizumab who stop drug administration after receiving 35 trial treatments for 
reasons other than disease progression or intolerability, or subjects who attain a complete 
response and stop trial treatment may be eligible for retreatment with pembrolizumab upon 
experiencing disease progression. The decision to retreat will be at the discretion of the 
investigator only if they meet the criteria for retreatment and the trial is ongoing. After the 
end of treatment each subject will be followed for a minimum of 30 days for adverse event 
(AE) monitoring. Serious adverse events (SAE) and Events of Clinical Interest (ECI) will 
be collected for 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. 
Subjects who discontinue for reasons other than disease progression will be monitored for
disease status in the Observation Phase until disease progression is confirmed by the site, a 
non-study cancer treatment is initiated, consent is withdrawn, or the subject is lost to 
follow-up. All subjects will be followed by telephone for overall survival until death, 
withdrawal of consent, or end of the study.
 
 
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Randomization Ratio
1:1
A list of abbreviations used in this document can be found in Section 12.7
2.0 TRIAL DESIGN
Trial Design
This is a multicenter, international, randomized, open-label, controlled trial of IV
pembrolizumab (also known as MK-3475) monotherapy versus (vs.) standard of care (SOC) 
platinum-based chemotherapy in subjects previously untreated for their advanced or 
metastatic, PD-L1 positive (TPS≥1% [tumor proportion score]) NSCLC. To target 
approximately 530 subjects with TPS≥50%, approximately 1240 NSCLC subjects whose 
tumors are classified as TPS>1% and in whom EGFR or ALK-directed therapy is not 
indicated. NSCLC subjects are projected to be enrolled in this trial for examination of the 
efficacy and safety of pembrolizumab vs. SOC chemotherapy. Subjects will be randomized 
1:1 to receive pembrolizumab 200 mg IV Q3W or the investigator’s choice of one of the 
platinum doublets specified below. The platinum doublet (including whether pemetrexed 
maintenance will be offered for those subjects with non-squamous histologies and who do 
not demonstrate PD after completion of at least 4 cycles of platinum doublet) as well as the 
dose (for example, AUC 5 OR 6 for carboplatin) to be administered must be identified prior 
to randomization:
1. Carboplatin AUC 5 or 6 Day 1 Q3W in combination with paclitaxel 200 mg/m2 Q3W for 
a maximum of 6 cycles followed by optional pemetrexed 500 mg/m2 Q3W.
2. Carboplatin AUC 5 or 6 Day 1 Q3W in combination with pemetrexed 500 mg/m2 Q3W 
for a maximum of 6 cycles followed by optional pemetrexed 500 mg/m2 Q3W. 
Only subjects with non-squamous histologies may receive pemetrexed. Pemetrexed 
maintenance is limited to subjects with non-squamous histologies who experience a stable 
disease (SD) or better after completion of a minimum of 4 cycles of the initial platinum 
doublet. Subjects who experience progressive disease (PD) after 4 cycles are not permitted to 
receive pemetrexed in the maintenance setting. Note: While pemetrexed maintenance is 
optional, it is STRONGLY recommended in subjects with non-squamous histologies and 
should be administered unless toxicity or decline in performance status precludes its 
administration, and radiographic imaging does not demonstrate PD after completion of at 
least 4 cycles of platinum doublet.
Subjects who received adjuvant therapy are permitted onto the study if completion of the 
adjuvant therapy was completed at least 6 months prior to the development of metastatic 
disease. If a subject received either carboplatin in combination with pemetrexed OR 
carboplatin in combination with paclitaxel in the adjuvant setting, that same platinum doublet 
may not be administered if the subject is randomized to the control arm.
 
 
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Subjects will be stratified by Eastern Cooperative Oncology Group (ECOG) Performance 
Scale (0 vs. 1), histology (squamous vs. non-squamous), geographic region of the enrolling 
site (East Asia vs. non-East Asia), and PD-L1 expression status (TPS ≥50% vs. TPS 1-49%) 
prior to randomization. 
Subjects will be evaluated every 9 weeks (63 ± 7 days) with radiographic imaging to assess 
response to treatment; treatment-based decisions should be based on the modified RECIST 
1.1 criteria (details are provided in the Image Acquisition Guidelines). All imaging obtained 
on study will be submitted for a central independent radiologists’ review that will assess the 
images using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for determination 
of objective response rate (ORR) and progression-free survival (PFS). Adverse event (AE)
monitoring will be ongoing throughout the trial and graded in severity according to the 
guidelines outlined in the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0. Treatment with pembrolizumab will continue until 35 
trial treatments have been administered, documented disease progression, unacceptable 
adverse event(s), intercurrent illness that prevents further administration of treatment, 
investigator’s decision to withdraw the subject, subject withdraws consent, pregnancy of the 
subject, noncompliance with trial treatment or procedure requirements, or administrative 
reasons. 
Pembrolizumab-treated subjects, who attain a confirmed complete response (CR) per 
modified RECIST 1.1 or who stop trial treatment after 35 administrations of study 
medication for reasons other than disease progression or intolerability, may consider stopping 
trial treatment. These subjects may be eligible for re-treatment with 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 towards the ORR and PFS endpoints in this trial. 
After the end of treatment, each subject will be followed for a minimum of 30 days for AE
monitoring. Serious adverse events (SAEs) and Events of Clinical Interest (ECI) will be 
collected for 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. Subjects will 
have post-treatment follow-up for disease status, including initiating a non-study cancer 
treatment and experiencing disease progression, until death, withdrawing consent, or 
becoming lost to follow-up. 
The primary endpoint of the trial is Overall Survival (OS) in subjects with TPS≥50%, 
TPS≥20%, and TPS≥1%. Secondary endpoints include PFS and ORR per RECIST 1.1 by 
central independent radiologists’ review in subjects with TPS≥50%, TPS≥20%, and 
TPS≥1%, and safety as assessed by a variety of parameters of AEs, including ECIs with a 
potential immunologic etiology as outlined in the ECI guidance document. Exploratory 
analyses include response duration per RECIST 1.1 by central independent radiologists’ 
review in subjects with TPS≥50%, TPS≥20%, and TPS≥1%, PFS and ORR per RECIST 1.1 
by investigator review in subjects with TPS≥50%, TPS≥20%, and TPS≥1.
 
 
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Participation in this trial will be dependent upon supplying tumor tissue from locations not 
radiated prior to biopsy; formalin-fixed specimens AFTER the subject has been diagnosed 
with metastatic disease will be required for determination of PD-L1 status prior to 
randomization. Biopsies obtained PRIOR to receipt of adjuvant chemotherapy are NOT 
permitted. Subjects who received adjuvant therapy are permitted onto the trial as long as 
therapy was completed at least 6 months prior to the diagnosis of metastatic disease.
The specimen will be evaluated at a central laboratory facility for expression status of PD-L1 
in a prospective manner. Only subjects whose tumors express PD-L1 at a predefined cut 
point as determined by the central laboratory facility will be eligible for randomization.
The first interim analysis (IA1) will be conducted after at least 250 deaths have occurred in 
both arms in the subjects with TPS≥50% and at least 6 months after the last patient is 
enrolled. The main purpose of this analysis is to demonstrate superiority of pembrolizumab 
in OS. The second interim analysis (IA2) will be conducted approximately 38 months
(February 2018) after enrollment completion. The final OS analysis will be conducted
approximately 45 months (September 2018) after enrollment completion. Both IA2 and the 
final analysis (FA) are based on calendar time. In addition, the trial may be stopped early at 
the recommendation of the Data Monitoring Committee (DMC) if the risk/benefit ratio to the 
trial population as a whole is unacceptable. Details are described in Section 8.0 – Statistical 
Analysis Plan.
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.
 
 
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Trial Diagram
Figure 1
Trial Diagram
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
1. Objective: To compare the overall survival (OS) in subjects with TPS≥50%, 1L 
advanced/metastatic NSCLC treated with pembrolizumab compared to standard of care 
(SOC) chemotherapies.
Hypothesis: Pembrolizumab prolongs OS in subjects with TPS≥50%, NSCLC compared 
to SOC chemotherapy.
 
 
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2. Objective: To compare the OS in subjects with TPS≥20%, 1L advanced/metastatic 
NSCLC treated with pembrolizumab compared to standard of care (SOC) 
chemotherapies.
Hypothesis: Pembrolizumab prolongs OS in subjects with TPS≥20% NSCLC compared 
to SOC chemotherapy.
3. Objective: To compare the OS in subjects with TPS≥1%, 1L advanced/metastatic 
NSCLC treated with pembrolizumab compared to SOC chemotherapies.
Hypothesis: Pembrolizumab prolongs OS in subjects with TPS≥1% NSCLC compared to 
SOC chemotherapy.
The study is considered to have met its primary objective if pembrolizumab is superior to 
SOC in OS at an interim analysis or the final analysis in the subjects with TPS≥50%.
Secondary Objective(s) & Hypothesis(es)
1. Objective: To compare the progression-free survival (PFS) by RECIST 1.1 as assessed 
by central independent radiologists’ review in subjects with TPS≥50%,
1L 
advanced/metastatic NSCLC treated with pembrolizumab compared to SOC 
chemotherapy.
Hypothesis: Pembrolizumab prolongs PFS by RECIST 1.1 (central independent 
radiologists’ review) in subjects with TPS≥50% NSCLC compared to SOC 
chemotherapy.
2. Objective: To compare the PFS by RECIST 1.1 as assessed by central independent 
radiologists’ review in subjects with TPS≥20%, 1L advanced/metastatic NSCLC treated 
with pembrolizumab compared to SOC chemotherapy.
Hypothesis: Pembrolizumab prolongs PFS by RECIST 1.1 (central independent 
radiologists’ review) in subjects with TPS≥20% NSCLC compared to SOC
chemotherapy. 
3. Objective: To compare the PFS as assessed by RECIST 1.1 by central independent 
radiologists’ review in subjects with TPS≥1%, 1L advanced/metastatic NSCLC treated 
with pembrolizumab compared to SOC chemotherapy.
Hypothesis: Pembrolizumab prolongs PFS by RECIST 1.1 (central independent 
radiologists’ review) in subjects with TPS≥1% NSCLC compared to SOC chemotherapy.
 
 
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4. Objective: To evaluate the ORR by RECIST 1.1 by central independent radiologists’ 
review in subjects with TPS≥50%, 1L advanced/metastatic NSCLC treated with 
pembrolizumab compared to SOC chemotherapy.
Hypothesis: Pembrolizumab improves ORR by RECIST 1.1 (central independent 
radiologists’ review) in subjects with TPS≥50% NSCLC compared to SOC 
chemotherapy.
5. Objective: To evaluate the ORR by RECIST 1.1 by central independent radiologists’ 
review in subjects with TPS≥20%, 1L advanced/metastatic NSCLC treated with 
pembrolizumab compared to SOC chemotherapy.
Hypothesis: Pembrolizumab improves ORR by RECIST 1.1 (central independent 
radiologists’ review) in subjects with TPS≥20% NSCLC compared to SOC 
chemotherapy.
6. Objective: To evaluate the ORR by RECIST 1.1 by central independent radiologists’ 
review in subjects with TPS≥1%, 1L advanced/metastatic NSCLC treated with 
pembrolizumab compared to SOC chemotherapy.
Hypothesis: Pembrolizumab improves ORR by RECIST 1.1 (central independent 
radiologists’ review) in subjects with TPS≥1% NSCLC compared to SOC chemotherapy.
7. Objective: To evaluate the safety and tolerability profile of pembrolizumab in subjects 
with TPS >1%, 1L advanced/metastatic NSCLC. 
Exploratory Objectives
o
Objective: To evaluate PFS per investigator-assessed RECIST 1.1 response criteria in 
subjects with TPS≥50%, TPS≥20%, and TPS≥1%, 1L advanced/metastatic NSCLC 
treated with pembrolizumab compared to SOC chemotherapy.
o
Objective: To evaluate ORR per investigator-assessed RECIST 1.1 response criteria in 
subjects with TPS≥50%, TPS≥20%, and TPS≥1%, 1L advanced/metastatic NSCLC 
treated with pembrolizumab compared to SOC chemotherapy.
o
Objective: To evaluate response duration per RECIST 1.1 by central independent 
radiologists’ review in subjects with TPS≥50%, TPS≥20%,
and TPS≥1%,
1L 
advanced/metastatic NSCLC treated with pembrolizumab
compared to SOC 
chemotherapy.
o
Objective: To evaluate the PFS as assessed by RECIST 1.1 by investigator review in the 
next line of therapy (PFS2) in subjects treated with pembrolizumab compared to SOC 
chemotherapy.
o
Objective: To evaluate genomic signatures that predict for response in subjects treated 
with pembrolizumab.
 
 
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o
Objective: To investigate the relationship between pembrolizumab treatment and 
biomarkers predicting response (e.g., PD-L1, genetic variation, serum sPDL1) utilizing 
newly obtained or archival FFPE tumor tissue and blood, including serum and plasma.
4.0 BACKGROUND & RATIONALE
Background
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on pembrolizumab.
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [1]. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18]
[19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36]. 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 (MEL) and renal cell carcinoma (RCC). TILs can be expanded ex vivo 
and re-infused, inducing durable objective tumor responses in cancers such as MEL [37]
[38].
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) 
[39] [40]. 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 [33] [41]. PD-1 was shown to be expressed on activated lymphocytes including 
peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells [42] [43]. 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 [41]
[44] [45] [46]. Both ligands are type I transmembrane receptors containing both IgV- and 
IgC-like domains in the extracellular region and contain short cytoplasmic regions with no 
known signaling motifs. Binding of either PD-1 ligand to PD-1 inhibits T-cell activation 
triggered through the T-cell receptor. PD-L1 is expressed at low levels on various non-
hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is only 
detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic 
inflammatory environments. PD-L2 is thought to control immune T-cell activation in 
lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral 
tissues [44]. 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 
 
 
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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 [47], pancreatic carcinoma 
[48], hepatocellular carcinoma [49], and ovarian carcinoma [50]. Furthermore, PD-1 has 
been suggested to regulate tumor-specific T-cell expansion in subjects with MEL [51].
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 II/III trial of pembrolizumab vs.
docetaxel in previously treated subjects with advanced or metastatic NSCLC.
Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated anti-tumor responses 
as a monotherapy in models of squamous cell carcinoma, pancreatic carcinoma, MEL, and 
colorectal carcinoma. Blockade of the PD-1 pathway effectively promoted CD8+ T-cell 
infiltration into the tumor and the presence of IFN-, granzyme B and perforin, indicating 
that the mechanism of action involved local infiltration and activation of effector T-cell 
function in vivo [48] [52] [53] [54] [55] [56]. In addition, the combination of gemcitabine 
and anti-PD-L1 mAb demonstrated synergy in the rejection of pancreatic mouse tumors [48].
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).
Recent clinical data of pembrolizumab suggest high sustained rates of tumor regression in 
patients with advanced melanoma. Pembrolizumab was dosed IV at a dose of 10 mg per 
kilogram (kg) of body weight every 2 or 3 weeks or 2 mg per kilogram every 3 weeks in 
patients with advanced melanoma, including a cohort of patients who had received prior 
treatment with the immune checkpoint inhibitor ipilimumab and those who had not. Tumor 
responses were assessed every 12 weeks. A total of 135 patients with advanced melanoma 
were treated. Common adverse events attributed to treatment were fatigue, rash, pruritus, and 
diarrhea; most of the adverse events were low grade. The confirmed response rate across all 
dose cohorts, evaluated by central radiologic review according to the RECIST 1.1, was 38% 
(95% confidence interval [CI], 25 to 44), with the highest confirmed response rate observed 
in the cohort that received 10 mg per kilogram every 2 weeks (52%; 95% CI, 38 to 66). The 
response rate did not differ significantly between patients who had received prior ipilimumab 
treatment and those who had not (confirmed response rate, 38% [95% CI, 23 to 55] and 37% 
[95% CI, 26 to 49], respectively). Responses were durable in the majority of patients (median 
follow-up, 11 months among patients who had a response); 81% of the patients who had a 
response (42 of 52) were still receiving treatment at the time of analysis in March 2013. The 
overall median progression-free survival among the 135 patients was longer than 7 months. 
These data indicate that high rates of durable responses are achieved with pembrolizumab in 
patients with advanced melanoma irrespective of any prior treatment with an immune 
checkpoint inhibitor. Furthermore, the toxicity profile was manageable with the majority 
grade of the toxicities grade 1 or 2 [52].
 
 
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Completed Clinical Trials
Three clinical studies have been conducted to evaluate the efficacy of pembrolizumab 
monotherapy in the treatment of 1L and 2L NSCLC:  Keynote-001, Keynote-010, and 
Keynote-024.
Keynote-001
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 three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks 
(Q2W), in subjects with advanced solid tumors. All three dose levels were well tolerated and 
no dose-limiting toxicities were observed. Based on pharmacokinetic (PK) data showing a 
half-life of 21 days, the protocol was amended to change the dosing frequency in the 
expansion cohort to Q3W. All cohorts have completed enrollment.
In Keynote-001, a total of 550 advanced NSCLC subjects were treated in several dose 
expansion cohorts with at least 1 dose of pembrolizumab. The initial data from 495 NSCLC 
subjects were published and reported. The objective response rate 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 (tumor proportion score ≥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 tumor proportion score 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 [57]. 
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 AE 
of an inflammatory or immune-mediated nature that occurred in more than 2% of subjects 
were infusion-related reactions (in 15 subjects [3.0%]), hypothyroidism (in 34 subjects
[6.9%]), and pneumonitis (in 18 subjects [3.6%]). One infusion reaction led to treatment 
discontinuation. All the subjects with hypothyroidism were successfully treated with medical 
therapy [58].
Keynote-010
Keynote-010 was a randomized, adaptively designed Phase II/III trial of pembrolizumab at 
2 dose levels versus docetaxel in subjects with NSCLC with PD-L1 positive tumors who had 
experienced disease progression after platinum-containing systemic therapy. Subjects were 
 
 
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randomized according to their TPS (extent of PD-L1 expression) defined as follows:  a TPS 
≥50% was considered strongly positive and a TPS = 1% to 49% was considered weakly 
positive.
Overall, the results from Keynote-001 and Keynote-010 demonstrated that pembrolizumab 
provided substantial, clinically meaningful benefits in OS, PFS, and ORR in subjects with 
NSCLC who progressed after platinum-containing chemotherapy and whose tumor cells 
expressed PD-L1. The PD-L1 selection employed in KEYNOTE-010 identified subjects 
more likely to benefit from pembrolizumab and resulted in favorable HRs in OS compared to 
docetaxel.
In previously treated subjects with NSCLC with PD-L1 TPS≥1% and disease progression 
following platinum-containing chemotherapy, pembrolizumab provided a statistically 
significant and clinically meaningful OS benefit compared to standard docetaxel 
chemotherapy [59].
Keynote-024
Keynote-024 was a multicenter, international, randomized, open-label, controlled trial of 
intravenous pembrolizumab monotherapy versus the choice of multiple standard of care 
platinum based chemotherapies in subjects previously untreated for their Stage IV NSCLC 
and whose tumors expressed PD-L1 at ≥50%. 
First-line treatment with pembrolizumab significantly prolonged PFS (hazard ratio [HR] 
0.50; 95% CI: 0.37, 0.68; p<0.001) and OS (HR 0.60; 95% confidence interval [CI]:  0.41, 
0.89; p=0.005) compared with SOC chemotherapy, inclusive of pemetrexed maintenance for
subjects with non-squamous tumors.
In addition, pembrolizumab was associated with a higher ORR, including a higher CR rate, 
as well as a longer duration of response as compared to SOC.
Pembrolizumab was better tolerated than chemotherapy and adverse events were 
manageable. The observed safety profile of the pembrolizumab arm was consistent with the 
safety profile for pembrolizumab established to date. Based on the mechanism of action of 
pembrolizumab, immune-mediated AEs, including pneumonitis occurred at a greater 
frequency with pembrolizumab compared to chemotherapy. Most immune-mediated events 
were of Grade 1 or 2 severity, and none led to death [60]. 
Information on Other Trial-Related Therapy
Platinum doublets are the standard of care for the treatment of patients with good 
performance status (ECOG 0 or 1), advanced or metastatic, previously untreated NSCLC and 
in whom EGFR or ALK-directed therapy is not indicated. Platinum doublets include a 
platinum compound in combination with gemcitabine, pemetrexed, docetaxel, or 
bevacizumab [53]. These combinations have demonstrated overall survival gain, improved 
quality of life, and control of disease-related symptoms compared to single agent regimens. 
 
 
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Multiple Phase III studies have demonstrated similar efficacy for carboplatin plus paclitaxel 
compared to other platinum doublets, including ECOG 1594 [61]. This is especially 
significant given that treatment options are limited for squamous histologies. 
Further gains in overall survival have been achieved with the administration of pemetrexed 
maintenance. A Phase III, double-blind study of maintenance pemetrexed plus best 
supportive care (BSC) versus placebo plus BSC was conducted in subjects with NSCLC 
whose disease had not progressed following 4 cycles of cisplatin + pemetrexed induction. 
Subjects were randomized 2:1 to pemetrexed + BSC or placebo + BSC, which were 
continued until disease progression or toxicity. The median OS for subjects in the intent-to-
treat (ITT) group was 13.4 months for subjects receiving pemetrexed and 10.6 months for 
those receiving placebo (hazard ratio [HR] of 0.79 [95 percent CI: 0.65, 0.95, p=0.012]).
Median OS was 15.5 months versus 10.3 months for subjects with non-squamous NSCLC 
receiving pemetrexed or placebo, respectively (HR of 0.70 [95 percent CI: 0.56, 0.88]). The 
median OS in subjects with squamous cell NSCLC receiving pemetrexed was 9.9 months 
versus 10.8 months for those receiving placebo (HR of 1.07 [95 percent CI: 0.77, 1.50]) [61].
These findings have established pemetrexed maintenance following completion of 4 cycles
of a platinum doublet induction as a safe and efficacious regimen in patients with advanced 
or metastatic non-squamous NSCLC.
Given the above, Keynote 042 will allow carboplatin AUC 5 or 6 in combination with either 
paclitaxel 200 mg/m2 or pemetrexed 500 mg/m2 dosed Q3W for a maximum of 6 cycles as a 
control, chemotherapy option. Each chemotherapy regimen will also allow optional
pemetrexed maintenance in patients with non-squamous histologies.
Rationale
Rationale for the Trial and Selected Subject Population
Lung cancer had the highest incidence of malignancies globally in 2008 with more than 
1.6 million cases. Mortality from lung cancer in 2008 was similar with over 1.4 million 
deaths from lung cancer globally [62]. NSCLC accounts for approximately 85% of all lung 
cancer cases.
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%, 
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 and maintenance strategies conferring the greatest advances in 
overall survival gains. 
Platinum-based combination chemotherapy prolongs survival, improves quality-of-life, and 
controls disease-related symptoms. Platinum chemotherapy, thus, is the backbone treatment 
for initial (first line) treatment of patients not candidates for treatment with tyrosine kinase 
inhibitors (TKIs). Approved therapies for previously untreated, advanced/metastatic NSCLC 
subjects in whom EGFR or ALK-directed therapy is not indicted include paclitaxel, 
 
 
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gemcitabine, docetaxel, pemetrexed, and bevacizumab, all in combination with platinum-
based chemotherapy. While ECOG 1594 demonstrated that the four platinum-doublets tested 
(cisplatin combined with either paclitaxel, gemcitabine, or docetaxel, and carboplatin and 
paclitaxel) have equivalent activity in the first-line setting [61], neither pemetrexed nor 
bevacizumab is appropriate for patients with squamous histology [56] [63] [64].
Recently, targeted therapies for specific tumor genetic alterations have resulted in higher 
response rates in specific subpopulations of NSCLC patients. Examples include inhibitors 
against the epidermal growth factor receptor (EGFR) family and the anaplastic lymphoma 
kinase (ALK). Because of the highly significant demonstration of clinical benefit in these 
molecularly defined sub-populations, ESMO and NCCN guidelines indicate that first-line 
treatment with an approved TKI should be prescribed to patients with tumors bearing an 
activating (sensitizing) epidermal growth factor receptor (EGFR) mutation because of 
significantly higher response rate (RR), longer PFS, and better quality of life (QoL) (ESMO) 
when compared with first-line chemotherapy [53]. Recently, a third EGFR inhibitor, afatinib, 
was approved for the treatment of EGFR inhibitor (TKI) naïve patients with advanced or 
metastatic NSCLC who bear EGFR-activating mutations on the basis of a significantly 
improved PFS and acceptable safety, as compared to a SOC platinum doublet of cisplatin + 
pemetrexed. The composite of data demonstrated a favorable benefit-risk ratio and thus 
contributes to the arsenal of options for NSCLC patients who harbor EGFR-activating 
mutations. 
Furthermore, recent retrospective analyses indicate that continuation of TKI treatment 
beyond RECIST-defined progression is associated with a significantly improved overall 
survival as compared to subjects who were switched to cytotoxic chemotherapies at the time 
of RECIST-defined PD [65]. The ongoing single arm, Phase II ASPIRATION trial 
(NCT01310036) aims to prospectively determine if continuation of erlotinib beyond 
RECIST-defined progression in Asian subjects with EGFR mutations confers clinical benefit. 
To our knowledge, no randomized studies comparing treatment beyond progression to the 
traditional paradigm in which cytotoxic chemotherapy is initiated at the time of progression 
have been performed. Despite these definitive data, the NCCN guidelines recommend that 
EGFR inhibitors be continued despite PD in asymptomatic patients who harbor EGFR
sensitizing mutations, further underscoring the potential to slow the rate of progression and 
ultimately provide clinical benefit in a patient population with limited therapeutic options in 
the 2L and beyond.
Patients with NSCLC harboring an anaplastic lymphoma kinase (ALK) translocation should 
be considered for crizotinib (Xalkori) for the treatment of ALK-translocated, previously 
treated NSCLC.
Despite the development of these targeted therapies, most patients relapse and die from their 
lung cancer; therefore, advanced and metastatic NSCLC remain a major unmet medical need.
Patients who harbor EGFR sensitizing mutations and/or ALK translocations will be excluded 
from this study. Significant preclinical and clinical data indicate that activation of these 
respective pathways fundamentally alter the natural history of tumors that bear these 
mutations as compared to tumors that do not, which ultimately affect sensitivity to standard 
 
 
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of care chemotherapies including pemetrexed in the case of ALK translocations [66]. In 
addition, EGFR sensitizing mutations confer significant prognostic implications as illustrated 
by the improved PFS to the SOC platinum doublet, carboplatin and paclitaxel, and overall 
survival in the EGFR sensitizing mutation population [67]. These mutations also potentially 
alter PD-L1 expression, likely due to yet undefined interactions between the PD-1/PD-L1/2, 
EGFR, and EML4/ALK pathways [68]. These observations indicate that tumors that bear 
EGFR sensitizing mutations or ALK translocations may be fundamentally different from 
tumors that do not bear these mutations and may have a different safety and efficacy profile 
with pembrolizumab as compared to tumors that do not bear these mutations. Given that little 
data exist regarding the safety and/or efficacy implications of pembrolizumab on these 
tumors, tumors that bear these mutations will be excluded from this study.
Details regarding specific benefits and risks for subjects participating in this clinical trial may 
be found in the accompanying Investigators Brochure (IB) and Informed Consent documents.
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
4.2.1.1
Benefit Risk
In Keynote-001, pembrolizumab continued to provide long-term OS benefit for PD-L1–
positive treatment-naive and previously treated NSCLC subjects. As of September 18, 2015, 
median follow-up duration was 23.1 months. Median OS was 22.1 months (17.1-27.2) for 
treatment-naive subjects and 10.6 months (8.6-13.3) for previously treated subjects. Eighteen 
month OS rates were 58.2% and 37.0% respectively; 24-month rates were 44.5% and 31.3%. 
Pembrolizumab continued to have a manageable safety profile, with no unexpected toxicities 
observed in long-term follow-up. Of 555 enrolled subjects, 386 (70.2%) experienced ≥1 
treatment-related AE, including 66 (12.0%) who experienced ≥1 treatment-related AE of 
Grade 3-5 severity. Treatment-related AEs led to death in 2 (0.4%) subjects (1 case each of 
interstitial lung disease and cardiopulmonary arrest) and treatment discontinuation in 29 
(5.3%) subjects. Immune-mediated AEs of any grade and grade 3-5 severity occurred in 89 
(16.2%) and 22 (4.0%) subjects, respectively and led to treatment discontinuation in 16 
(2.9%) subjects. Treatment-related AEs of an inflammatory or immune-mediated nature that 
occurred in more than 2% of subjects were hypothyroidism (in 44 subjects [8.0%]), 
pneumonitis (in 22 subjects [4.0%]), and infusion reactions (in 15 subjects [2.7%]). The 
efficacy results in this study in conjunction with the favorable safety profile demonstrate an 
overall positive benefit risk assessment.
In addition to Keynote-001 (1L, 2L), Keynote-010 (2L), and Keynote-024 (1L), the ongoing 
Keynote-042 (IL) study will assess the benefit of pembrolizumab in a previously untreated, 
advanced NSCLC population who tumors express PD-L1>50%, PD-L1>20%, and >1%.
Details regarding specific benefits and risks for subjects participating in this clinical trial may 
be found in the Investigators Brochure (IB) and Informed Consent documents.
 
 
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Rationale for Dose Selection/Regimen/Modification
The planned dose of pembrolizumab for this trial is 200 mg every 3 weeks (Q3W). Based on 
the totality of data generated in the pembrolizumab development program, 200 mg Q3W is 
the appropriate pembrolizumab dose across all indications, regardless of tumor type. As 
outlined below, this dose is justified by:

Clinical data from 8 randomized trials demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W)

Clinical data showing a meaningful improvement in the benefit-risk relationship,
including OS, at 200 mg Q3W across multiple indications

Pharmacology data showing full target saturation in both systemic circulation 
(inferred from PK data) and tumor (inferred from physiologically based 
pharmacokinetic [PBPK] analysis) at 200 mg Q3W.
In the 8 randomized dose comparison trials, 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). Five trials (KN001 B2, KN001 D, KN002, KN010, and 
KN021) compared 2 mg/kg Q3W vs 10 mg/kg Q3W, and 3 trials (KN001 B3, KN001 F2, 
and KN006) compared 10 mg/kg Q3W vs 10 mg/kg Q2W. All these trials demonstrated flat 
dose- and exposure-response relationships across the doses studied, representing an 
approximate 5 to 7.5-fold difference in exposure. Responses to the dose of 2 mg/kg (or 200 
mg fixed dose) Q3W were similar to responses to the highest doses studied. Subsequently, 
flat dose/exposure-response relationships were 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 interacts with 
immune cells and does not act via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data from KN001, evaluating target-mediated drug disposition, conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W. Second, a 
PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor 
penetration and PD-1 expression. This evaluation concluded that pembrolizumab at 200 mg 
Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis for pembrolizumab, which characterized the influence of 
body weight and other subject covariates on exposure, has shown that fixed dosing provides 
control of PK variability similar to that with weight-based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and the 2 mg/kg Q3W 
dose. Supported by these PK characteristics, and given that a fixed dose has advantages of 
less dosing complexity and reduced potential for dosing errors, the 200 mg Q3W fixed dose 
was selected for evaluation across all pembrolizumab protocols.
 
 
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Rationale for Endpoints
4.2.3.1
Efficacy Endpoints
Primary: Overall survival is a standard assessment of clinical benefit in subjects with 
advanced and metastatic NSCLC. 
Secondary: Progression free survival and ORR are acceptable measures of clinical benefit 
for a randomized Phase III 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, they are endorsed regulatory endpoints for 1L NSCLC trials with recent 
FDA and EMA approvals including the EGFR inhibitors, afatinib, and erlotinib. PFS and 
ORR will be assessed per RECIST 1.1 by central independent radiologists’ review that will 
be blinded to the treatment assignment to minimize any bias in the response assessments.
4.2.3.2
Planned Exploratory Biomarker Research
Additional biomarker research to identify factors important for pembrolizumab therapy may 
also be pursued. For example, tumor and blood samples (including serum and plasma) from 
this study may undergo proteomic, genomic, metabolomic and transcriptional analyses. 
Additional research may evaluate factors important for predicting responsiveness or 
resistance to pembrolizumab therapy and other immunologic targets. 
Assays may include but are not be limited to: 
Immunohistochemistry
PD-L1 expression in tumor tissue will be characterized by immunohistochemistry to explore 
the relationship between tumor PD-L1 expression and response to treatment with 
pembrolizumab. Other exploratory biomarkers (e.g., PD-1 expression, markers of T-cell 
phenotype) may also be evaluated.
Transcriptional Analyses
Messenger RNA (mRNA) expression profiling in archival material (biopsy specimens, 
peripheral blood) will be completed to assess expression of approximately 700 genes and 
attempt to define a gene set critical for clinical response to pembrolizumab. The hypothesis 
to be tested is that pembrolizumab induces responses in tumors that reflect an inflamed/ 
immune phenotype based on gene expression signatures capturing PD-L1 and interferon-
gamma transcriptional programs. Global profiling will also be pursued. Expression of 
individual genes related to the immune system may also be evaluated such as immune 
signatures and critical cytokines (e.g., IL-10). microRNA profiling may also be pursued in 
serum samples.
 
 
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Proteomic Analysis
In addition to expression on the tumor tissue, PD-L1 can be shed from tumor and released 
into the blood. Enzyme-linked immunoassay can measure PD-L1 in serum and correlate this 
expression with response to pembrolizumab therapy, as well as levels of PD-L1 IHC or 
protein in the tumor. Blood would be a less invasive compartment compared to tumor from 
which to measure PD-L1 protein biomarker. In addition to this specific protein biomarker, 
both tissue and blood derivatives can be subjected to proteomic profiling studies using a 
variety of platforms that could include but are not limited to immunoassay, Liquid 
Chromatography/Mass Spectrometry. This approach could identify novel protein biomarker 
that could aid in patient selection for pembrolizumab therapy.
Gene Analyses
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to define certain tumor types at the genetic level as being 
‘hypermutated’ or can detect the presence of specific T-cell clones within the tumor 
microenvironment or in the peripheral blood. There is a potential that the hypermutated state 
and/or increased T-cell clonality may correlate with response to pembrolizumab therapy, 
and/or that the converse, ‘hypomutated’ state or lack of dominant T-cell clones may correlate 
with non-response.
In addition, understanding genetic determinants of drug response is an important endeavor 
during medical research. This research will evaluate whether genetic variation within a 
clinical trial population correlates with response to the treatment(s) under evaluation. If 
genetic variation is found to predict efficacy or adverse events, the data might inform optimal 
use of therapies in the patient population.
4.2.3.3
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens routinely and 
specifically collected during this clinical trial. This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. For instance, exploratory 
pharmacogenetic 
(PGt) 
studies 
may 
be 
performed 
if 
significant 
Pharmacokinetic/Pharmacodynamic (PK/PD) relationships are observed or adverse events 
are identified.  Genomic markers of disease may also be investigated.  Such retrospective 
pharmacogenetic studies will be conducted with appropriate biostatistical design and analysis 
and compared to PK/PD results or clinical outcomes. Any significant PGt relationships to 
outcome would require validation in future clinical trials. The overarching goal is to use such 
information to develop safer, more effective drugs/vaccines, and/or to ensure that subjects 
 
 
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receive the correct dose of the correct drug/vaccine at the correct time.  The details of this 
Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male/female subjects with NSCLC who do not have an EGFR sensitizing mutation and are 
ALK translocation negative, whose tumors demonstrate PD-L1 expression as determined by 
a central laboratory, who have received no systemic anti-cancer therapy for their advanced or 
metastatic NSCLC, and are at least 18 years of age will be enrolled in this trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Have measurable disease based on RECIST 1.1 as determined by the site.
2. Be ≥18 years of age on the day of signing informed consent.
3. Have a life expectancy of at least 3 months.
4. Have not received prior systemic chemotherapy treatment for their advanced/metastatic 
NSCLC.
Note: Treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant
therapy is allowed as long as therapy was completed at least 6 months prior to the 
diagnosis of advanced or metastatic disease.
5. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group 
(ECOG) Performance Status.
6. Have adequate organ function as indicated by the following laboratory values in 
Table 1.
 
 
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Table 1
Adequate Organ Function Lab Values
System
Laboratory Valuea
Hematological
Absolute neutrophil count (ANC)
≥1,500/mcL
Platelets
≥100,000/mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L 
Renal
Serum creatinine OR calculated 
creatinine clearance (CrCl)b
(GFR can also be used in place of 
creatinine or CrCl)
≤1.5 × upper limit of normal (ULN) OR
≥50 mL/min for subjects with creatinine levels
>1.5 × institutional ULN
Hepatic
Serum total bilirubin
≤ULN 
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN OR
≤5 × ULN for patients with liver metastases
Endocrine
Thyroid stimulating hormone (TSH)
Within normal limits. Note: If TSH is not within normal limits 
at baseline, the subject may still be eligible if T3 and free T4 
are within the normal limits
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
Activated Partial Thromboplastin
Time (aPTT)
≤1.5 × ULN unless the subject is receiving
anticoagulant therapy
≤1.5 × ULN unless the subject is receiving
anticoagulant therapy
a All screening laboratory tests (local or central) must be reviewed by the investigator or qualified designee 
and acceptable prior to randomization.
b Creatinine clearance should be calculated per institutional standard. If no local guideline is available, 
creatinine clearance should be calculated using the Cockcroft-Gault Method:
CrCl = [(140-age) * weight (kg) * (0.85 for females only)] / (72 * serum creatinine)
7. Have no history of prior malignancy, with the exception of basal cell carcinoma of the 
skin, superficial bladder cancer, squamous cell carcinoma of the skin, or in situ cervical 
cancer, or have undergone potentially curative therapy with no evidence of that disease 
recurrence for 5 years since initiation of that therapy.
8. Have provided formalin-fixed tumor tissue sample from a biopsy of a tumor lesion either 
at the time of or after the diagnosis of advanced or metastatic disease has been made 
AND from a site not previously irradiated to assess for PD-L1 status. 
Note: Biopsies obtained PRIOR to the administration of any systemic therapy 
administered for the treatment of a subject’s tumor (such as adjuvant therapy) will not 
permitted for analysis. The tissue sample must be received by the central vendor prior to 
randomization. Fine needle aspirates are not acceptable. Core needle or excisional 
biopsies or resected tissue is required. 
 
 
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9. Have a histologically or cytologically confirmed diagnosis of advanced or metastatic 
NSCLC and not have an EGFR sensitizing (activating) mutation or an ALK 
translocation.
Note: EGFR sensitizing mutations are those mutations that are amenable to treatment 
with TKIs including erlotinib, gefitinib, or afatinib. Investigators must be able to produce 
the source documentation of the EGFR mutation and ALK translocation in all subjects 
with non-squamous histologies AND for subjects in whom testing is clinically 
recommended. If either an EGFR sensitizing mutation or ALK translocation is detected, 
additional information regarding the mutation status of the other molecule is not required.
If documentation is unavailable or the site is unable to test for these molecular changes, 
formalin-fixed paraffin embedded tumor tissue of any age should be submitted to a 
central laboratory designated by the Sponsor for such testing. Subjects with non-
squamous histologies will not be randomized until EGFR mutation status and/or ALK 
translocation status is available in source documentation at the site.
10. Have a PD-L1 positive (TPS≥1%) tumor as determined by IHC at a central laboratory.
Note: Only PD-L1 positive (TPS≥1%) subjects will be randomized. If the tumor 
specimen is not evaluable for PD-L1 expression by the central laboratory, the subject is 
not eligible to participate in the study.
11. Female subjects must have a negative urine or serum pregnancy test at screening (within 
72 hours of first dose of study medication) if of childbearing potential or be of non-child 
bearing potential. If the urine test is strong or cannot be confirmed as negative, a serum 
pregnancy test will be required. The serum pregnancy test must be negative for the 
subject to be eligible. Non-childbearing potential is defined as (by other than medical 
reasons):
a.
≥45 years of age and has not had menses for greater than 1 year,
b. Amenorrheic for <2 years without a hysterectomy and oophorectomy and an FSH 
value in the postmenopausal range upon pretrial (screening) evaluation,
c.
Whose status is post hysterectomy, oophorectomy, or tubal ligation. Documented 
hysterectomy or oophorectomy must be confirmed with medical records of the actual 
procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with 
medical records of the actual procedure otherwise the subject must be willing to use 
two adequate barrier methods throughout the study, starting with the screening visit 
through 120 days after the last dose of study therapy. Please see Section 5.7.2 for a 
list of acceptable birth control methods. Information must be captured appropriately 
within the site's source documents.
12. If of childbearing potential, female subjects must be willing to use two adequate barrier 
methods or a barrier method plus a hormonal method throughout the study, starting with 
the screening visit (Visit 1) through 120 days after the last dose of pembrolizumab is 
received and through 180 days after last dose of chemotherapeutic agents as specified in 
 
 
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the protocol. Such methods of contraception, or true abstinence from heterosexual 
activity, when this is in line with the preferred and usual lifestyle of the subject, are 
required (periodic abstinence, e.g., calendar, ovulation, symptothermal, post-ovulation 
methods and withdrawal are not acceptable methods of contraception). Please see Section 
5.7.2 for a list of acceptable birth control methods.
13. Male subjects with a female partner(s) of child-bearing potential must agree to use two 
adequate barrier methods or a barrier method plus a hormonal method throughout the trial 
starting with the screening visit (Visit 1) through 120 days after the last dose of 
pembrolizumab is received and through 180 days after the last dose of chemotherapeutic 
agents as specified in the protocol. Such methods of contraception, or true abstinence 
from heterosexual activity, when this is in line with the preferred and usual lifestyle of 
the subject, are required (periodic abstinence, e.g., calendar, ovulation, symptothermal, 
post-ovulation methods and withdrawal are not acceptable methods of contraception).
Males with pregnant partners must agree to use a condom; no additional method of 
contraception is required for the pregnant partner. Please see Section 5.7.2 for a list of 
acceptable birth control methods.
14. Have voluntarily agreed to participate by giving written informed consent/assent for the 
trial. The subject may also provide consent/assent for Future Biomedical Research. 
However, the subject may participate in the main trial without participating in Future 
Biomedical Research.
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Has an EGFR sensitizing mutation and/or ALK translocation.
Note: For patients enrolled who are known to have a tumor of predominantly squamous 
histology, molecular testing for EGFR mutation and ALK translocation will not be 
required as this is not standard of care and is not part of current diagnostic guidelines.
2. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 
4 weeks of the first dose of trial treatment.
3. Tumor specimen is not evaluable for PD-L1 expression by the central laboratory. If an 
additional tumor specimen is submitted AND evaluable for PD-L1 expression, the subject 
will be eligible to participate if PD-L1 expression is assessed as positive (TPS≥1%) by 
the central laboratory. 
4. Subjects with squamous histology who received carboplatin in combination with 
paclitaxel in the adjuvant setting.
5. Is receiving systemic steroid therapy <3 days prior to the first dose of trial treatment or 
receiving any other form of immunosuppressive medication.
 
 
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Notes: 
a.
Corticosteroid use on study after Cycle 1 for management of AEs, SAEs and ECIs, as 
a pre-medication for the control chemotherapies, as a pre-medication for IV contrast 
allergies/reactions or if considered necessary for a subject’s welfare is allowed.
b. Subjects who receive daily steroid replacement therapy serve as an exception to this 
rule. Daily prednisone at doses of 5-7.5 mg is an example of replacement therapy.
c.
Equivalent hydrocortisone doses are also permitted if administered as a replacement 
therapy.
6. The subject’s NSCLC can be treated with curative intent with either surgical resection 
and/or chemoradiation.
7. Is expected to require any other form of systemic or localized antineoplastic therapy 
while on trial (including maintenance therapy with another agent for NSCLC, radiation 
therapy, and/or surgical resection).
8. Has received any prior systemic cytotoxic chemotherapy, biological therapy OR had
major surgery within 3 weeks of the first dose of trial treatment; received lung radiation 
therapy of >30 Gy within 6 months of the first dose of trial treatment.
9. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, 
or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or 
checkpoint pathways).
10. Has known central nervous system metastases and/or carcinomatous meningitis.
Note: Subjects with previously treated brain metastases may participate provided they are 
clinically stable (neurologically asymptomatic) and have no evidence of new or enlarging 
brain metastasis by imaging at least 4 weeks after treatment of the brain metastases 
(e.g., surgery, RT) and are off steroids for at least 3 days prior to the first dose of study 
medication.
11. Has active autoimmune disease that has required systemic treatment in past 2 years 
(i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
Note: Replacement therapy (i.e., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment. Subjects that require inhaled corticosteroids would not be excluded 
from the study. Subjects with vitiligo or resolved childhood asthma/atopy would not be 
excluded from the study. Subjects that require local steroid injections would not be 
excluded from the study.
12. Has had an allogeneic tissue/solid organ transplant.
 
 
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13. Has interstitial lung disease OR has had a history of pneumonitis that has required oral or 
IV steroids. 
14. Has received or will receive a live vaccine within 30 days prior to the first administration 
of study medication. Seasonal flu vaccines that do not contain live vaccine are permitted.
15. Has an active infection requiring intravenous systemic therapy.
16. Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
Note: HIV testing is required at screening as indicated in Section 6.0 – Trial Flow Chart.
17. Has known active Hepatitis B or C. Subjects with a positive HBsAg result would be 
excluded. 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.  
Note: Hepatitis B and Hepatitis C testing is required at screening as indicated in 
Section 6.0 – Trial Flow Chart.
18. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating Investigator.
19. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial.
20. Is, at the time of signing informed consent, a regular user (including “recreational use”) 
of any illicit drugs or had a recent history (within the last year) of substance abuse 
(including alcohol).
21. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit (Visit 1) through 120 days 
after the last dose of pembrolizumab or 180 days after the last dose of SOC 
chemotherapy.
Trial Treatment(s)
The treatment(s) to be used in this trial are outlined below in Table 2. 
 
 
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Table 2
Trial Treatment
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment Period
Pembrolizumab
200 mg
Q3W
IV
Day 1 of each 21-day cycle
Paclitaxel
200 mg/m2
Q3W
IV
Day 1 of each 21-day cycle
Carboplatin
AUC 5 or 6
Q3W
IV
Day 1 of each 21-day cycle
Pemetrexed
500 mg/m2
Q3W
IV
Day 1 of each 21-day cycle
and as maintenance in subjects 
with non-squamous 
histologies
Trial treatment should begin on the day of randomization or as close as possible to the date 
on which the subject is allocated/assigned.
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 will be responsible for recording the lot number, manufacturer and expiry date 
of any locally purchased product.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
5.2.1.1
Dose Selection (Preparation)
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.
Details on the dose calculation, preparation and administration are provided in the Pharmacy
Manual.
Carboplatin, paclitaxel, and pemetrexed will be prepared and administered as per the 
approved product label.
 
 
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5.2.1.2
Dose Modification (Escalation/Titration/Other)
Paclitaxel/Carboplatin and Optional Pemetrexed Chemotherapy Regimen
Refer to approved product labels for subjects receiving this regimen.
Pemetrexed/Carboplatin and Optional Pemetrexed Chemotherapy Regimen
Refer to approved product labels for subjects receiving this regimen.
5.2.1.2.1 Immune-Related 
Events 
and 
Dose 
Modification 
(Withhold, 
Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation. Based on the severity of irAEs, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids. 
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 3.
 
 
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Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 
after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 

Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper

Monitor participants for signs and symptoms of 
pneumonitis

Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment

Add prophylactic antibiotics for opportunistic 
infections
Recurrent Grade 2 
or Grade 3 or 4 
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold

Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper

Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood 
or mucus in stool with or without fever) and of 
bowel perforation (ie, peritoneal signs and ileus)

Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis

Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear fluids. 
If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV 
infusion.
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
 
 
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST / ALT 
Elevation or 
Increased 
Bilirubin
Grade 2
Withhold

Administer corticosteroids 
(initial dose of 0.5-1 mg/kg 
prednisone or equivalent) 
followed by taper

Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable)
Grade 3 or 4 
Permanently 
discontinue

Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure
Withhold a

Initiate insulin replacement 
therapy for participants 
with T1DM

Administer anti-
hyperglycemic in 
participants with 
hyperglycemia

Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold

Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated

Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue a
Hyperthyroidism 
Grade 2
Continue

Treat with non-selective 
beta-blockers (eg, 
propranolol) or 
thionamides as appropriate

Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
Permanently 
discontinue a
 
 
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidism
Grade 2-4
Continue

Initiate thyroid replacement 
hormones (eg, 
levothyroxine or 
liothyronine) per standard 
of care

Monitor for signs and symptoms of thyroid 
disorders
Nephritis and 
renal dysfunction
Grade 2
Withhold

Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by 
taper

Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1 
Withhold

Based on severity of AE 
administer corticosteroids

Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
All Other irAEs
Persistent Grade 2
Withhold

Based on severity of AE 
administer corticosteroids

Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold or 
discontinue b
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 
1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
b
Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically important irAEs 
(eg, vasculitis and sclerosing cholangitis).
 
 
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Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient's study record.
Timing of Dose Administration
Trial treatment may be administered up to 3 days after randomization for Cycle 1 Day 1 due 
to administrative reasons unless the subject requires pemetrexed pre-medications. For these 
subjects, the required pre-medications should be administered as close to randomization as 
possible. After Cycle 1, there is a 3-day window for all trial treatment.
The specific time of pembrolizumab administration (e.g., time of the week for first 
administration; time of the day for each administration) should take into consideration study 
visit procedures.
All trial treatments will be administered on an outpatient basis.
Pembrolizumab: Pembrolizumab will be administered as a 30-minute IV infusion Q3W.
Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window 
of
-5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: 
-5 min/+10 min).
The Pharmacy Manual contains specific instructions for pembrolizumab dose calculation, 
preparation of the infusion fluid, and administration.
Carboplatin: Carboplatin AUC 5 or 6 will be administered as an IV infusion over 30-60 
minutes on Day 1 of every 3-week cycle following paclitaxel or pemetrexed infusions (or per 
local standard practice). 
Pemetrexed: Pemetrexed 500 mg/m2 will be administered as an IV infusion over 10 minutes 
every 3 weeks and should precede infusion with carboplatin (or per local standard practice). 
All patients should be pre-medicated with steroids as per approved label and local standard 
practices. In addition, all subjects assigned to pemetrexed must take a folic acid preparation 
or multivitamin with folic acid containing between 350 to 1000 mcg daily. At least 5 daily 
doses of folic acid must be taken during the 7-day period preceding the first dose of 
pemetrexed and dosing should continue during the full course of therapy and for 21 days 
after the last dose of pemetrexed.
Subjects must also receive one intramuscular injection of vitamin B12 1000 mcg during the 
week preceding the first dose of pemetrexed and every 3 cycles thereafter. Subsequent 
vitamin B12 injections may be given the same day as pemetrexed.
Initiation of the folic acid and vitamin B12 should occur as close to randomization as 
possible. Pemetrexed will be administered on Cycle 1 Day 1 and every 21 days thereafter. 
 
 
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Paclitaxel: Paclitaxel 200 mg/m2 will be administered as an IV infusion over 3 hours (or per 
local standard practice) on Day 1 of every 3-week cycle and should precede infusion with 
carboplatin. 
All subjects receiving the above chemotherapy(s) should be pre-medicated with oral or 
injectable steroids according to the approved product label and/or standard practice. 
Additional pre-medications should be administered as per standard practice.
For additional details, refer to approved product labels for details regarding dose calculation, 
reconstitution, preparation of the infusion fluid, and administration for each of the standard 
of care chemotherapies. 
Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Imaging data for the primary analysis will be centrally reviewed by independent 
radiologist(s) without knowledge of subject treatment assignment. The subject-level PD-L1 
biomarker results (TPS results) will be masked in the database to the study team at the 
Sponsor including clinical, statistical, statistical programming, and data management 
person. Access to the PD-L1 subject-level biomarker results (TPS results) will be limited to 
an unblinded Sponsor clinical scientist, unblinded data management analyst, unblinded 
Sponsor statistician, and unblinded Sponsor statistical programmer who will be responsible 
for data review to ensure validity of results but who will have no other responsibilities 
associated with the study.
Randomization or 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 SOC, respectively. The investigator’s choice 
of SOC doublet will be documented prior to randomization in IVRS/IWRS.
Stratification
Randomization will be stratified according to the following factors:
1. Geography: East Asia vs. non-East Asia
2. ECOG PS: 0 vs. 1
3. Histology: Squamous vs. non-squamous
4. PD-L1 Expression: TPS ≥50% vs. TPS 1-49%
 
 
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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 case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids. If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date will also be included on the CRF.
Palliative and supportive care is permitted during the course of the trial for underlying 
medical conditions and management of symptoms. Surgery for tumor control or symptom 
management is not permitted during the study. Palliative radiotherapy is permitted to a single 
lesion if considered medically necessary by the treating physician as long as the lesion is 
NOT a RECIST 1.1 defined target lesion and is NOT administered for tumor control. Trial 
therapy should be held during the course of palliative radiotherapy and should be resumed no 
earlier than the next scheduled administration of trial therapy. The specifics of the radiation 
treatment, including the location, will be recorded. 
All concomitant medications received within 30 days before the first dose of trial treatment 
through the Safety Follow-up Visit should be recorded. After the Safety Follow-up Visit,
record all medications taken for SAEs and ECIs as defined in Section 7.2.
Prohibited Concomitant Medications and/or Treatments
Subjects are prohibited from receiving the following therapies during the Screening, 
Treatment, and Second Course Phases of this trial.

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Surgery for symptom management or tumor control

Radiation therapy to measurable disease
 
 
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
Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, seasonal flu (that 
contain a live virus), H1N1 flu, rabies, BCG, and typhoid vaccine.

Glucocorticoids for any purpose other than to modulate symptoms from an adverse 
event, serious adverse event, event of clinical interest, for use as a pre-medication for 
chemotherapeutic agents specified in the protocol, or for use as a pre-medication in 
subjects with a known history of an IV contrast allergy administered as part of CT 
radiography. Replacement doses of steroids (for example, prednisone 5-7.5 mg daily) 
are permitted while on study.

For subjects assigned to the control arm, concomitant meds should be prohibited as 
per local standard of care practices and/or the respective package insert details. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. 
Subjects may receive other medications that the investigator deems to be medically 
necessary.
The Exclusion Criteria describes other medications that are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
Rescue Medications & Supportive Care
Supportive Care Guidelines
Pembrolizumab
Pembrolizumab subjects should receive appropriate supportive care measures as deemed 
necessary by the treating investigator including but not limited to the items outlined below.

Diarrhea: Subjects should be carefully monitored for signs and symptoms of 
enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, with or 
without fever) and of bowel perforation (such as peritoneal signs and ileus). In 
symptomatic subjects, infectious etiologies should be ruled out, and if symptoms are 
persistent and/or severe, endoscopic evaluation should be considered. All subjects 
who experience diarrhea 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.
For additional guidance and/or treatment recommendation, please refer to the separate 
Events of Clinical Interest (ECI) and Immune-related Adverse Events (irAE) 
Guidance Document. For guidelines for continuing treatment with pembrolizumab, 
see Section 5.2. 
 
 
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
Nausea/Vomiting: Administration of prophylaxis for nausea and vomiting should be 
administered per institutional guidelines and local standard practices for the standard 
of care chemotherapies offered for the control arm. For MK-3475, the therapy is 
considered to be of low to moderate emetogenic potential. Consideration for chemo-
induced nausea and vomiting prophylaxis should be given in subsequent cycles of the 
administration according to standard institutional practice. Subjects should be 
strongly encouraged to maintain liberal oral fluid intake.

Anemia: Transfusions and/or erythropoietin may be utilized as clinically indicated for 
the treatment of anemia, but should be clearly noted as concomitant medications. 
Consider a potential immunologic etiology.

Neutropenia: Prophylactic use of colony-stimulating factors including Granulocyte 
Colony-Stimulating Factor (G-CSF), pegylated G-CSF or Granulocyte Macrophage 
Colony-Stimulating Factor (GM CSF) is not allowed in this trial. Therapeutic use of 
G-CSF is allowed in subjects with Grade 3-4 febrile neutropenia. Consider a potential 
immunologic etiology.

Thrombocytopenia: Transfusion of platelets may be used if clinically indicated. ITP 
should be ruled out before initiation of platelet transfusion.

Anti-infectives: Subjects with a documented infectious complication should receive 
oral or IV antibiotics or other anti-infective agents as considered appropriate by the 
treating Investigator for a given infectious condition, according to standard 
institutional practice.

Events of Clinical Interest (ECI) with a Potential Immunologic Etiology: Please see 
the separate guidance document in the administrative binder regarding identification, 
evaluation, and management of adverse experiences of a potential immunologic 
etiology. Depending on the type and severity of an ECI, oral or intravenous treatment 
with a corticosteroid should be considered, in addition to appropriate symptomatic 
treatment of a given condition.
Overview 
of 
Guidelines 
for 
Managing 
Suspected 
Pneumonitis 
From 
Pembrolizumab
The treatment of symptomatic subjects with pneumonitis differs from asymptomatic subjects 
with pneumonitis. Subjects with symptomatic pneumonitis should immediately stop 
receiving pembrolizumab and have an evaluation, with consideration of further work up 
including a bronchoscopy, cultures, and pulmonary function tests, to assess severity and to 
rule out other causes such as infection.
Please consult the ECI and irAE Guidance document in the Administrative Binder for this 
study for a more in depth discussion of pneumonitis.
 
 
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Guidelines for Infusion Reactions
Pembrolizumab
Acute infusion reactions (which can include cytokine release syndrome, angioedema, or 
anaphylaxis) are different from allergic/hypersensitive reactions, although some of the 
manifestations are common to both AEs. Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of completion of 
infusion. Signs/symptoms may include: allergic reaction/hypersensitivity (including drug 
fever); arthralgia (joint pain); bronchospasm; cough; dizziness; dyspnea (shortness of breath); 
fatigue (asthenia, lethargy, malaise); headache; hypertension; hypotension; myalgia (muscle 
pain); nausea; pruritus/itching; rash/desquamation; rigors/chills; sweating (diaphoresis); 
tachycardia; tumor pain (onset or exacerbation of tumor pain due to treatment); urticaria 
(hives, welts, wheals); vomiting.
Table 4 shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab:
Table 4
Pembrolizumab Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Pre-medication at Subsequent 
Dosing
Grade 1
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator.
None
Grade 2
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated 
for ≤24 hours
Stop Infusion
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator.
If symptoms resolve within 1 hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g., from 100 mL/hr to 50 mL/hr). 
Otherwise dosing will be held until 
symptoms resolve and the subject should be 
pre-medicated for the next scheduled dose.
Subjects who develop Grade 2 toxicity 
despite adequate pre-medication should be 
permanently discontinued from further trial 
treatment administration.
Subject may be pre-medicated 1.5
hours ± 30 minutes prior to 
infusion of pembrolizumab with:
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine)
Acetaminophen 500-1000 mg po
(or equivalent dose of analgesic)
 
 
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NCI CTCAE Grade
Treatment
Pre-medication at Subsequent 
Dosing
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator.
Hospitalization may be indicated.
Subject is permanently discontinued from 
further trial treatment administration.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period 
of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 at 
http://ctep.cancer.gov.
Diet/Activity/Other Considerations
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea, or vomiting.
Contraception
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm. Chemotherapy can 
cause fetal harm if administered to pregnant women. Therefore, non-pregnant, non-
breastfeeding women may be enrolled if they are considered highly unlikely to conceive. 
Highly unlikely to conceive is defined as (1) surgically sterilized or (2) postmenopausal (a 
woman who is ≥45 years of age and has not had menses for greater than 1 year will be 
considered postmenopausal) or (3) amenorrheic for <2 years without a hysterectomy and 
oophorectomy and with a documented FSH value in the postmenopausal range or (4) not 
heterosexually active for the duration of the study or (5) heterosexually active and willing to 
use two methods of birth control (which is also recommended for the female partners of male 
subjects). The two birth control methods can be either two barrier methods or a barrier 
method plus a hormonal method to prevent pregnancy. Subjects should start using birth 
control from study Visit 1 throughout the study period up to 120 days after the last dose of 
pembrolizumab and up to 180 days after last dose of chemotherapeutic agents as specified in 
the protocol.
 
 
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The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide, as per local regulations 
and guidelines. Appropriate hormonal contraceptives will include any registered and 
marketed contraceptive agent that contains an estrogen and/or a progestational agent 
(including oral, subcutaneous, intrauterine, or intramuscular agents). Subjects should be 
informed that taking the study medication may involve unknown risks to the fetus (unborn 
baby) if pregnancy were to occur during the study. In order to participate in the study they 
must adhere to the contraception requirement (described above) for the duration of the study 
and during the follow-up period defined in Section 7.2.2 – Reporting of Pregnancy and 
Lactation to the Sponsor. If there is any question that a subject will not reliably comply with 
the requirements for contraception, that subject should not be entered into the study.
Such methods of contraception, or true abstinence from heterosexual activity, when this is in 
line with the preferred and usual lifestyle of the subject, are required (periodic abstinence, 
e.g., calendar, ovulation, symptothermal, post-ovulation methods and withdrawal are not 
acceptable methods of contraception). Males with pregnant partners must agree to use a 
condom; no additional method of contraception is required for the pregnant partner.
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 (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn). The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the Sponsor. If 
a male subject impregnates his female partner, the study personnel at the site must be
informed immediately and the pregnancy reported to the Sponsor and followed as described 
above and in Section 7.2.2.
Use in Nursing Women
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment.
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.
 
 
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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.  Once a 
subject has discontinued treatment, even though he/she continues to be monitored in the trial, 
he/she may be allowed to begin treatment again if deemed medically appropriate.
A subject must be discontinued from the trial for any of the following reasons:
●
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.
Discontinuation From Treatment
A subject must be discontinued from treatment (but may continue to be monitored in the 
trial) for any of the following reasons:

The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.

Documented progression
Note: If a subject has confirmed progression of disease by modified RECIST 1.1, it is 
recommended that the subject be discontinued from trial unless, in the investigator’s 
opinion, the subject is deriving benefit from treatment. Clinically stable subjects as 
defined below may continue to receive trial therapy after consultation with the 
Sponsor. Subjects exhibiting toxicity from trial therapy as outlined in Sections 5.2.1.2 
and 7.2 may NOT continue to receive trial therapy. Regardless of clinical benefit, the 
maximum number of treatments a subject may receive is 35. If a subject has 
unconfirmed progression of disease and is clinically stable, it is at the discretion of 
the investigator to continue treating the subject with the assigned treatment per 
protocol until progression of disease is confirmed at least 28 days from the date of the 
scan suggesting progression of disease. If progression is not confirmed on the 
subsequent scan, the subject should continue to receive study therapy and 
radiographic scans obtained to monitor for disease status every 9 weeks as defined in 
Section 7.1.2.6.
Clinical Stability is defined as:
1. Absence of symptoms and signs indicating clinically significant progression of 
disease (including worsening of laboratory values) indicating disease progression.
2. No decline in ECOG performance status.
3. Absence of rapid progression of disease or progressive tumor at critical
anatomical sites (e.g., cord compression) requiring urgent alternative medical 
intervention.

Unacceptable adverse experiences as described in Section 5.2.1.2.
 
 
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
Two years of uninterrupted delivery of pembrolizumab every 3 weeks and no 
documented progression of disease, or 35 administrations of study medication, 
whichever is later

Intercurrent illness that prevents further administration of treatment

Investigator’s decision to withdraw the subject

The subject has a confirmed strong serum pregnancy test

Noncompliance with trial treatment or procedure requirements

The subject is lost to follow-up

Administrative reasons
If a pembrolizumab treated subject attains an investigator-assessed CR according to modified 
RECIST 1.1, has been treated for at least 6 months with pembrolizumab, and has at least two 
treatments with pembrolizumab beyond the date when the initial CR was declared, the 
subject and investigator may consider stopping therapy with pembrolizumab. Subjects who 
discontinue pembrolizumab after attaining a CR (or have experienced a PR or SD after 35 
administrations of pembrolizumab) and then experience radiographic disease progression 
according to modified RECIST 1.1 will 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. 
Subjects randomized to pembrolizumab who discontinue therapy due to a PR and/or SD after 
35 trial treatments should follow procedures as scheduled in the End of Treatment Phase of 
the study and then move to the Follow-up Phase of the study and have assessments 
performed as indicated in Section 6.0.
Chemotherapy may be discontinued when a subject has received the maximum number of 
cycles as outlined in the protocol.
If subjects discontinue treatment for any reason other than progression or pregnancy, the 
same assessments and frequency of assessments should be obtained as outlined in the 
Observation Phase of the study.
After the end of treatment, each subject will be followed for a minimum of 30 days for 
adverse event monitoring (SAEs and ECI will be collected for 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, as described in Section 7.2.3.1). Subjects will have 
post-treatment follow-up for disease status with pembrolizumab. 
Pembrolizumab End of Treatment Follow-up
A subject may discontinue treatment for any of the reasons outlined in Section 5.8.1;
however, they will remain in the trial for post-treatment observation for disease status until
disease progression, initiating a non-study cancer treatment, withdrawing consent, becoming 
 
 
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lost to follow-up or entering the Second Course Phase. After documented disease progression 
and/or cessation of treatment with pembrolizumab, each subject will be followed for overall 
survival until death.
Subject Replacement Strategy
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last trial visit, discontinues from the trial or is 
lost to follow-up (i.e. the subject is unable to be contacted by the investigator).
At the time the OS analysis has been triggered, all subjects will have the opportunity to 
complete at least 24 months of treatment (or discontinue from treatment for progression or 
other reasons). The last visit of the last subject will be considered the end of the trial.
Upon study completion, subjects are discontinued and may be enrolled in a pembrolizumab 
extension study, if available.
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
The trial will be stopped early if the risk/benefit ratio to the trial population as a whole is 
unacceptable.
Statistical criteria for stopping the trial are provided in Section 8.0 – Statistical Analysis Plan.
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
Pembrolizumab Arm: Treatment and Follow-up Phase 
Screen-
ing
(Visit 1)
Treatment Cycles1
End of Treatment 
Phase
Observation 
Phase2
(pre-PD)
Follow-up Phase3
Survival 
Follow-
up4
1
2 
Every 3 
Months 
after  
Visit 2
Approx. 
Every 2 
Months
Treatment Cycle/
Scheduled Time
-42 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13
and 
be-
yond
Discon-
tinuation
Visit5
Safety
Follow-up
Visit6
Observation 
Visits7
Follow-
up 
Visit 18
Follow-
up Visit 
28
Follow-
up Visit 
3 and 
beyond8
Survival 
Follow-
up Visit 
1 and 
beyond
Scheduling Window 
(Days):9
±3
±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3
±3
±3
±3
±3
At study 
drug 
discontin-
uation
±3
30 days 
from last 
dose
±3
±3 days
±7 days ±7 days
±7 days
±14 
days
Administrative Procedures
Informed Consent
X
Informed Consent for 
Future Biomedical 
Research (optional)
X
Inclusion/Exclusion 
Criteria
X
Subject ID Card
X
Demographics and 
Medical History
X
Review Prior and 
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
NSCLC Disease Details 
and Prior Treatment
X
Subsequent 
Antineoplastic Therapy 
Status
X
X
X
X
X
X
X
 
 
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Confidential
Screen-
ing
(Visit 1)
Treatment Cycles1
End of Treatment 
Phase
Observation 
Phase2
(pre-PD)
Follow-up Phase3
Survival 
Follow-
up4
1
2 
Every 3 
Months 
after  
Visit 2
Approx. 
Every 2 
Months
Treatment Cycle/
Scheduled Time
-42 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13
and 
be-
yond
Discon-
tinuation
Visit5
Safety
Follow-up
Visit6
Observation 
Visits7
Follow-
up 
Visit 18
Follow-
up Visit 
28
Follow-
up Visit 
3 and 
beyond8
Survival 
Follow-
up Visit 
1 and 
beyond
Scheduling Window 
(Days):9
±3
±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3
±3
±3
±3
±3
At study 
drug 
discontin-
uation
±3
30 days 
from last 
dose
±3
±3 days
±7 days ±7 days
±7 days
±14 
days
Survival Status4,10
X
Clinical Procedures/Assessments
Review Adverse 
Events11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Full Physical 
Examination
X
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs and Weight12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
ECOG Performance 
Status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Central Laboratory Procedures/Assessments
Blood for Future 
Biomedical Research 
(Optional)13
X
Blood for Serum 
Biomarkers14
X
Blood for Plasma 
Biomarkers14
X
Correlative Studies 
Blood Collection (DNA 
and RNA)15
X
X
X
X
 
 
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Confidential
Screen-
ing
(Visit 1)
Treatment Cycles1
End of Treatment 
Phase
Observation 
Phase2
(pre-PD)
Follow-up Phase3
Survival 
Follow-
up4
1
2 
Every 3 
Months 
after  
Visit 2
Approx. 
Every 2 
Months
Treatment Cycle/
Scheduled Time
-42 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13
and 
be-
yond
Discon-
tinuation
Visit5
Safety
Follow-up
Visit6
Observation 
Visits7
Follow-
up 
Visit 18
Follow-
up Visit 
28
Follow-
up Visit 
3 and 
beyond8
Survival 
Follow-
up Visit 
1 and 
beyond
Scheduling Window 
(Days):9
±3
±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3
±3
±3
±3
±3
At study 
drug 
discontin-
uation
±3
30 days 
from last 
dose
±3
±3 days
±7 days ±7 days
±7 days
±14 
days
Blood for Genetics16
X
Study Drug Administration
Pembrolizumab17
X
X
X
X
X
X
X
X
X
X
X
X
X17
Local Laboratory Procedures/Assessments
Pregnancy Test - Urine 
or Serum β-HCG18
X18
PT/INR and aPTT19
X20
CBC with 
Differential21,22
X20
X
X
X
X
X
X
X
X
X
X21
X
X
X23
Comprehensive 
Chemistry Panel21, 22
X20
X
X
X
X
X
X
X
X
X
X21
X
X
X23
Urinalysis22,24
X20
X
X
X25
X
X
X23
T3, FT4 and TSH22,25
X20
X
X
X
X
X
X25
X
X
X23
ALK Translocation 
Testing26
X
EGFR Mutation 
Testing26
X
HBsAG27
X
Anti HCV27
X
Anti HIV27
X
 
 
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Confidential
Screen-
ing
(Visit 1)
Treatment Cycles1
End of Treatment 
Phase
Observation 
Phase2
(pre-PD)
Follow-up Phase3
Survival 
Follow-
up4
1
2 
Every 3 
Months 
after  
Visit 2
Approx. 
Every 2 
Months
Treatment Cycle/
Scheduled Time
-42 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13
and 
be-
yond
Discon-
tinuation
Visit5
Safety
Follow-up
Visit6
Observation 
Visits7
Follow-
up 
Visit 18
Follow-
up Visit 
28
Follow-
up Visit 
3 and 
beyond8
Survival 
Follow-
up Visit 
1 and 
beyond
Scheduling Window 
(Days):9
±3
±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3
±3
±3
±3
±3
At study 
drug 
discontin-
uation
±3
30 days 
from last 
dose
±3
±3 days
±7 days ±7 days
±7 days
±14 
days
Efficacy Measurements
Tumor Imaging28
X
X
X
X
X
X28
X28
X28
X8
X10
X10
Tumor Biopsies/Archival Tissue Collection
Tumor Tissue Collection 
for PD-L1 Expression29
X
 
 
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1
In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of trial treatment for each cycle unless otherwise specified. Treatment cycles are 
3 weeks (21 days). If treatment cycles are adjusted, all procedures except imaging will be completed according to the cycle number and not weeks on treatment; imaging 
will be performed every 9 weeks ± 7 days from the date of randomization regardless of any treatment delays.
2
The Observation Phase is for any subject that discontinued study treatment for reasons other than pregnancy or PD (e.g., toxicity). Pembrolizumab subjects remain in the 
Observation Phase until the time of PD, pregnancy, or the start of a new antineoplastic therapy. 
3
Subjects who stop pembrolizumab after 35 trial treatments and have achieved PR and/or SD 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 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. 
4
Once the subject stops the imaging assessments for this protocol (e.g., for PD or starting a new antineoplastic therapy), the subject moves into the Survival Follow-up Phase 
and should be contacted by telephone approximately every 2 months to assess for survival status. Post-study treatments and the subject’s response to them will also be 
collected. Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will not 
have a scheduled study visit or study contact during the Sponsor defined time period will be contacted for their survival status and its respective entry into the database
(excluding subjects who have a death event previously recorded).
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. Imaging assessments should continue as per the interval stated in the 
protocol: every 9 weeks for the first 15 cycles and then every 12 weeks thereafter. Additional imaging at the discontinuation visit is not required provided that imaging 
assessments have been performed per schedule.
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 comes first. Subjects with an AE of Grade >1 will be further followed until the resolution of the AE to Grade 0-1 or until beginning of a 
new antineoplastic therapy, whichever occurs first. Subjects who are eligible for treatment with pembrolizumab during the Second Course Phase may have up to two Safety 
Follow-up Visits, one after the Treatment Phase and the second after the Second Course Phase. 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. Imaging assessments should continue as per the interval stated in the 
protocol: every 9 weeks for the first 15 cycles and then every 12 weeks thereafter. Additional imaging at the Safety Follow-up Visit is not required provided that imaging 
assessments have been performed per schedule.
7
Observation visits should begin 4 weeks (28 days ± 7 days) from the Safety Follow-up Visit and follow a Q3W (21 days ± 3 days) schedule thereafter. Tumor imaging for 
the Observation Visits should be maintained Q9W by following the same calendar day schedule that was initiated during Treatment Cycles. For subjects who have received 
at least 15 treatment cycles of pembrolizumab, the frequency of tumor imaging may be reduced to every 12 weeks (84 ± 7 days) during the Observation Visits. 
8
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 beginning of a new antineoplastic therapy, whichever occurs first.
9
In general, the window for each visit is 3 days unless otherwise specified.
10 Tumor imaging is not needed for subjects who start another anti-cancer treatment regimen.
11 Once a subject discontinues study treatment, report all SAEs (related and unrelated to trial treatment), ECIs, and irAEs 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 and ECIs that are 
considered related to trial treatment.
12 Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure. Height will be measured at screening only.
13 Informed consent for Future Biomedical Research (FBR) samples must be obtained before the DNA sample is drawn. DNA sample for analysis should be obtained pre-dose, 
on Cycle 1 (or with the next scheduled blood draw), as the last sample drawn, on allocated subjects only, or at a later date as soon as the informed consent is obtained. This 
sample should only be taken once from each subject. See Section 12.2 for guidance regarding the collection and management of specimens for FBR.
14 Samples for plasma and serum biomarkers should be obtained pre-dose Cycle 1.
15 Samples for correlative studies should be obtained pre-dose at Cycles 1, 2, 3, and at the time of study drug discontinuation.
16 Blood for genetics sample will be collected to explore host genetics and to identify genetic predictors that may have a role in therapeutic response to pembrolizumab. This 
sample should be drawn for planned, exploratory genetic analysis of DNA unless there is either a documented law or regulation prohibiting collection, or unless the IRB/IEC 
 
 
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does not approve of the collection.
17 Pembrolizumab can be administered for up to 35 treatments.
18 For women of reproductive potential, a urine pregnancy test will be performed within 72 hours prior to first dose of trial treatment. If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test, performed by the local study site laboratory, will be required. Pregnancy tests (serum and/or urine tests) should be repeated if 
required by local guidelines.
19 Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
20 Laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment.
21 CBC with differentials and chemistry will be performed every cycle up to Cycle 10, then every other cycle thereafter.
22 After Cycle 1, lab samples can be collected up to 7 days prior to the scheduled time point. Laboratory results must be known and acceptable prior to dosing.
23 During the Observation Phase, these laboratory assessments should be obtained every 12 weeks.
24 Perform every 4 cycles.
25 Thyroid function tests will be performed by a central laboratory only if the local laboratory is unable to perform this service. Thyroid function tests will be performed every 
other cycle.
26 Site must be able to provide documentation of the subject’s tumor EGFR mutation and/or ALK translocation mutation status if clinically indicated. If the site is unable to 
provide this source documentation, or site level testing, then the Sponsor will offer this molecular testing of the tumor.
27 The need for additional testing due to positive test results will be at the discretion of the Investigator.
28 Sponsor will collect radiological assessments for analysis by a central vendor. The initial tumor imaging will be performed within 30 days prior to the date of randomization. 
Scans performed as part of routine clinical management are acceptable for use as the screening scan if they are of diagnostic quality and performed within 30 days prior to 
the date of randomization. On study imaging will be performed every 9 weeks (63 ± 7 days) after the date of randomization or more frequently if clinically indicated and 
submitted for central radiology review. The timing for imaging studies should follow calendar days and should not be adjusted for delays in cycle starts or extension of 
pembrolizumab cycle frequencies. The same imaging technique should be used in a subject throughout the trial. After week 45 tumor imaging, tumor imaging should be 
performed every 12 weeks (84 ± 7 days). CT scan of the chest, abdomen and pelvis is required for the baseline assessment. After the first documentation of progression (if 
the subject is clinically stable) or response per modified RECIST 1.1 repeat imaging for confirmation may be performed. Confirmatory imaging may be performed as early 
as 28 days later; alternately, the scan performed at the next scheduled time point (e.g., every 63 ±7 days) may be used as confirmation. Details are provided in the Image 
Acquisition Guidelines.
29 Tumor tissue for biomarker analysis from a biopsy of a tumor lesion not previously irradiated must be provided. Only biopsies obtained AFTER the diagnosis of metastatic 
disease will be evaluated for PD-L1 expression. Any leftover tumor tissue will be stored for future research if the subject signs the optional FBR consent. If a tumor biopsy 
was obtained from a target lesion during eligibility assessment, it is preferred to obtain a new baseline scan. Biopsy of lesions on study should be limited to non-target 
lesions or new lesions if their pathologic etiology is ambiguous.
 
 
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Standard of Care Arm: Treatment and Follow-up Phase
Screening
(Visit 1)
Treatment Cycles1
End of Treatment Phase
Observation
Phase2 
(pre-PD)
Survival 
Follow-up3
Approx. 
Every 
2 Months
Treatment Cycle/
Scheduled Time
-42 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13 and 
beyond
Discontinuation 
Visit4
Safety Follow-
up Visit5
Observation 
Visits6,7
Survival 
Follow-up 
Visit 1 and 
beyond
Scheduling Window 
(Days):8
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At study drug 
discontinuation
±3
30 days from 
last dose
±3
±3 days
±14 days
Administrative Procedures
Informed Consent
X
Informed Consent for 
Future Biomedical 
Research
(optional)
X
Inclusion/Exclusion 
Criteria
X
Subject Identification 
Card
X
Demographics and 
Medical History
X
Review Prior and 
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
NSCLC Disease 
Details and Prior 
Treatment
X
Subsequent 
Antineoplastic Therapy 
Status
X
X
X
X
Survival Status3,9
X
 
 
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Confidential
Screening
(Visit 1)
Treatment Cycles1
End of Treatment Phase
Observation
Phase2 
(pre-PD)
Survival 
Follow-up3
Approx. 
Every 
2 Months
Treatment Cycle/
Scheduled Time
-42 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13 and 
beyond
Discontinuation 
Visit4
Safety Follow-
up Visit5
Observation 
Visits6,7
Survival 
Follow-up 
Visit 1 and 
beyond
Scheduling Window 
(Days):8
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At study drug 
discontinuation
±3
30 days from 
last dose
±3
±3 days
±14 days
Clinical Procedures/Assessments
Review Adverse 
Events10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Full Physical 
Examination
X
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs and 
Weight11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
ECOG Performance 
Status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Central Laboratory Procedures/Assessments
Blood for Future 
Biomedical Research 
(Optional)12
X
Blood for Serum 
Biomarkers13
X
Blood for Plasma 
Biomarkers13
X
Correlative Studies 
Blood (DNA and 
RNA)14
X
X
X
X
Blood for Genetics15
X
 
 
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Confidential
Screening
(Visit 1)
Treatment Cycles1
End of Treatment Phase
Observation
Phase2 
(pre-PD)
Survival 
Follow-up3
Approx. 
Every 
2 Months
Treatment Cycle/
Scheduled Time
-42 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13 and 
beyond
Discontinuation 
Visit4
Safety Follow-
up Visit5
Observation 
Visits6,7
Survival 
Follow-up 
Visit 1 and 
beyond
Scheduling Window 
(Days):8
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At study drug 
discontinuation
±3
30 days from 
last dose
±3
±3 days
±14 days
Study Drug Administration
Paclitaxel/
Carboplatin16
X
X
X
X16
X16
X16
Pemetrexed/
Carboplatin16
X
X
X
X16
X16
X16
Pemetrexed
X
X
X
X
X
X
X
X
X
Local Laboratory Procedures/Assessments
Pregnancy Test - Urine 
or Serum β-HCG17
X17
PT/INR and aPTT18
X19
CBC with 
Differential20,21
X19
X
X
X
X
X
X
X
X
X
X20
X
X
X22
Comprehensive 
Chemistry Panel20, 21
X19
X
X
X
X
X
X
X
X
X
X20
X
X
X22
Urinalysis21, 23
X19
X
X
X23
X
X
X22
T3, FT4 and TSH21, 24
X19
X
X
X
X
X
X24
X
X
X22
ALK Translocation 
Testing25
X
EGFR Mutation 
Testing25
X
HBsAG26
X
Anti HCV26
X
Anti HIV26
X
 
 
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Protocol/Amendment No.: 042-08 
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Confidential
Screening
(Visit 1)
Treatment Cycles1
End of Treatment Phase
Observation
Phase2 
(pre-PD)
Survival 
Follow-up3
Approx. 
Every 
2 Months
Treatment Cycle/
Scheduled Time
-42 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13 and 
beyond
Discontinuation 
Visit4
Safety Follow-
up Visit5
Observation 
Visits6,7
Survival 
Follow-up 
Visit 1 and 
beyond
Scheduling Window 
(Days):8
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At study drug 
discontinuation
±3
30 days from 
last dose
±3
±3 days
±14 days
Efficacy Measurements
Tumor Imaging27
X
X
X
X
X27
X27
X27
X9,27
Tumor Biopsies/Archival Tissue Collection
Tumor Tissue 
Collection for PD-L1 
Expression28
X
 
 
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1 In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of trial treatment for each cycle unless otherwise specified. Treatment cycles are 3 
weeks (21 days). If treatment cycles are increased all procedures except imaging will be completed according to the cycle number and not weeks on treatment; imaging will be 
performed every 9 weeks ± 7 days from the date of randomization regardless of any treatment delays.
2 The Observation Phase is for any subject that discontinued study treatment for reasons other than pregnancy or PD. 
3 Subjects who experiences disease progression or start a new antineoplastic therapy will move into Survival Follow-up and should be contacted by telephone approximately 
every 2 months to assess for survival status and the start of any new antineoplastic therapy. The subject’s response to new treatments will also be collected. Updated survival 
status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or 
study contact during the Sponsor defined time period will be contacted for their survival status and its respective entry into the database (excluding subjects who have a death 
event previously recorded).
4
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. Imaging assessments should continue as per the interval stated in the protocol:
every 9 weeks for the first 15 cycles and then every 12 weeks thereafter. Additional imaging at the Discontinuation Visit is not required provided that imaging assessments 
have been performed per schedule.
5
The mandatory Safety Follow-up Visit for all subjects should be conducted approximately 30 days after the last dose of trial treatment or before the initiation of new 
antineoplastic treatment, whichever comes first. Subjects with an AE of Grade >1 will be further followed until the resolution of the AE to Grade 0-1 or until beginning of a 
new antineoplastic therapy, whichever occurs first. Subjects who are eligible for treatment with pembrolizumab during the Second Course Phase may have up to two Safety 
Follow-up Visits, one after the Treatment Phase and the second after the Second Course Phase. If the Discontinuation Visit occurs approximately 30 days ± 3 days from last 
dose of trial treatment the same procedures do not need to be repeated for the Safety Follow-up Visit. Imaging assessments should continue as per the interval stated in the 
protocol: every 9 weeks for the first 15 cycles and then every 12 weeks thereafter. Additional imaging at the Safety Follow-up Visit is not required provided that imaging 
assessments have been performed per schedule.
6 Observation visits should begin 4 weeks (28 days ± 7 days) from the Safety Follow-up Visit and follow a Q3W (21 days ± 3 days) schedule thereafter. All assessments and 
procedures should be obtained per the Observation Visit schedule until the subject experiences PD. Tumor imaging for the Observation Visits should be maintained Q9W by 
following the same calendar day schedule that was initiated during Treatment Cycles. Subjects who have received total of 15 cycles (SOC plus pemetrexed maintenance) may 
reduce the frequency of tumor imaging to every 12 weeks (84 ± 7 days) during the Observation Visits. 
7 Subjects with an AE of Grade >1 will be further followed until the resolution of the AE to Grade 0-1 or until beginning of a new antineoplastic therapy, whichever occurs first.
8 In general, the window for each visit is 3 days unless otherwise specified.
9 Tumor imaging is not needed for subjects who start another anti-cancer treatment regimen.
10 Once a subject discontinues study treatment, report all SAEs (related and unrelated to trial treatment), ECIs, and irAEs 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 and ECIs that are 
considered related to trial treatment.
11 Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure. Height will be measured at screening only.
12 Informed consent for Future Biomedical Research (FBR) samples must be obtained before the DNA sample is drawn. DNA sample for analysis should be obtained pre-dose, on 
Cycle 1 (or with the next scheduled blood draw), as the last sample drawn, on allocated subjects only, or at a later date as soon as the informed consent is obtained. This sample 
should only be taken once from each subject. See Section 12.2 for guidance regarding the collection and management of specimens for FBR.
13 Samples for plasma and serum biomarkers should be obtained pre-dose Cycle 1.
14 Samples for correlative studies should be obtained pre-dose at Cycles 1, 2, 3, and at the time of study drug discontinuation. 
15 Blood for genetics sample will be collected to explore host genetics and to identify genetic predictors that may have a role in therapeutic response to pembrolizumab. This 
sample should be drawn for planned, exploratory genetic analysis of DNA unless there is either a documented law or regulation prohibiting collection, or unless the IRB/IEC
does not approve of the collection.
16 SOC will be administered for 4 - 6 cycles.
17 For women of reproductive potential, a urine pregnancy test will be performed within 72 hours prior to first dose of trial treatment. If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test, performed by the local study site laboratory, will be required. Pregnancy tests (serum and/or urine tests) should be repeated if 
required by local guidelines.
 
 
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18 Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
19 Laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment.
20 CBC with differentials and chemistry will be performed every cycle up to Cycle 10, then every other cycle thereafter.
21 After Cycle 1, lab samples can be collected up to 7 days prior to the scheduled time point. Laboratory results must be known and acceptable prior to dosing.
22 During the Observation Phase laboratory assessments should be obtained every 12 weeks.
23 Perform every 4 cycles.
24 Thyroid function tests will be performed by a central laboratory only if the local laboratory is unable to perform this service. Thyroid function tests should be performed every 
other cycle.
25 Site must be able to provide documentation of the subject’s tumor EGFR mutation and/or ALK translocation mutation status if clinically indicated. If the site is unable to 
provide this source documentation, or site level testing, then the Sponsor will offer this molecular testing of the tumor.
26 The need for additional testing due to positive test results will be at the discretion of the Investigator.
27 Sponsor will collect radiological assessments for analysis by a central vendor. The initial tumor imaging will be performed within 30 days prior to the date of randomization. 
Scans performed as part of routine clinical management are acceptable for use as the screening scan if they are of diagnostic quality and performed within 30 days prior to the 
first dose of trial treatment. On study imaging will be performed every 9 weeks (63 ± 7 days) after the date of randomization or more frequently if clinically indicated and 
submitted for central radiology review. Imaging studies should follow calendar days and should not be adjusted for delays in cycle starts or extension. The same imaging 
technique should be used in a subject throughout the trial. After week 45 tumor imaging, tumor imaging should be performed every 12 weeks (84 ± 7 days). CT scan of the 
chest, abdomen and pelvis is required for the baseline assessment. After the first documentation of progression (if the subject is clinically stable) or response per modified 
RECIST 1.1 repeat imaging for confirmation may be performed. Confirmatory imaging may be performed as early as 28 days later; alternately, the scan performed at the next 
scheduled time point (e.g., every 63 ±7 days) may be used as confirmation. Details are provided in the Image Acquisition Guidelines.
28 Tumor tissue for biomarker analysis from a biopsy of a tumor lesion not previously irradiated must be provided. Only biopsies obtained AFTER the diagnosis of metastatic disease will be 
evaluated for PD-L1 expression. Any leftover tumor tissue will be stored for future research if the subject signs the optional FBR consent. If a tumor biopsy was obtained from a target lesion 
during eligibility assessment, it is preferred to obtain a new baseline scan. Biopsy of lesions on study should be limited to non-target lesions or new lesions if their pathologic etiology is 
ambiguous.
 
 
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Second Course Treatment and Follow-up Phase for Pembrolizumab Arm
Second Course Treatment Cycles1
End of Second Course 
Treatment
Follow-up2
Survival 
Follow-up3
1
2
Every 3 
Months 
after Visit 2
Approx. 
Every 2 
Months
Treatment 
Cycle/ Scheduled 
Time
1
2
3
4
5
6
7
8
9
10
11
12
13 and 
beyond
Discontinuatio
n Visit
Safety 
Follow-
up Visit4
Follow-up 
Visit 1
Follow-up 
Visit 2
Follow-up 
Visit 3 and 
Beyond
Survival 
Follow-up 
Visit 1 and 
Beyond
Scheduling 
Window (Days):5
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At study drug 
discontinuation
±3
30 days 
from last 
dose
±3
±7 days
̉±7 days
±7 days
±14 days
Administrative Procedures
Eligibility Criteria
X
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subsequent 
Antineoplastic 
Therapy Status
X
X
X
X
X
X
Survival Status3,6
X
Study Drug Administration
Pembrolizumab7
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Procedures/Assessments
Review Adverse 
Events6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Full Physical 
Examination
X
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs and 
Weight8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG 
Performance 
Status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
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Second Course Treatment Cycles1
End of Second Course 
Treatment
Follow-up2
Survival 
Follow-up3
1
2
Every 3 
Months 
after Visit 2
Approx. 
Every 2 
Months
Treatment 
Cycle/ Scheduled 
Time
1
2
3
4
5
6
7
8
9
10
11
12
13 and 
beyond
Discontinuatio
n Visit
Safety 
Follow-
up Visit4
Follow-up 
Visit 1
Follow-up 
Visit 2
Follow-up 
Visit 3 and 
Beyond
Survival 
Follow-up 
Visit 1 and 
Beyond
Scheduling 
Window (Days):5
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At study drug 
discontinuation
±3
30 days 
from last 
dose
±3
±7 days
̉±7 days
±7 days
±14 days
Laboratory Procedures/Assessments: Analysis Performed by Local Laboratory11
Pregnancy Test -
Urine or Serum 
β-HCG9
X
PT/INR and 
aPTT10
X11
CBC with 
Differential12, 14
X11
X
X
X
X
X
X
X
X
X
X12
X
X13
X13
X13
Comprehensive 
Chemistry 
Panel12,14
X11
X
X
X
X
X
X
X
X
X
X12
X
X13
X13
X13
Urinalysis15
X11
X
X
X15
X
X
T3, FT4 and 
TSH14, 16
X11
X
X
X
X
X
X16
X
X13
X13
X13
Efficacy Measurements
Tumor 
Imaging17,18
X
X
X
X
X18
X
X17
X
X
X
 
 
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1
In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of trial treatment for each cycle unless otherwise specified. Treatment cycles are 3 weeks 
(21 days). If treatment cycles are adjusted, all procedures except imaging will be completed according to the cycle number and not weeks on treatment; imaging will be performed 
every 9 weeks (63 ± 7 days) from the date of randomization regardless of any treatment delays.
2
Subjects who discontinue trial treatment for a reason other than disease progression will move into the Follow-up Phase and should be assessed every 9 weeks (63 ± 7 days) by 
radiologic imaging to monitor disease status. Follow-up Visit 1 should be scheduled 3 months after the last dose of trial treatment. Follow-up Visit 2 should occur 6 months after the 
last dose of trial treatment. After Follow-up Visit 2 subjects only need to be assessed every 9 weeks (63 ± 7 days) by radiologic imaging to monitor disease status, development of 
drug-related SAEs and ECIs, and initiation of new antineoplastic therapy. Unless otherwise noted in the flow chart, every effort should be made to collect subject information until the 
start of new antineoplastic therapy, disease progression or death, whichever occurs first.
3
Once a subject experiences disease progression or starts a new antineoplastic therapy, the subject moves into the Survival Follow-up Phase and should be contacted by telephone 
approximately every 2 months to assess for survival status and start of new antineoplastic therapy if applicable. Updated survival status may be requested by the Sponsor at any time 
during the course of the study. Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or study contact during the Sponsor defined time period will be 
contacted for their survival status and its respective entry into the database (excluding subjects who have a death event previously recorded).
4
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last dose of trial treatment or before the initiation of a new antineoplastic treatment, 
whichever comes first. Subjects with an AE of Grade >1 will be further followed until the resolution of the AE to Grade 0-1 or until beginning of a new antineoplastic therapy, 
whichever occurs first. Subjects who are eligible per the requirements in Section 7.1.5.5 for treatment with pembrolizumab during the Second Course Phase may have up to two Safety 
Follow-up Visits, one after the Treatment Phase and the second after the Second Course Phase.
5
In general, the window for each visit is 3 days unless otherwise specified.
6
Record all AEs occurring within 30 days after the last dose of trial treatment. Report all SAEs (related and unrelated to trial treatment), ECIs, and irAEs occurring within 90 days 
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 and 
ECIs that are considered related to trial treatment.
7
Pembrolizumab can be administered up to 17 trial treatment in Second Course Phase.
8
Vital signs to include temperature, pulse, respiratory rate, blood pressure, and weight.
9
For women of reproductive potential, a urine pregnancy test will be performed within 72 hours prior to the first Second Course dose. If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test, performed by the local study site laboratory, will be required. Pregnancy tests (serum and/or urine tests) should be repeated if required by local 
guidelines.
10
Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
11
Laboratory tests for determining eligibility for Second Course Phase are to be performed within 10 days prior to the first dose of pembrolizumab. See Section 7.1.3 for details 
regarding laboratory tests.
12
CBC with differentials and chemistry will be performed every cycle up to Cycle 10, then every other cycle thereafter.
13
Every effort should be made to collect blood samples at the Safety Follow-up Visit, Follow-up Visit 1, and Follow-up Visit 2 until the start of new antineoplastic therapy, disease 
progression or death, whichever comes first.
14
After the first dose, lab samples can be collected up to 7 days prior to the scheduled time point. Laboratory results must be known and acceptable prior to dosing. See Section 7.1.3 for 
details regarding laboratory tests.
15
Perform every 4 cycles.
16
Thyroid function tests will be performed by a central laboratory only if the local laboratory is unable to perform this service. Thyroid function tests should be performed every other 
cycle. 
17
Subjects who discontinue trial treatment due to reasons other than disease progression should continue to be assessed every 9 weeks (63 ± 7 days) by radiologic imaging until the start 
of a new antineoplastic therapy, documented disease progression, or death, whichever occurs first. If trial treatment is discontinued after Cycle 13, tumor imaging should be performed 
every 12 weeks (84 days ± 7 days). Continued imaging is not needed for subjects who start another antineoplastic treatment. The same imaging technique should be used in a subject 
throughout the trial.
18
Sponsor will collect radiological assessments for analysis by a central vendor. If the subject enters the Second Course Phase, Cycle 1 scan may be performed up to 30 days prior to the 
first dose of trial treatment in the Second Course Phase. Imaging will be performed every 9 weeks (63 7 days) after the first dose of Second Course Phase trial treatment up until 
Cycle 13 and every 12 weeks (84 ± 7 days) thereafter. The timing of imaging should follow calendar days and should not be adjusted for delays in cycle starts or extension of 
pembrolizumab cycle frequencies. The same imaging technique should be used in a subject throughout the trial.
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator. In addition, record any prior 
cancer other than NCSLC even if diagnosed greater than 10 years prior to Visit 1. NSCLC 
history will be recorded separately and not listed as Medical History. Medical history will 
also include an assessment of smoking history.
7.1.1.5
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 30 days before the first dose of trial treatment. In addition, record all treatments for a 
prior cancer other than NSCLC even if taken greater than 30 days prior to first dose. Prior 
treatments for NSCLC will be recorded separately and not listed as a prior medication.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial through the 30-day Safety Follow-up Visit. After the Safety Follow-up Visit 
record all medications related to reportable SAEs and ECIs as defined in Section 7.2.
 
 
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7.1.1.6
Non-Small Cell Lung Cancer (NSCLC) Disease Details and Treatments
7.1.1.6.1 Disease Details
The investigator or qualified designee will obtain prior and current NSCLC disease details.
7.1.1.6.2 Prior Treatment
The investigator or qualified designee will review all prior treatments for NSCLC including 
systemic treatments, radiation, and surgeries.
7.1.1.6.3 Subsequent Antineoplastic Therapy Status
The investigator or qualified designee will review all new antineoplastic therapy initiated 
after the last dose of trial treatment. If a subject initiates a new antineoplastic therapy within 
30 days after the last dose of trial treatment, the “30-day Safety Follow-up visit” must occur 
before the first dose of the new therapy. Once new antineoplastic therapy has been initiated
the subject will move into Survival Follow-up.
7.1.1.7
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or 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. 
7.1.1.8
Assignment of Randomization Number
All eligible subjects will be randomly allocated and will receive a randomization number.  
The randomization number identifies the subject for all procedures occurring after 
randomization.  Once a randomization number is assigned to a subject, it can never be re-
assigned to another subject.
A single subject cannot be assigned more than 1 randomization number.
7.1.1.9
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment plan for greater than 12 weeks due to 
pembrolizumab toxicity require consultation between the investigator and the Sponsor and 
written documentation of the collaborative decision on subject management.
 
 
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Administration of trial medication will be witnessed by the investigator and/or trial staff. The 
total volume of trial treatment infused will be compared to the total volume prepared to 
determine compliance with each dose administered.
Clinical Procedures/Assessments
7.1.2.1
Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated. Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 4.0 (see Section 12.5). Toxicities 
will be characterized in terms including seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment.
An immune-related adverse event (irAE) may be defined as an adverse event of unknown 
etiology, associated with drug exposure and is consistent with an immune phenomenon. 
Efforts should be made to rule out neoplastic, infectious, metabolic, toxin or other etiologic 
causes prior to labeling an adverse event immune-related. Immunological, serological and 
histological (biopsy) data should be used to support the diagnosis of an immune-related 
toxicity. Following the guidance described in Section 7.2.3.2, certain irAEs should also be 
reported to the Sponsor as ECIs. (See the separate guidance document in the administrative 
binder regarding the identification, evaluation, and management of irAEs and ECIs.)
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs.
7.1.2.2
Physical Exam
7.1.2.2.1 Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the 
screening period. Clinically significant abnormal findings should be recorded as medical 
history. The 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.
7.1.2.2.2 Directed Physical Exam
For cycles that do not required a full physical exam per the Section 6.0 – Trial Flow Chart, 
the investigator or qualified designee will perform a directed physical exam as clinically 
indicated prior to trial treatment administration. New clinically significant abnormal findings 
should be recorded as AEs.
 
 
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7.1.2.3
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and during the Follow-up period as specified in 
the Trial Flow Chart. Vital signs include temperature, pulse, respiratory rate, weight, and 
blood pressure. Height will be measured at Visit 1 only.
7.1.2.4
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. 
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (see Section 12.4) at 
screening, prior to the administration of each dose of trial treatment and during the Follow-up 
period as specified in the Trial Flow Chart. ECOG status must be 0 or 1 at time of first dose 
of study medication.
7.1.2.6
Tumor Assessments and Imaging
Sponsor will collect radiological assessments for analysis by a central vendor. 
The initial tumor imaging will be performed within 30 days of randomization date. Scans 
performed as part of routine clinical management are acceptable for use as the screening scan 
if they are of diagnostic quality and performed within 30 days prior to the randomization 
date. CT scan of the chest, abdomen, and pelvis is required for the baseline assessment.
On-study tumor assessments for subjects randomized to either the pembrolizumab or control 
arms are to be performed every 9 weeks (63 ± 7 days) or more frequently if clinically
indicated, from the date of randomization until radiographic PD has been established. For 
subjects who continue on therapy beyond week 45, tumor imaging should be performed 
every 12 weeks (84 ± 7 days). Timing should follow calendar days and should not be 
adjusted for delays in cycle starts or extension of cycle frequencies.
After the first documentation of response per modified RECIST 1.1, confirmatory scans may 
be performed as early as 28 days later; alternately, the scan performed at the next scheduled 
time point (e.g., every 63 ±7 days) may be used as confirmation for response. After the first
documentation of progression per modified RECIST 1.1, confirmatory scans may be 
performed 4 to 6 weeks later (if the subject is clinically stable).
After the first documentation of progression, it is at the discretion of the investigator to keep 
a clinically stable subject on trial treatment or to stop trial treatment until repeat imaging 
performed 4-6 weeks later confirms progression. 
 
 
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Clinical Stability is defined as:
1. Absence of symptoms and signs indicating clinically significant progression of
disease (including worsening of laboratory values) indicating disease progression.
2. No decline in ECOG performance status.
3. Absence of rapid progression of disease or progressive tumor at critical anatomical 
sites (e.g., cord compression) requiring urgent alternative medical intervention.
Subjects that are deemed clinically unstable are not required to have repeat imaging for
confirmation. If progression is confirmed, it is recommended that the subject be discontinued 
from trial treatment unless, in the investigator’s opinion, the subject is deriving benefit from 
treatment. Clinically stable subjects as defined above may continue to receive trial therapy
after discussion with the Sponsor. Subjects exhibiting toxicity from trial therapy as outlined 
in Sections 5.2.1 and 7.2 may NOT continue to receive trial therapy. Regardless of clinical 
benefit, the maximum number of treatments a subject may receive is 35.
If progression is not confirmed, then the subject should resume/continue trial treatment and 
have their next scan according to the every 9-week (63 ± 7 days) schedule from first dose of 
study treatment, which would be approximately 9 weeks from the date of the scan that first 
showed progression. When feasible, subjects should not be discontinued until progression is 
confirmed.
Subjects who move into the Second Course Phase will continue to have scans performed
every 9 weeks (63 ± 7 days) up to Cycle 13 and then every 12 weeks (84 ± 7 days).
The same imaging technique should be used in a subject throughout the trial. Details are 
provided in the Procedures Manual.
7.1.2.7
Tumor Tissue Collection
Tumor tissue for biomarker analysis from formalin-fixed paraffin embedded tumor tissue 
sample or newly obtained formalin-fixed biopsy of a tumor lesion not previously irradiated 
must be provided in the form of a tissue block or unstained slides and received by the central 
vendor before randomization. Only subjects whose tumors demonstrate positive (TPS ≥1%) 
PD-L1 expression are eligible for enrollment. A fine needle aspirate or cytologic specimen 
will not be acceptable. Core needle or excisional biopsies, or resected tissue is required. 
Newly obtained formalin-fixed specimens are encouraged and highly recommended if the 
patient’s archival sample was obtained ≥6 months prior to screening.
If the subject signs the Future Biomedical Research (FBR) consent, any leftover tissue 
biopsies that would ordinarily be discarded at the end of the main study will be retained for 
FBR, again providing the subject has signed the FBR consent.
 
 
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Detailed instructions for tissue collection, processing and shipment are provided in the 
Procedures Manual. Older biopsy material or surgical specimens may be used to assess 
EGFR mutation.
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the Procedures 
Manual.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 5.
Table 5
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Follicle stimulating
hormone (FSH)
Hemoglobin
Alkaline phosphatase
Glucose
Serum β-human chorionic 
gonadotropin (β-hCG)
Platelet count
Alanine aminotransferase 
(ALT)
Protein
Triiodothyronine (T3 or 
FT3)
WBC (total and/or
differential)
Aspartate aminotransferase 
(AST)
Specific gravity 
Free thyroxine (FT4)
RBC
Carbon dioxide (CO2 or
bicarbonate)a
Microscopic exam, if 
abnormal results are noted
Thyroid stimulating 
hormone (TSH) 
Calcium
PT (INR)
Chloride
aPTT
Creatinine
Blood for FBR (optional)
Glucose
Blood for genetics
Magnesium
Blood for correlative studies
Phosphorus
Blood for biomarkers
Potassium
HBs AG
Sodium
Anti HCV
Total bilirubin  
Anti HIV
Direct bilirubin, if total 
bilirubin is elevated above the 
upper limit of normal
Total protein
Blood urea nitrogen (BUN)b
Ureab
Uric acid 
a If these tests are not done as part of standard of care in your region then these tests do not need to be performed.
b BUN or Urea should be collected per institutional standard. It is not required to perform both of these laboratory tests.
Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 10 days prior to the first dose of trial treatment. After Cycle 1, pre-dose laboratory 
procedures can be conducted up to 7 days prior to dosing. 
 
 
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All protocol required screening and safety lab results must be reviewed by the investigator or 
qualified designee and found to be acceptable prior to each dose of trial treatment.
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations
Accumulation of robust PK and ADA data has allowed adequate characterization of the 
clinical pharmacology of pembrolizumab across indications. Therefore, collection of PK and 
ADA samples is being discontinued for subjects enrolled under Amendment 06. Blood 
samples for PK and ADA collected prior to Amendment 06 may be stored. Analysis will be 
performed only if required.
7.1.3.3
Molecular Testing
Site must be able to provide documentation of subject’s tumor EGFR mutation and/or ALK 
translocation status. If the site is unable to provide this source documentation, then the 
Sponsor will offer this molecular testing of the tumor. Detailed instructions for tissue 
collection, processing and shipment are provided in the Procedures Manual.
7.1.3.4
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:

Blood for genomics use

Leftover tumor tissue
Other Procedures
7.1.4.1
Withdrawal/Discontinuation
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
, and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
 
 
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analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
7.1.4.2
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
7.1.4.3
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 with the study 
documentation 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

Safety equipment – as required for safety assessments 

Drug administration equipment
–
as required for storage, preparation and 
administration of study drugs
See protocol-specific Administrative Binder, Pharmacy Manual, operations/laboratory 
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.
7.1.5.1
Screening
Approximately 42 days prior to randomization, potential subjects will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.1. Screening 
procedures may be repeated after consultation with the Sponsor.
 
 
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Written consent must be obtained prior to performing any protocol specific procedure. 
Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. Screening procedures are to be completed within 42 days prior to the first dose of trial 
treatment except for the following:

Laboratory tests are to be performed within 10 days prior to the first dose of trial 
treatment.

For women of reproductive potential, a urine pregnancy test will be performed within 
72 hours prior to first dose of trial treatment. If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test, performed by the local study site 
laboratory, will be required.

Tumor imaging must be performed within 30 days prior to the date of 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 Phase
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 – Trial Procedures.
7.1.5.3
End of Treatment Visits
7.1.5.3.1 Discontinuation Visit
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. Procedures 
at the time of discontinuation are detailed in Section 6.0. Imaging assessments should 
continue as per the interval stated in the protocol: every 9 weeks for the first 15 cycles and 
then every 12 weeks thereafter. Additional imaging at the discontinuation visit is not required 
provided that imaging assessments have been performed per schedule.
7.1.5.3.2 Safety Follow-up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new antineoplastic treatment, 
whichever comes first. Subjects with an AE of Grade >1 will be further followed until the 
resolution of the AE to Grade 0-1 or until beginning of a new antineoplastic therapy, 
whichever occurs first. 
 
 
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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 two Safety Follow-up 
Visits, one after the Treatment Phase and the second after the Second Course Phase.
Imaging assessments should continue as per the interval stated in the protocol: every 9 weeks 
for the first 15 cycles and then every 12 weeks thereafter. Additional imaging at the Safety 
Follow-up Visit is not required provided that imaging assessments have been performed per 
schedule.
7.1.5.3.3 Observation Visit
Subjects who complete their fixed number of 4 - 6 cycles of SOC or who stop either SOC 
(including pemetrexed maintenance) or pembrolizumab for reasons other than PD or 
pregnancy, should move into the Observation Phase of the study and complete the 
assessments in the Observation Visits schedule as outlined in the study flow chart in 
Section 6.0. If a subject experiences PD, they automatically move to the Survival Follow-up 
Phase of the flowchart.
Subjects randomized to pembrolizumab who discontinue therapy due to a PR and/or SD after 
35 trial treatments should follow procedures in the End of Treatment Phase and Follow-up
Phase of the study. If PD is established during the assessments obtained during the Follow-up 
Phase of the study, the subject may be eligible for the Second Course Phase.
Laboratory tests including CBC with differentials, thyroid function tests, CMP and urinalysis 
should be obtained every 3 months during the Observation Visit Phase. 
7.1.5.4
Follow-up Phase
All subjects will have post-treatment follow-up for disease status, including initiating a non-
study cancer treatment and experiencing disease progression, until death, withdrawing 
consent, or becoming lost to follow-up.
7.1.5.4.1 Follow-up Visits
All subjects who discontinue trial treatment for a reason other than disease progression 
should continue to receive all assessments as outlined in the Observation Phase of the study 
in Section 6.0 until PD by investigator-assessed modified RECIST 1.1 or initiation of a new 
antineoplastic therapy. 
Subjects who are randomized to pembrolizumab and have received the maximum 
administrations of pembrolizumab indicated above, should be followed as indicated in the 
Follow-up Phase of the study outlined in Section 6.0.
Follow-up Visit 1 should be scheduled 3 months after the last dose of trial treatment. 
Assessment for drug-related immune-related adverse events should occur at Follow-up Visit 
1. Follow-up Visit 2 should occur 6 months after the last dose of trial treatment. Unless 
 
 
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otherwise noted in the flowchart, every effort should be made to collect subject information 
on the start of new antineoplastic therapy, disease progression, death.
Subjects who are eligible to receive re-treatment with pembrolizumab according to the 
criteria in Section 7.1.5.5 will move to the Second Course Phase when they experience 
disease progression
Imaging will be performed every 9 weeks (63 ± 7 days) after the first dose of Second Course 
Phase trial treatment until Cycle 13 and then every 12 weeks (84 ± 7 days) thereafter. The 
timing of imaging should follow calendar days and should not be adjusted for delays in cycle 
starts or extension of pembrolizumab cycle frequencies. The same imaging technique should 
be used in a subject throughout the trial. Subjects who discontinue trial treatment from the 
Second Course Phase for a reason other than disease progression will move into the Follow-
up Phase and should continue to be assessed every 9 weeks (63 ± 7 days) by radiologic 
imaging to monitor disease status or every 12 weeks (84 ± 7 days) after Cycle 13. Continued
imaging is not needed for subjects who start another anti-cancer treatment regimen.
7.1.5.4.2 Survival Follow-up
Once the subject stops the imaging assessments for this protocol (e.g., for PD or starting a 
new antineoplastic therapy), the subject moves into the Survival Follow-up Phase and should 
be contacted by telephone approximately every 2 months to assess for survival status. 
Survival assessments and its respective entry into the database may be required more 
frequently around the projected analysis. Post-study treatments and the subject’s response to 
them will also be collected.
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 may be eligible to receive up to 17 trial treatments of 
pembrolizumab in the Second Course Phase. After the Second Course Phase subjects should 
be followed for progression and survival as indicated, with no option for retreatment with 
pembrolizumab on study.
Subjects will be eligible to receive pembrolizumab in the Second Course Phase of this study 
if the subject:
•
Stopped their initial treatment with pembrolizumab after attaining a confirmed CR 
according to modified RECIST 1.1, was treated for at least 6 months with 
pembrolizumab, and received at least two treatments with pembrolizumab beyond the 
date when the initial CR was declared. A CR by modified RECIST 1.1 means that all 
index lesions have resolved (none have bidimensional measurements), all non-index 
lesions have disappeared, and no new lesions have been identified. These findings 
must be confirmed on subsequent imaging at least 4 weeks later for the call of CR by 
modified RECIST 1.1 to be appropriate. As such, the subject will have no evidence of 
 
 
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metastatic cancer in order for the subject and his/her physician to consider the 
subject’s participation in this Second Course Phase.
•
Experienced an investigator-determined confirmed radiographic disease progression
according to modified RECIST 1.1 after stopping their initial treatment with 
pembrolizumab due to achievement of a confirmed CR.
•
Have received 35 administrations of pembrolizumab while in SD or better and then 
experience an investigator-determined confirmed radiographic disease progression 
according to modified RECIST 1.1. 
•
Did not receive any anti-cancer treatment since the last dose of pembrolizumab.
•
Continues to meet inclusion criteria 3, 5, 6, 11, 12, and 13.
•
Does not meet exclusion criteria 3, 5, 9 to 18, and/or 19.
Subjects will be re-treated at the same dose as when they last received pembrolizumab. An 
objective response or progression of disease assessed by investigator-reviewed modified 
RECIST 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
Survival Status
To ensure current and complete survival data are available at the time of database locks, 
updated survival data may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to but not limited to an external Data 
Monitoring Committee (DMC) review, interim, and/or final analysis. Upon Sponsor 
notification, all subjects who do not/will not have a scheduled study visit or study contact 
during the Sponsor-defined time period will be contacted for their survival status and its 
respective entry into the database (excluding subjects who have a previously recorded death 
event in the collection tool).
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
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.  
 
 
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Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Progression of the cancer under study is not considered an adverse event.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
From the time of treatment allocation/randomization through 30 days following cessation of 
treatment, all adverse events must be reported by the investigator. Such events will be 
recorded at each examination on the Adverse Event case report forms/worksheets.  The 
reporting timeframe for adverse events meeting any serious criteria is described in section 
7.2.3.1. The investigator will make every attempt to follow all subjects with non-serious 
adverse events for outcome.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
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 the SOC chemotherapy by more than 20%. For subjects treated with pembrolizumab
an overdose will be defined as any dose exceeding 5 x the protocol-prescribed dose. No 
specific information is available on the treatment of overdose of pembrolizumab. In the event 
of overdose, pembrolizumab or the chemotherapy 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 
 
 
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reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product, or 30 
days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, must be reported by the investigator.  All reported pregnancies must be 
followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of 
infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper.  Sponsor Contact information can be found in the Investigator Trial File Binder (or 
equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
 
 
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●
Is an other important medical event 
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to Table 6 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study (reference 
Section 7.2.3.3 for additional details), that occurs to any subject must be reported within 24 
hours to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or follow up 
to a serious adverse event, including death due to any cause other than progression of the 
cancer under study (reference Section 7.2.3.3 for additional details), whether or not related to 
the Sponsor's product, must be reported within 24 hours to the Sponsor either by electronic 
media or paper. Electronic reporting procedures can be found in the EDC data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time 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, 
 
 
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or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, 
whether or not related to the Sponsor’s product, must be reported within 24 hours to the 
Sponsor, either by electronic media or paper.  Electronic reporting procedures can be found 
in the EDC data entry guidelines.  Paper reporting procedures can be found in the 
Investigator Trial File Binder (or equivalent).
Events of clinical interest for this trial include:
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).
3. Additional adverse events:
A separate guidance document has been provided entitled “Event of Clinical Interest 
Guidance Document” (previously entitled, “Event of Clinical Interest and Immune-
Related Adverse Event Guidance Document”). This document can be found in the 
administrative binder and provides guidance regarding identification, evaluation, and 
management of ECIs and irAEs.
ECIs (both non-serious and serious adverse events) identified in this guidance document 
from the date of first dose through 90 days following cessation of treatment, or 30 days 
after the initiation of a new anticancer therapy, whichever is earlier, need to be reported 
to the Sponsor within 24 hours of the event, regardless of attribution to study treatment,
consistent with standard SAE reporting guidelines and either by electronic media or 
paper. Sponsor Contact information can be found in the administrative binder.
Subjects should be assessed for possible ECIs prior to each dose. Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an 
immune-related event. Subjects who develop an ECI thought to be immune related 
 
 
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should have additional testing to rule out other etiologic causes. If lab results or 
symptoms indicate a possible immune-related ECI, then additional testing should be 
performed to rule out other etiologic causes. If no other cause is found, then it is assumed 
to be immune related.
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 7.2.3 – Immediate Reporting of Adverse Events to the Sponsor.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to global safety as a SAE within 
24 hours of determination that the event is not progression of the cancer under study
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4. 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 6
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not 
include an adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization 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) or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. 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 
test drug 
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event will be provided 
by an investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality 
noted on the AE form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required 
regulatory time frame. The criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between 
the test drug and the adverse event based upon the available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the 
components and their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance 
assessment (pill count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did the AE follow in a reasonable temporal sequence from administration of the Sponsor’s product?
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors
 
 
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite 
continuation of the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug 
trial); or (3) Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE 
BEEN CAUSED BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL 
POTENTIAL SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY 
THE SPONSOR CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the 
Sponsor's product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is 
not reasonable OR there is another obvious cause of the AE.  (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.
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.
Trial Steering Committee
This trial will be conducted in consultation with a Trial Steering Committee.  The Trial 
Steering Committee comprises:
•
Sponsor personnel 
•
Investigators participating in the trial 
•
Consulting therapeutic-area experts and clinical trialists 
Specific details regarding responsibilities and governance of the Trial Steering Committee 
will be described in a separate charter.
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
Data Monitoring Committee (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 8.1.5 - Interim 
Analyses) and recommend to the EOC if the trial should continue in accordance with the 
protocol.
 
 
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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.
A DMC recommendation will be communicated to the EOC as agreed to in the DMC charter.
8.0 STATISTICAL ANALYSIS PLAN
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this trial. Full detail is in 
the Statistical Analysis Plan (SAP) (Section 8.2).
Study Design 
Overview
A Randomized, Open Label, Phase III Study of Overall Survival Comparing 
Pembrolizumab versus Platinum Based Chemotherapy in Treatment Naïve Subjects 
with TPS≥1% Advanced or Metastatic Non-Small Cell Lung Cancer 
Treatment 
Assignment
Subjects will be randomized in a 1:1 ratio to receive pembrolizumab or SOC 
chemotherapy. Stratification factors are in Section 5.4. 
Analysis 
Populations
Efficacy: Intent to Treat (ITT) subjects with TPS≥50%, TPS≥20%, and TPS≥1%
Safety: All Subjects as Treated (ASaT)
Primary 
Endpoints
1.
Overall Survival (OS) in subjects with TPS≥50%, 1L advanced/metastatic NSCLC
2.
OS in subjects with TPS≥20%, 1L advanced/metastatic NSCLC
3.
OS in subjects with TPS≥1%, 1L advanced/metastatic NSCLC
Statistical 
Methods for Key 
Efficacy Analyses
The primary hypotheses will be evaluated by comparing pembrolizumab arm to SOC 
chemotherapy arm on OS using a stratified Log-rank test. Estimation of the hazard ratio 
(HR) will be done using a stratified Cox regression model. Event rates over time will be 
estimated within each treatment group using the Kaplan-Meier method.
Statistical 
Methods for Key
Safety Analyses
The analysis of safety results will follow a tiered approach. There is no Tier I safety 
endpoint for this trial. Point estimates and 95% confidence intervals (CIs) for between-
treatment comparisons via the Miettinen and Nurminen method will be provided for 
Tier 2 safety endpoints; only point estimates by treatment group will be provided for 
Tier 3 safety endpoints. 
Interim Analyses
Two interim analyses will be performed in this study. Results will be reviewed by an 
external DMC. Details are provided in Section 8.2.9.

Interim Analysis 1 (IA1)
1. Timing: At least 250 deaths observed in 2 arms in the subjects with TPS≥50% 
AND at least 6 months after last subject is enrolled. When IA1 was conducted
at 32 months after study start, 293 deaths were observed in the subjects with 
TPS≥50%
2. Purpose: Demonstrate superiority of pembrolizumab in OS

Interim Analysis 2 (IA2)
1.
Timing: About 38 months after study start
2.
Purpose: Demonstrate superiority of pembrolizumab in OS

Final Analysis (FA)
1.
Timing: About 45 months after study start
2.
Purpose: Demonstrate superiority of pembrolizumab in OS
 
 
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Multiplicity
The overall Type-I error is strongly controlled at 2.5% (1-sided) for the 3 primary 
hypotheses (superiority of pembrolizumab in OS in subjects with TPS≥50%, TPS≥20% 
and TPS≥1%) and 6 secondary hypotheses (superiority of pembrolizumab in PFS in 
subjects with TPS≥50%, TPS≥20% and TPS≥1%, superiority of pembrolizumab in 
ORR in subjects with TPS≥50%, TPS≥20% and TPS≥1%). The hypotheses will be 
tested sequentially at the type I error rate of 2.5% (one-sided) in the following order: 
1.
Superiority of pembrolizumab in OS in the subjects with TPS≥50% 
2.
Superiority of pembrolizumab in OS in the subjects with TPS≥20%
3.
Superiority of pembrolizumab in OS in the subjects with TPS≥1%
4.
Superiority of pembrolizumab in PFS in the subjects with TPS≥50%
5.
Superiority of pembrolizumab in PFS in the subjects with TPS≥20%
6.
Superiority of pembrolizumab in PFS in the subjects with TPS≥1% 
7.
Superiority of pembrolizumab in ORR in the subjects with TPS≥50%
8.
Superiority of pembrolizumab in ORR in the subjects with TPS≥20%
9.
Superiority of pembrolizumab in ORR in the subjects with TPS≥1%.
Under this sequential testing strategy, a hypothesis will be tested only if superiority is 
established for all the preceding ones.
The initial alpha allocation is revised to reflect the change of the criteria for the conduct 
of the FA and the addition of IA2. The reallocation of alpha occurs after IA1, and 
proper adjustment is made to maintain the control of family-wise type I error rate with 
the implementation of this change. The type I error actually spent at IA1 will be kept 
intact and the re-allocation will only be applied to the remaining unspent alpha. No 
futility boundary will be set as before. 
Both IA2 and FA will be conducted based on calendar time. Specifically, IA2 and FA 
will occur about 38 and 45 months (i.e., about 1148 and 1353 days, respectively) after 
study start (19-DEC-2014), given that IA1 was performed based on the cutoff date of 
30-AUG-2017 (which is 986 days or ~32 months from the study start). Under the 
revised alpha allocation, the alpha spending is determined by the Hwang-Shih-DeCani 
alpha 
spending 
function 
with 
the 
gamma 
parameter 
-0.9023. With this spending function, the alpha level at IA1 is the same as the actual 
spent at IA1 (one-sided 1.576%) based on the scale of calendar time fraction 0.729 (i.e., 
986/1353). The cumulative alpha (one-sided) spending at the planned time of IA2 and 
FA becomes 1.94% and 2.5%, regardless of the actual number of deaths observed at the 
IA2 and FA. The corresponding stopping bounds at IA2 and FA will then be calculated 
based on the cumulative alpha spent and actual number of deaths observed at each 
analysis.
Testing of the PFS hypotheses will be performed at the same interim analyses and FA. 
The cumulative alpha spending is determined by the same alpha spending function (on 
the scale of calendar time) defined above for the OS hypotheses. Statistical significance 
under multiplicity control can only be established once the OS hypotheses have been 
established at an interim or the FA. Otherwise, nominal p-values will be reported as a 
measure of strength of association for the PFS hypotheses.
Testing of the ORR hypotheses will be based on the IA1 data. Statistical significance 
under multiplicity control can only be established once the OS and PFS hypotheses 
have both been established. Otherwise, nominal p-values will be reported as a measure 
of strength of association for the ORR hypotheses. If OS and PFS are not statistically 
significant at IA1, then the ORR at IA1 will be considered without any data update if 
the step-down criteria allow formal testing based on a later analysis of OS and PFS.
 
 
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Sample Size and 
Power
The sample size for subjects with TPS≥50% is targeted at approximately 530, and the 
overall sample size for this study is projected to be approximately 1240. The number of 
randomized subjects with TPS≥50% drives the end of enrollment.
The FA of the study is based on calendar time and will occur about 45 months after the 
first subject randomized, at which time approximately 398 deaths (projections updated 
in November 2017) will have been observed between the 2 arms in the subjects with 
TPS≥50%. With 398 deaths, the study has approximately 99% power to detect a 0.65 
hazard ratio on OS at alpha=2.5% (one-sided). By the same time, about 557 and 900
deaths are expected in the subjects with TPS≥20% and TPS≥1%. With 557 deaths, the 
study has approximately 98% power to detect a piecewise hazard ratio with 0.8 before 
month 6 and 0.64 after month 6 at alpha=2.5% (one-sided) in the subjects with 
TPS≥20%. With 900 deaths, the study has approximately 91% power to detect a 
piecewise hazard ratio with 0.92 by month 6 and 0.73 after month 6 at alpha=2.5% 
(one-sided) in the subjects with TPS≥1%. The assumed hazard ratios are based on 
results from Keynote 010 and Keynote 024 (see Section 4.1.2).
Efficacy Analyses
The intention-to-treat (ITT) populations in the subjects with TPS≥50%, TPS≥20% and
TPS≥1% will serve as the primary populations for the analyses of efficacy data in this trial. 
The primary efficacy endpoint is overall survival (OS) (i.e., the time from randomization to 
death due to any cause). The secondary efficacy endpoints are progression-free survival 
(PFS) (i.e., time from randomization to documented progressive disease or death due to any 
cause, whichever occurs first) per RECIST 1.1 based on blinded central independent 
radiologists’ review, and objective response rate (ORR) per RECIST 1.1 based on blinded 
central independent radiologists’ review. An outline of the analysis strategy for key efficacy 
endpoints is presented in Table 7.
Table 7
Analysis Strategy for Key Efficacy Endpoints
Endpoint
(Description, Time 
Point)
Statistical Method
Analysis 
Population
Missing Data Approach
Primary
OS
Testing: Stratified Log-rank test
Estimation: Stratified Cox model with 
Efron's tie handling method
ITT with 
TPS≥50%, 
TPS≥20% and 
TPS≥1%
Model based 
Secondary
PFS 
(per blinded central
independent 
radiologists’-
assessed RECIST 1.1) 
Testing: Stratified Log-rank test
Estimation: Stratified Cox model with 
Efron's tie handling method
ITT with 
TPS≥50%, 
TPS≥20% and 
TPS≥1%
Model based 
ORR 
(per blinded central 
independent 
radiologists’-
assessed RECIST 1.1)
Testing: stratified Miettinen and 
Nurminen method with weights 
proportional to the stratum size
ITT with 
TPS≥50%, 
TPS≥20% and 
TPS≥1%
Subjects with missing 
data are considered 
non-responders
 
 
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Safety Analyses
The All Subjects as Treated (ASaT) population in the subjects with TPS≥1% will be used for 
the primary analysis of safety data in this study. 
Investigators will be asked to report adverse experiences at every visit on this study (at least 
every 3 weeks during treatment) using Common Terminology Criteria for Adverse Events, 
Version 4.0. The attribution to drug, time-of-onset, duration of the event, its resolution, and 
any concomitant medications administered will be reported. AEs will be analyzed and 
reported for between arm differences in various parameters, including Events of Clinical 
Interest outlined in the separate Event of Clinical Interest Guidance Document, all AEs, 
SAEs, fatal AEs, and laboratory changes. Safety analyses follow a tiered approach and the 
details are stated in Section 8.2.5.2.
Multiplicity Adjustment
The multiplicity strategy specified in this section will be applied to the ITT populations with 
TPS≥50%, TPS≥20%, and TPS≥1% for the testing of the OS, PFS, and ORR hypotheses. 
The overall type I error is strongly controlled at 2.5% (one-sided). The hypotheses will be 
tested sequentially at the type I error rate of 2.5% (one-sided) in the following order: 
superiority of pembrolizumab in OS in the subjects with TPS≥50%, superiority of 
pembrolizumab in OS in the subjects with TPS≥20%, superiority of pembrolizumab in OS in 
the subjects with TPS≥1%, superiority of pembrolizumab in PFS in the subjects with 
TPS≥50%, superiority of pembrolizumab in PFS in the subjects with TPS≥20%, superiority 
of pembrolizumab in PFS in the subjects with TPS≥1%, superiority of pembrolizumab in 
ORR in the subjects with TPS≥50%, superiority of pembrolizumab in ORR in the subjects 
with TPS≥20%, and superiority of pembrolizumab in ORR in the subjects with TPS≥1%. 
Under this sequential testing strategy, a hypothesis will be tested only if superiority is 
established for all the preceding ones.
The initial alpha allocation is revised to reflect the change of the criteria for the conduct of 
the FA and the addition of IA2. The reallocation of alpha occurs after the conduct of IA1, 
and proper adjustment is made to maintain the control of family-wise type I error rate with 
the implementation of this change. The type I error actually spent at IA1 will be kept intact 
and the re-allocation will only be applied to the remaining unspent alpha. No futility 
boundary will be set as before. 
Both IA2 and FA will be conducted based on calendar time [69]. Specifically, IA2 and FA 
will occur about 38 months (about 1148 days) and 45 months (about 1353 days) after the date 
when the first subject was randomized (19-DEC-2014), given that IA1 was conducted based 
on the cutoff date of 30-AUG-2017 (about 986 days or 32 months from the first subject 
randomized). Under the revised alpha allocation, the alpha spending at IA2 and FA is 
determined by the Hwang-Shih-DeCani alpha spending function with the gamma parameter -
0.9023. With this spending function, the alpha level at IA1 is the same as the actual spent at 
IA1 (one-sided 1.576%), since the information fraction is 0.729 (i.e., 986/1353) on the scale 
of calendar time. The cumulative alpha (one-sided) spending at the planned time of IA2 and 
FA becomes 1.94% and 2.5%, regardless of the actual number of deaths observed at the IA2 
 
 
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and FA. The corresponding stopping bounds at IA2 and FA will then be calculated based on 
the cumulative alpha spent and actual number of deaths observed at each analysis.
If the pembrolizumab arm demonstrates superior OS in the subjects with TPS≥50% at an 
interim or FA, the OS hypothesis in the subjects with TPS≥20% will be tested based on the 
same group sequential approach (on the scale of calendar time) so that the cumulative alpha 
spent up to each interim analysis is at the same level as the alpha spent for testing the OS 
hypothesis in the subjects with TPS≥50% up to that analysis [70]. Note that, based on the 
above sequential testing strategy, if the OS superiority is demonstrated at an interim analysis
in the subjects with TPS≥50%, the OS superiority in the subjects with TPS≥20% may be 
demonstrated at a later analysis. If the pembrolizumab arm demonstrates superior OS in the 
subjects with both TPS≥50% and TPS≥20%, the OS hypothesis in the subjects with TPS≥1%
will be tested using the same approach.
Testing of the PFS hypotheses will be performed at the same interim analyses and FA. The 
cumulative alpha spending is determined by the same alpha spending function (on the scale 
of calendar time) defined above for the OS hypotheses. The corresponding stopping bounds 
for PFS at IA2 and FA will then be calculated based on the actual number of deaths observed 
at each analysis. Statistical significance under multiplicity control can only be established 
once the OS hypotheses have been established at an interim or the FA. Otherwise, nominal p-
values will be reported as a measure of strength of association for the PFS hypotheses.
Testing of the ORR hypotheses will be based on the IA1 data. Statistical significance under 
multiplicity control can only be established once the OS and PFS hypotheses have both been 
established. Otherwise, nominal p-values will be reported as a measure of strength of 
association for the ORR hypotheses. If OS and PFS are not statistically significant at IA1, 
then the ORR at IA1 will be considered without any data update if the step-down criteria 
allow formal testing based on a later analysis of OS and PFS.
Power and Sample Size
The study will randomize subjects in a 1:1 ratio into the pembrolizumab arm and the SOC 
arm. The sample size for subjects with TPS≥50% is targeted at approximately 530, and the 
overall sample size for this study is projected to be approximately 1240. The number of 
randomized subjects with TPS≥50% drives the end of enrollment.
The final analysis of the study is based on calendar time and will occur about 45 months after
the first subject randomized, at which time approximately 398 deaths (projections updated in 
November 2017) will have been observed between the two arms in the subjects with 
TPS≥50%. With 398 deaths, the study has approximately 99% power to detect a 0.65 hazard 
ratio on OS at alpha=2.5% (one-sided). By the same time, about 557 and 900 deaths are 
expected in the subjects with TPS≥20% and TPS≥1%. With 557 deaths, the study has 
approximately 98% power to detect a piecewise hazard ratio with 0.8 before month 6 and 
0.64 after month 6 at alpha=2.5% (one-sided) in the subjects with TPS≥20%. With 900
deaths, the study has approximately 91% power to detect a piecewise hazard ratio with 0.92 
by month 6 and 0.73 after month 6 at alpha=2.5% (one-sided) in the subjects with TPS≥1%.
The assumed hazard ratios are based on results from Keynote-010 and Keynote-024 (see 
 
 
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Section 4.1.2). The assumptions and details for the sample size and power calculations are in 
Section 8.2.7.
Interim Analysis
Two interim analyses are currently planned in this trial. Table 8 provides the summary of the 
strategy and timing of the interim and final analyses. Details of interim analyses are provided 
in the DMC Charter.
Table 8
Summary of Interim and Final Analysis Strategy
Analysis
Targeted Number of Events/Targeted 
Study Time
Expected Approximate 
Timing of Analysis 
(from study start)
Primary Purpose
IA1
At least 250 deaths observed in two 
arms in the subjects with TPS≥50%
AND at least 6 month after last subject 
is enrolled
About 32 months 
Demonstrate 
superiority of 
pembrolizumab in OS
IA2
About 38 months after study start (ie, 
first subject randomized)
About 38 months
Demonstrate 
superiority of 
pembrolizumab in OS
FA
About 45 months from study start
About 45 months
Demonstrate 
superiority of 
pembrolizumab in OS
Statistical Analysis Plan
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The IVRS vendor will generate the randomized allocation schedule(s) for study treatment 
assignment for this protocol, and the randomization will be implemented in IVRS. 
Although the trial is open-label, analyses or summaries generated by randomized treatment 
assignment, actual treatment received, and/or PD-L1 biomarker status will be limited and 
documented. In addition, the independent radiologist(s) will perform the central imaging 
review without knowledge of treatment group assignment.
The study team at the Sponsor consisting of clinical, statistical, statistical programming and 
data management personnel, will be blinded to subject-level PD-L1 biomarker results. An 
unblinded Sponsor clinical scientist, unblinded data management analyst, unblinded Sponsor 
statistician and unblinded Sponsor statistical programmer will have access to the subject-
level PD-L1 results for the purpose of data review and will have no other responsibilities 
associated with the study. A summary of PD-L1 biomarker prevalence may be provided to 
 
 
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the study team at the Sponsor by the IVRS vendor, the unblinded Sponsor clinical scientist or
the unblinded Sponsor statistician.
Access to the allocation schedule and the subject-level PD-L1 results for summaries or 
analyses for presentation to the eDMC will be restricted to an unblinded external statistician, 
and, as needed, an external scientific programmer performing the analysis, who will have no 
other responsibilities associated with the study.
Planned interim analyses are described in Section 8.2.9. The eDMC will serve as the primary 
reviewer of the unblinded results of the interim analyses and will make recommendations for 
discontinuation of the study or modification to an Executive Oversight Committee of the 
Sponsor. Depending on the recommendation of the eDMC, the Sponsor may prepare a 
regulatory submission. If the eDMC recommends modifications to the design of the protocol 
or discontinuation of the study, this executive oversight committee may be unblinded to 
results at the treatment level in order to act on these recommendations. Additional logistical 
details and data monitoring guidance will be provided in the eDMC Charter. Key aspects of 
the interim analyses are described in Section 8.2.9.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0. Due to the gate-keeping 
procedure where the OS hypothesis in the subjects with TPS≥50% will be tested first, the
study is considered to have met its primary objective in the primary population of the 
subjects with TPS≥50% if the pembrolizumab arm is superior to the SOC arm in OS at an
interim analysis or the final analysis.
Analysis Endpoints
8.2.3.1
Efficacy Endpoints
Primary 
Overall Survival
Overall Survival (OS) is defined as the time from randomization to death due to any cause. 
Subjects without documented death at the time of the analysis will be censored at the date of 
the last follow-up.
Secondary
Progression-Free Survival – RECIST 1.1
Progression-free survival (PFS) is defined as the time from randomization to the first 
documented disease progression per RECIST 1.1 based on blinded independent radiologists’ 
assessment or death due to any cause, whichever occurs first. See Section 8.2.5.1.2 for
definition of censoring.
 
 
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Objective Response Rate – RECIST 1.1
Objective response rate (ORR) is defined as the proportion of the subjects in the analysis 
population who have a confirmed complete response (CR) or partial response (PR) per 
RECIST 1.1 based on blinded independent radiologists’ assessment.
Exploratory 
For subjects who demonstrated confirmed CR or PR, response duration is defined as the time 
from the first documented evidence of CR or PR until disease progression. 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. ORR based on investigator’s assessed RECIST 1.1 will 
be examined.
PFS by investigator’s assessed RECIST 1.1 will also be one of the exploratory endpoints. 
PFS2, defined as the time from randomization to subsequent disease progression after 
initiation of new anti-cancer therapy, or death from any cause, whichever first, will be carried 
out. If progression after next-line therapy cannot be measured, a PFS event is defined as end 
or discontinuation of next-line treatment or death from any cause, whichever occurs first.
Subjects alive and for whom a PFS event has not been observed will be censored at the last 
time known to be alive and without second disease progression.
8.2.3.2
Safety Endpoints
Safety measurements are described in Section 7.0 – Trial Procedures.
Analysis Population
8.2.4.1
Efficacy Analysis Population
The primary efficacy analysis will be carried out in the intention-to-treat (ITT) population, 
i.e., subjects alive at the time of randomization will be included in the treatment group to 
which they are randomized with TPS≥50%, TPS≥20% and TPS≥1%. Details on the approach 
to handling missing data are provided in Section 8.2.5 Statistical Methods.
8.2.4.2
Safety Analysis Populations
The primary safety analysis will be based on the All Subjects as Treated (ASaT) population 
with TPS≥1%.
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 trial 
treatment they actually received for the analysis of safety data. Subjects who take incorrect 
trial treatment for the entire treatment period will be included in the treatment group 
corresponding to the trial treatment actually received. At least one laboratory or vital sign 
measurement obtained subsequent to at least one dose of trial treatment is required for 
 
 
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inclusion in the analysis of each specific parameter. To assess change from baseline, a 
baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in Section 
8.2.5 – Statistical Methods.
Statistical Methods
Statistical testing and inference for safety analyses are described in Section 8.2.5.2. Efficacy 
results that will be considered to be statistically significant after consideration of the strategy 
for controlling the type I error are described in Section 8.2.6 – Multiplicity. Nominal 
p-values may be computed for other efficacy analyses as a measure of strength of association 
between the endpoint and the treatment effect rather than formal tests of hypotheses.
8.2.5.1
Statistical Methods for Efficacy Analyses
The strategy to address multiplicity issues with regard to multiple efficacy endpoints and 
interim analyses is described in Section 8.2.6 and Section 8.2.9.
8.2.5.1.1 Overall Survival (OS)
The Kaplan-Meier method will be used to estimate the survival curves. The treatment 
difference in survival will be assessed by the stratified log-rank test. A stratified Cox 
proportional hazard model with Efron's method of tie handling will be used to assess the 
magnitude of the treatment difference (i.e., the hazard ratio). The hazard ratio and its 95% 
confidence interval from the stratified Cox model with a single treatment covariate will be 
reported. The same stratification factors used for randomization (see Section 5.4) will be 
applied to both the stratified log-rank test and the stratified Cox model.
As an exploratory analysis, recognized methods, e.g., the Rank Preserving Structural Failure 
Time (RPSFT) model [71], two-stage method, etc., will be used to adjust for the effect of 
crossover on OS based upon the appropriateness of the data to the assumption required by the 
methods. The RPSFT model provides a randomization-based estimate of treatment effect 
(RBEE) corrected for the bias induced by crossover. The 95% confidence intervals of the 
hazard ratio for OS after adjustment of the effect of crossover will be provided. The Kaplan-
Meier estimates of the OS rate at 6 months, 1 year, and other time points of interest will also 
be compared between the two treatment groups to explore the confounding effect of 
subsequent treatments. To further account for the possible confounding effect, a sensitivity 
analysis of OS that censors subjects at the time of initiation of new therapy will be performed 
and an OS analysis that treats initiation of new therapy as a time-dependent binary covariate 
will also be conducted. In case the proportional hazards assumption does not hold, Fleming 
and Harrington’s weighted log-rank test, Restricted Mean Survival Time (RMST) method or 
other methods, as appropriate, will be conducted, possibly after proper adjustment of the 
crossover effect over time.
 
 
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8.2.5.1.2 Progression-Free Survival (PFS)
The Kaplan-Meier method will be used to estimate the PFS curve in each treatment group. 
The treatment difference in PFS will be assessed by the stratified log-rank test. A stratified 
Cox proportional hazard model with Efron's method of tie handling will be used to assess the 
magnitude of the treatment difference (i.e., hazard ratio) between the treatment arms. The 
hazard ratio and its 95% confidence interval from the stratified Cox model with Efron's 
method of tie handling and with a single treatment covariate will be reported. The same 
stratification factors used for randomization (see Section 5.4) will be applied to both the 
stratified log-rank test and the stratified Cox model. 
Since disease progression is assessed periodically, progressive disease (PD) can occur any 
time in the time interval between the last assessment where PD was not documented and the 
assessment when PD is documented. In 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 documented based on blinded central independent radiologists’ assessment
per RECIST 1.1, regardless of discontinuation of study drug. Death is always considered as a 
confirmed PD event.
In order to evaluate the robustness of the PFS endpoint, we will perform two sensitivity 
analyses with a different set of censoring rules. The first sensitivity analysis is the same as 
the primary analysis except that it censors at the last disease assessment without PD when PD 
or death is documented after more than one missed disease assessment. The second 
sensitivity analysis is the same as the primary analysis except that it considers 
discontinuation of treatment or initiation of new anticancer treatment, whichever occurs later, 
to be a PD event for subjects without documented PD or death. The censoring rules for 
primary and sensitivity analyses are summarized in Table 9. In case there is an imbalance 
between the treatment groups on disease assessment schedules or censoring patterns, we will 
also perform the following two additional PFS sensitivity analyses: 1) a PFS analysis using 
time to scheduled tumor assessment visit from randomization as opposed to actual tumor 
assessment time; 2) Finkelstein’s likelihood-based score test for interval-censored data [72]
which modifies the Cox proportional hazard model for interval censored data, will be used as 
a supportive analysis for the PFS endpoint. The interval will be constructed so that the left 
endpoint is the date of the last disease assessment without documented PD and the right 
endpoint is the date of documented PD or death, whichever occurs earlier. In case the 
proportional hazards assumption does not hold, Fleming and Harrington’s weighted log-rank 
test, Restricted Mean Survival Time (RMST) method or other methods, as appropriate, may
be conducted.
 
 
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Table 9
Censoring Rules for Primary and Sensitivity Analyses of PFS
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
No PD and no death; 
new anticancer treatment 
is not initiated
Censored at last 
disease assessment 
Censored at last disease 
assessment 
Censored at last disease 
assessment if still on study 
therapy; progressed at 
treatment discontinuation 
otherwise
No PD and no death; 
new anticancer treatment 
is initiated
Censored at last 
disease assessment 
before new anticancer 
treatment
Censored at last disease 
assessment before new 
anticancer treatment
Progressed at date of new 
anticancer treatment
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
As a supportive analysis, PFS by investigator’s assessed RECIST 1.1 will be also carried out.
8.2.5.1.3 Objective Response Rate (ORR)
Stratified Miettinen and Nurminen’s method [73] with weights proportional to the stratum 
size will be used for comparison of the ORR between the treatment arms. A 95% CI for the 
difference in response rates between the pembrolizumab arm and the control arm will be 
provided. The stratification factors used for randomization will be applied to the analysis.  
8.2.5.1.4 Exploratory Analyses
If sample size permits, response duration will be summarized descriptively using Kaplan-
Meier medians and quartiles. Only the subset of subjects who show a complete response or 
partial response will be included in this analysis.
An exploratory analysis of PFS2, defined in Section 8.2.5.1.2, will be carried out using the 
Kaplan-Meier method, stratified log-rank test and stratified Cox model with Efron’s tie 
handling method for estimation.
8.2.5.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, vital signs, and ECG measurements.
 
 
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The analysis of safety results will follow a tiered approach (Table 10). The tiers differ with 
respect to the analyses that will be performed. Safety parameters or adverse experiences of 
special interest that are identified a priori constitute “Tier 1” safety endpoints that will be 
subject to inferential testing for statistical significance with p-values and 95% confidence 
intervals provided for between-group comparisons. For this protocol, there are no Tier 1 AEs.
Other safety parameters will be considered Tier 2 or Tier 3. Tier 2 parameters will be 
assessed via point estimates with 95% confidence intervals provided for between-group 
comparisons; only point estimates by treatment group are provided for Tier 3 safety 
parameters.
Adverse experiences (specific terms as well as system organ class terms) and predefined 
limits of change in laboratory, vital signs, and ECG parameters that are not pre-specified as 
Tier 1 endpoints will be classified as belonging to "Tier 2" or "Tier 3", based on the number 
of events observed. Membership in Tier 2 requires that at least 4 subjects in any treatment 
group exhibit the event; all other adverse experiences and predefined limits of change will 
belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences. Because many 95% confidence intervals 
may be provided without adjustment for multiplicity, the confidence intervals should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of the between-group differences in adverse experiences 
and predefined limits of change.
Continuous measures such as changes from baseline in laboratory, vital signs, and ECG 
parameters 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. 
To properly account for the potential difference in follow-up time between the study arms, 
which is expected to be longer in the pembrolizumab arm, an analysis of Grade 3-5 AEs will 
be based on the time to first event using the same time-to-event analysis methods as for OS 
(i.e., the stratified log-rank test will be used for testing the time to AEs, and the Cox model 
with Efron's tie handling method will be used for estimating the hazard ratio and its 95% 
confidence interval). For other AEs with potentially differential follow-up time, such analysis 
may also be explored.
In addition, the broad clinical and laboratory AE categories consisting of the percentage of 
subjects with any AE, any drug-related AE, any Grade 3-5 AE, any serious AE, any AE 
which is both drug related and Grade 3-5, any AE which is both serious and drug-related, 
dose modification due to AE, and who discontinued due to an AE, and death will be 
considered Tier 2 endpoints. 95% confidence intervals (Tier 2) will be provided for between-
treatment differences in the percentage of subjects with events; these analyses will be 
performed using the Miettinen and Nurminen method. Detailed kinetics and characteristics of 
immune-mediated AEs will be summarized separately in the study.
 
 
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Based on emerging external data, the analysis strategy for safety parameters may be modified 
to improve the integrity and efficiency of the design. Should this happen, the change will be 
documented elsewhere, if not in a protocol amendment, at the earliest time before any 
unblinding of the data.
Table 10
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE
X
X
Any Grade 3-5 AE
X
X
Any Serious AE
X
X
Onset and Duration of First Grade 3-5 AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Any Grade3-5 and Drug-Related AE
X
X
Dose Modification Due to AE
X
X
Discontinuation Due to AE
X
X
Death
X
X
Specific AEs, SOCs (including ≥4 of subjects in one 
of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs (incidence <4 of subjects in 
all of the treatment groups)
X
Change from Baseline Results (Labs, ECGs, Vital 
Signs)
X
There are no Tier 1 AEs pre-specified in this protocol.
8.2.5.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
The comparability of the treatment groups for each relevant baseline characteristic will be 
assessed by the use of tables and/or graphs. No statistical hypothesis tests will be performed 
on these characteristics. The number and percentage of subjects randomized and the primary 
reason for discontinuation will be displayed. Demographic variables (such as age) and 
baseline characteristics will be summarized by treatment either by descriptive statistics or 
categorical tables in subjects with TPS≥50%, TPS≥20%, and TPS≥1%. The reasons for 
exclusion from the ITT population (if any) will be summarized.
Multiplicity
The multiplicity strategy specified in this section will be applied to the subjects with
TPS≥50%, TPS≥20%, and TPS≥1% for the testing of the OS, PFS, and ORR hypotheses. 
The overall type I error is strongly controlled at 2.5% (one-sided). The hypotheses will be 
tested sequentially at the type I error rate of 2.5% (one-sided) in the following order: 
superiority of pembrolizumab in OS in the subjects with TPS≥50%, superiority of 
pembrolizumab in OS in the subjects with TPS≥20%, superiority of pembrolizumab in OS in 
the subjects with TPS≥1%, superiority of pembrolizumab in PFS in the subjects with 
 
 
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TPS≥50%, superiority of pembrolizumab in PFS in the subjects with TPS≥20%, superiority 
of pembrolizumab in PFS in the subjects with TPS≥1%, superiority of pembrolizumab in 
ORR in the subjects with TPS≥50%, superiority of pembrolizumab in ORR in the subjects 
with TPS≥20%, and superiority of pembrolizumab in ORR in the subjects with TPS≥1%.
Under this sequential testing strategy, a hypothesis will be tested only if superiority is 
established for all the preceding ones.
The initial alpha allocation is revised to reflect the change of the criteria for the conduct of 
the FA and the addition of IA2. The reallocation of alpha occurs after the conduct of IA1, 
and proper adjustment is made to maintain the control of family-wise type I error rate with 
the implementation of this change. The type I error actually spent at IA1 will be kept intact 
and the re-allocation will only be applied to the remaining unspent alpha. No futility 
boundary will be set as before. 
Both IA2 and FA will be conducted based on calendar time [69]. Specifically, IA2 and FA 
will occur about 38 months (about 1148 days) and about 45 months (about 1353 days) after 
the date when the first subject was randomized (19-DEC-2014), given that IA1 was 
conducted based on the cutoff date of 30-AUG-2017 (about 986 days or 32 months from the 
first subject randomized). Under the revised alpha allocation, the alpha spending at IA2 and 
FA is determined by the Hwang-Shih-DeCani alpha spending function with the gamma 
parameter -0.9023. With this spending function, the alpha level at IA1 is the same as the 
actual spent at IA1 (one-sided 1.576%), since the information fraction is 0.729 (i.e., 
986/1353) on the scale of calendar time. The cumulative alpha (one-sided) spending at the 
planned time of IA2 and FA becomes 1.94% and 2.5%, regardless of the actual number of 
deaths observed at the IA2 and FA. The corresponding stopping bounds at IA2 and FA will 
then be calculated based on the cumulative alpha spent and actual number of deaths observed 
at each analysis.
If the pembrolizumab arm demonstrates superior OS in the subjects with TPS≥50% at an 
interim or final analysis, the OS hypothesis in the subjects with TPS≥20% will be tested 
based on a group sequential approach with the cumulative alpha spent up to each interim 
analysis at the same level as the alpha spent for testing the OS hypothesis in the subjects with 
TPS≥50% up to that analysis [70]. Note that, based on the above sequential testing strategy, 
if the OS superiority is demonstrated at an interim analysis in the subjects with TPS≥50%, 
the OS superiority in the subjects with TPS≥20% may be demonstrated at a later analysis. If 
the pembrolizumab arm demonstrates superior OS in the subjects with both TPS≥50% and 
TPS≥20%, the OS hypothesis in the subjects with TPS≥1% will be tested using the same 
approach.
Testing of the PFS hypotheses will be performed at the same interim analyses and FA. The 
cumulative alpha spending is determined by the same alpha spending function (on the scale 
of calendar time) defined above for the OS hypotheses. The corresponding stopping bounds 
for PFS at IA2 and FA will then be calculated based on the actual number of deaths observed 
at each analysis. Statistical significance under multiplicity control can only be established 
once the OS hypotheses have been established at an interim or final analysis. Otherwise, 
 
 
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nominal p-values will be reported as a measure of strength of association for the PFS 
hypotheses.
Testing of the ORR hypotheses will be based on the IA1 data. Statistical significance under 
multiplicity control can only be established once the OS and PFS hypotheses have both been 
established. Otherwise, nominal p-values will be reported as a measure of strength of 
association for the ORR hypotheses. If OS and PFS are not statistically significant at IA1, 
then the ORR at IA1 will be considered without any data update if the step-down criteria 
allow formal testing based on a later analysis of OS and PFS.
Sample Size and Power Calculation
The study will randomize subjects in a 1:1 ratio into the pembrolizumab arm and the SOC 
arm. The sample size for the subjects with TPS≥50% is targeted at approximately 530, and 
the overall sample size for this study is projected to be approximately 1240. The number of 
randomized subjects with TPS≥50% drives the end of enrollment.
The final analysis of the study is based on calendar time and will occur about 45 months after
the first subject randomized (study start), at which time approximately 398 deaths 
(projections updated in November 2017) will have been observed between the two arms in 
the subjects with TPS≥50%. With 398 deaths, the study has approximately 99% power to 
detect a 0.65 piece-wise hazard ratio on OS at alpha=2.5% (one-sided) in the subjects with 
TPS≥50%. By the same time, the expected numbers of deaths are about 557 and 900 in the 
subjects with TPS≥20% and TPS≥1%, respectively. With 557 deaths, the study has 
approximately 98% power to detect a piecewise hazard ratio on OS with 0.8 before month 6 
and 0.64 after month 6 at alpha=2.5% (one-sided) in the subjects with TPS≥20%. With 900
deaths, the study has approximately 91% power to detect a piecewise hazard ratio with 0.92 
by month 6 and 0.73 after month 6 at alpha=2.5% (one-sided) in the subjects with TPS≥1%.
The assumed hazard ratios were based on results from studies KN010 and KN024 (see 
Section 4.1.2). Details on the nominal alpha and the approximate efficacy boundary at each 
interim analysis are summarized in Section 8.2.9. The nominal alpha levels will be re-
calculated based upon the actual observed number of deaths at each interim analysis. 
The above calculations are based on the following assumptions: 1) OS in the standard of care 
arm follows an exponential distribution with a median of 13 months, 2) hazard ratio on OS 
between pembrolizumab and control is 0.65 in the subjects with TPS≥50%, 3) an enrollment 
period of ~26 months and a minimal 19-month follow-up period after enrollment completion,
4) a dropout rate of 0.003 per month for OS. The assumption for the median OS of 13 months 
in the subjects with TPS≥50% in the control arm does not take into account potential 
prognostic implications in a biomarker selected population. As such, the actual medians in 
control arm may be different. The sample size and power calculation were performed in the 
software EAST and R (package “gsDesign”).
 
 
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Subgroup Analyses and Effect of Baseline Factors
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the primary
endpoint will be estimated and plotted within each category of the following classification 
variables:

Age category (≤65 vs. >65 years)

Sex (female vs. male)

Race (white vs. non-white)

ECOG status (0 vs. 1)

Geographic region of enrolling site (East Asia vs. non-East Asia and East Asia vs. 
Europe vs. Latin America vs. Other)

Histology (squamous vs. non-squamous)

Smoking status (never vs. former vs. current)

PD-L1 status (TPS≥50% vs. TPS 1-49%, TPS≥20% vs. TPS 1-19%, and TPS≥50% vs. 
TPS 20-49% vs. TPS 1-19%)

Investigators’ choice of standard of care chemotherapy prior to randomization
(Pemetrexed vs. No Pemetrexed)

Disease stage (advanced vs. metastatic)

Brain metastasis status (baseline brain metastasis vs. no baseline brain metastasis)

Baseline tumor size (at/above median vs. below median)
The consistency of the treatment effect will be assessed descriptively via summary statistics 
by category for the classification variables listed above. These subgroup analyses will be 
carried out in the subjects with TPS≥50%, TPS≥20%, and TPS≥1%.
Interim Analyses
There are 2 planned interim analyses. The totality of the data from the interim analyses will 
be reviewed by a data monitoring committee (DMC). Further details of interim analyses are 
provided below. Table 11 summarizes the timing, target events, and decision guidance for the 
interim and final OS analyses based on the projected number of deaths in subjects with
TPS≥50%, TPS≥20% and TPS≥1%. These details will be incorporated into the DMC 
Charter.
 
 
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The IA1 will be conducted after at least 250 deaths are observed between the pembrolizumab 
arm and control arm in the subjects with TPS≥50% and at least 6 months after last subject 
enrolled. Any change to the timing, along with its rationale, will be documented in a memo 
to the study file before the database lock for IA1.
At IA1, a total of 293 deaths were actually observed in the subjects with TPS≥50%. With 293
deaths observed at IA1 in the subjects with TPS≥50% between two arms, the nominal alpha 
for testing the OS hypothesis at IA1 was 1.576% (one-sided) according to the O’Brien-
Fleming-type (Lan-DeMets) spending function. A p-value <1.576% (one-sided) would 
demonstrate OS superiority in the subjects with TPS≥50% at IA1. If the pembrolizumab arm 
demonstrates superior OS in the subjects with TPS≥50% at IA1, the testing of the OS 
hypothesis will be performed sequentially at the nominal alpha 1.576% (one-sided) in the 
subjects with TPS≥20%. Similarly, if the pembrolizumab arm demonstrates superior OS in 
the subjects with both TPS≥50% and TPS≥20% at IA1, the testing of the OS hypothesis will 
be performed sequentially at the nominal alpha 1.576% (one-sided) in the subjects with 
TPS≥1% at IA1. If the pembrolizumab arm demonstrates superior OS in the subjects with 
TPS≥50%, TPS≥20%, and TPS≥1% at IA1, the testing of the PFS hypotheses will be 
performed sequentially at the type I error rate 1.576% (one-sided) in the subjects with 
TPS≥50%, TPS≥20%, and TPS≥1% based on data at IA1. PFS hypotheses will also be tested 
at IA2 and FA with the alpha spent determined by the same alpha spending function (on the 
scale of calendar time) defined for the OS hypotheses. For the testing of the ORR hypotheses 
in the subjects with TPS≥50%, TPS≥20% and TPS≥1%, the three nominal p-values on ORR 
from IA1 will be sequentially compared to 2.5% (one-sided) if both the OS and PFS 
hypotheses are demonstrated (at IA1, IA2, or FA).
The IA2 will be conducted about 38 months after first subject randomized (study start). By 
then, about 340 deaths are projected to occur in the subjects with TPS≥50%. The boundary 
nominal alpha can then be calculated based on the actual number of deaths observed at IA1 
and IA2 with the cumulative alpha determined by the Hwang-Shih-DeCani alpha spending 
function with the gamma parameter -0.9023 on the scale of calendar time. If the OS 
superiority is demonstrated in the subjects with TPS≥50%, the OS hypotheses in the subjects 
with TPS≥20% and TPS≥1% will be tested based on a group sequential approach with the 
cumulative alpha spent up to each interim analysis the same as the alpha spent for testing the 
OS hypothesis in the subjects with TPS≥50% up to that interim analysis. The projected 
numbers of deaths at IA2 are 474 and 780 in subjects with TPS≥20% and TPS≥1%, 
respectively. 
The FA will take place about 45 months after the first subject is randomized. By then, about 
398 deaths are projected to occur between the pembrolizumab arm and the control arm in the
subjects with TPS≥50%. According to Table 11, the nominal alpha for the final OS testing is 
1.521% (one-sided) for the subjects with TPS≥50% in the hypothetical scenario where the 
actual number of deaths is the same as the projected. A nominal alpha < 1.521% corresponds 
to the approximate observed hazard ratio for OS superiority <0.80, i.e., at least 3.3-month 
improvement in the median OS in the subjects with TPS≥50%. Table 11 also summarizes the 
efficacy criteria for the rest of TPS populations in a hypothetical scenario after the OS 
superiority is demonstrated in the subjects with TPS≥50%. The nominal alpha level for OS 
 
 
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hypothesis testing at the final analysis will be re-calculated if the actual number of deaths 
differs from the projected. While the cumulative alpha levels for the OS hypothesis at each
analysis in the subjects with TPS≥20% and TPS≥1% are the same as TPS≥50%, the nominal 
alpha levels for the OS hypothesis at the FA in the subjects with TPS≥20% and TPS≥1% will 
be adjusted accordingly to control the type I error rate based on the actually observed number 
of deaths (assuming OS superiority has been demonstrated in the subjects with TPS≥50%). 
The cumulative alpha spent up to each analysis will be the same across populations. A 95% 
confidence interval will be provided for hazard ratio to characterize the OS effect in case the 
superiority is not demonstrated. As an exploratory analysis, the RPSFT method will be used 
to adjust for the potential crossover effect to other anti-PD-1/PD-L1 therapies.
 
 
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Table 11
Decision Guidance for the Primary OS Hypotheses at the Interim Analyses and Final Analysis under a Hypothetical 
Scenario
Analysis
Targeted Number of 
Events/Targeted Study Time
Cumulative 
Alpha
Efficacy Bars in Subjects 
with TPS≥50%1
Efficacy Bars in Subjects 
with TPS≥20% (if OS 
positive in TPS≥50%)1
Efficacy Bars in Subjects 
with TPS≥1% (if OS 
positive in both 
TPS≥50% and 
TPS≥20%)1
IA1
At least 250 deaths observed in 
two arms in the subjects with 
TPS≥50% AND at least 6 
month after last subject is 
enrolled (~32
months after 
study start)
At IA1, 293 deaths were 
observed in the subjects with 
TPS≥50% 
1.576%
(One-sided) 
p-value 
for 
OS < 1.576%, 
i.e., observed 
HR < ~0.78
(~3.7-month 
improvement)
(One-sided) p-value for 
OS < 1.576%, 
i.e., observed 
HR < ~0.81
(~3.1-month 
improvement)
(One-sided) 
p-value 
for 
OS < 1.576%, 
i.e., an 
observed 
HR < ~0.85 (2.3-month 
improvement)
IA2
About 38 months after study 
start2
1.94%
(One-sided) p-value for 
OS < 1.233%, 
i.e., observed 
HR < ~0.78 (3.6-month 
improvement)
(One-sided) p-value for 
OS < 1.197%, 
i.e., observed 
HR < ~0.81 (3.0-month 
improvement)
(One-sided) 
p-value 
for 
OS < 1.228%, 
i.e., observed 
HR < ~0.85 (2.3-month 
improvement)
FA
About 45 months after study 
start2
2.5%
(One-sided) p-value for 
OS < 1.521%, 
i.e., observed 
HR < ~0.80 (3.2-month 
improvement)
(One-sided) p-value for 
OS < 1.497%, 
i.e., observed 
HR < ~0.83 (2.6-month 
improvement)
(One-sided) 
p-value 
for 
OS < 1.556%, 
i.e., observed 
HR < ~0.87 (2.0-month 
improvement)
1 Nominal alpha and boundaries will be re-calculated if the actual number of events at analyses is altered from the expected. In this hypothetical scenario, the numbers of death
at IA2 and final are assumed to be the same as the projected, i.e., 340 and 398 in the subjects with TPS≥50%, 474 and 557 in the subjects with TPS≥20%, and 780 and 900 in 
the subjects with TPS≥1%. The actual boundaries will need to be recalculated based on the observed number of deaths.
2 Study start is defined as the date when the first subject was randomized.
 
 
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Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study. Compliance 
with trial treatment administration will be measured by subjects: 1) receiving unscheduled 
study agent infusions/injections; 2) missing an infusion/injection. Numbers and percentages 
of subjects and infusion/injection visits with any deviation in these measures will be reported 
for the ITT population.
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles. Dose intensity 
will also be summarized as appropriate.
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
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.
All supplies indicated in Table 12 will be provided per the “Source/Additional Information” 
column depending on local country operational requirements.
Any commercially available product not included in Table 12 will be provided by the trial 
site, subsidiary or designee.
Table 12
Product Descriptions
Product Name & Potency
Dosage Form
Source/Additional Information
Pembrolizumab 100 mg/4 mL
Injection
Provided centrally by the Sponsor
Carboplatin 10 mg/mL, 60 mL 
Injection
Provided centrally by the Sponsor or locally by the 
trial site, subsidiary, or designee
Paclitaxel 6 mg/mL, 16.7 mL
Injection
Provided centrally by the Sponsor or locally by the 
trial site, subsidiary, or designee
Pemetrexed 500 mg/vial
Injection
Provided centrally by the Sponsor or locally 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 will be responsible for recording the lot number, manufacturer and expiry date of 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
 
 
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Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive open label vials or kits. All kitted products will contain 1 vial per kit 
box.
Clinical Supplies Disclosure
The trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. The product identification (name, strength or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
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.
Standard Policies
Trial site personnel will have access to a central electronic randomization system 
(IVRS/IWRS system) to allocate subjects, to assign treatment to subjects and to manage the 
distribution of clinical supplies. Each person accessing the IVRS system must be assigned an 
individual unique PIN.  They must use only their assigned PIN to access the system, and they 
must not share their assigned PIN with anyone.
 
 
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10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
 
 
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investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor or through a secure password-protected electronic portal provided by the 
Sponsor.  The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on
Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
 
 
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The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
 
 
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The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Merck, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements.  Merck entries are not limited to FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.    
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
 
 
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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.
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, 
 
 
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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.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
 
 
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11.0 LIST OF REFERENCES
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[3]
Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat Rev Immunol 
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Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz O, Wood CR, et al. 
Blockade of programmed death-1 ligands on dendritic cells enhances T cell 
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Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et 
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[7]
Hino R, Kabashima K, Kato Y, Yagi H, Nakamura M, Honjo T, et al. Tumor 
cell expression of programmed cell death-1 ligand 1 is a prognostic factor for 
malignant melanoma. Cancer 2010;116:1757-66.
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Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, et al. Clinical 
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Gao Q, Wang X-Y, Qiu S-J, Yamato I, Sho M, Nakajima Y, et al. 
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[10]
Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, et al. 
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[11]
Fourcade J, Kudela P, Sun Z, Shen H, Land SR, Lenzner D, et al. PD-1 is a 
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[12]
Cai G, Karni A, Oliveira EML, Weiner HL, Hafler DA, Freeman GJ. PD-1 
ligands, negative regulators for activation of naïve, memory, and recently 
activated human CD4+ T cells. Cell Immunol 2004;230(2):89-98.
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Blank C, Mackensen A. Contribution of the PD-L1/PD-1 pathway to T-cell 
exhaustion: an update on implications for chronic infections and tumor evasion. 
Cancer Immunol Immunother. 2007 May;56(5):739-45.
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Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of 
PD-L1 on tumor cells in the escape from host immune system and tumor 
immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A 
2002;99(19):12293-7.
[15]
Tsushima F, Tanaka K, Otsuki N, Youngnak P, Iwai H, Omura K, et al. 
Predominant expression of B7-H1 and its immunoregulatory roles in oral 
squamous cell carcinoma. Oral Oncol 2006;42:268-74.
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Korman A, Chen B, Wang C, Wu L, Cardarelli P, Selby M. Activity of anti-PD-
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PD-1 and anti-CTLA-4 [Abstract]. J Immunol 2007;178:48.37.
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Oble DA, Loewe R, Yu P, Mihm MC Jr. Focus on TILs: prognostic significance 
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Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et 
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[19]
Patnaik A, Kang SP, Tolcher AW, Rasco DW, Papadopoulos KP, Beeram M, et 
al.  2012 ASCO Annual Meeting:  Phase I study of MK-3475 (anti-PD-1 
monoclonal antibody) in patients with advanced solid tumors.
[20]
Phase I Study of Single Agent MK-3475 in Patients with Progressive Locally 
Advanced or Metastatic Carcinoma, Melanoma, and Non-Small Cell Lung 
Carcinoma (P001)
[21]
Chapman PB, Hauschild A, Robert C, Hannen JB, Ascierto P, Larkin J, et al. 
Improved survival with vemurafenib in melanoma with BRAF V600E mutation. 
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Bellati F, Visconti V, Napoletano C, Antonilli M, Frati L, Benedetti Panici P, et 
al. Immunology of gynecologic neoplasms: analysis of the prognostic 
significance of the immune status. Curr Cancer Drug Targets 2009;9(4):541-65.
 
 
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Ruffell B, DeNardo DG, Affara NI, Coussens LM. Lymphocytes in cancer 
development: polarization towards pro-tumor immunity. Cytokine Growth 
Factor Rev 2010;21:3-10.
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Shirabe K, Motomura T, Muto J, Toshima T, Matono R, Mano Y, et al. Tumor-
infiltrating lymphocytes and hepatocellular carcinoma: pathology and clinical 
management. Int J Clin Oncol 2010;15:552-8.
[25]
Al-Shibli K, Al-Saad S, Andersen S, Donnem T, Bremnes RM, Busund L-T. 
The prognistic value of intraepithelial and stromal CD3-, CD117- and CD138-
positive cells in non-small cell lung carcinoma. APMIS 2010;118:371-82.
[26]
Clark CE, Beatty GL, Vonderheide RH. Immunosurveillance of pancreatic 
adenocarcinoma: insights from genetically engineered mouse models of cancer. 
Cancer Lett 2009;279:1-7.
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Diederichsen ACP, Hjelmborg JvB, Christensen PB, Zeuthen J, Fenger C. 
Prognostic value of the CD4+/CD8+ ratio of tumour infiltrating lymphocytes in 
colorectal cancer and HLA-DR expression on tumour cells. Cancer Immunol 
Immunother 2003;52:423-8.
[28]
Gao Q, Qiu S-J, Fan J, Zhou J, Wang X-Y, Xiao Y-S, et al. Intratumoral balance 
of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular 
carcinoma after resection. J Clin Oncol 2007;25(18):2586-93.
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Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, 
Winnepenninckx V, et al. Leukocyte infiltration and tumor cell plasticity are 
parameters of aggressiveness in primary cutaneous melanoma. Cancer Immunol 
Immunother 2008;57(1):97-106.
[30]
Laghi L, Bianchi P, Miranda E, Balladore E, Pacetti V, Grizzi F, et al. CD3+ 
cells at the invasive margin of deeply invading (pT3-T4) colorectal cancer and 
risk of post-surgical metastatsis: a longitudinal study. Lancet Oncol 
2009;10:877-84.
[31]
Li JF, Chu YW, Wang GM, Zhu TY, Rong RM, Hou J, et al. The prognostic 
value of peritumoral regulatory T cells and its correlation with intratumoral 
cyclooxygenase-2 expression in clear cell renal cell carcinoma. BJU Intern 
2008;103:399-405.
[32]
Nemolato S, Fanni D, Naccarato AG, Ravarino A, Bevilacqua G, Faa G. 
Lymphoepithelioma-like hepatocellular carcinoma: a case report and a review of 
the literature. World J Gastroenterol 2008;14(29):4694-6.
 
 
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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.
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Oshikiri T, Miyamoto M, Shichinohe T, Suzuoki M, Hiraoka K, Nakakubo Y, et 
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duct carcinoma as essential immune response. J Surg Oncol 2003;84:224-8.
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Piersma SJ, Welters MJP, van der Burg SH. Tumor-specific regulatory T cells in 
cancer patients. Human Immunol 2008;69:241-9.
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Rao UNM, Lee SJ, Luo W, Mihm Jr. MC, Kirkwood JM. Presence of tumor-
infiltrating lymphocytes and a dominant nodule within primary melanoma are 
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melanoma: pathologic analysis of the E1690 and E1694 intergroup trials. Am J 
Clin Pathol 2010;133:646-53.
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Sasaki A, Tanaka F, Mimori K, Inoue H, Kai S, Shibata K, et al. Prognostic 
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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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Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: 
Jekyll or Hyde. Cancer Metastasis Rev 2007;26(3-4):373-400.
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factors in renal cell carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81.
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Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema 
H, et al. Prognostic significance of tumor-infiltrating T-lymphocytes in primary 
and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol 
Immunother 2009;58(3):449-59.
[42]
Nishimura H, Honjo T, Minato N. Facilitation of beta selection and modification 
of positive selection in the thymus of PD-1-deficient mice. J Exp Med. 2000 Mar 
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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.
 
 
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Suzuki H, Chikazawa N, Tasaka T, Wada J, Yamasaki A, Kitaura Y, et al. 
Intratumoral CD8+ T/FOXP3+ cell ratio is a predictive marker for survival in 
patients with colorectal cancer. Cancer Immunol Immunother 2010;59:653-61.
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Chew V, Tow C, Teo M, Wong HL, Chan J, Gehring A, et al. Inflammatory 
tumor microenvironment is associated with superior survival in hepatocellular 
carcinoma patients. J Hepatol 2010;52:370-9.
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Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of 
regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes 
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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.
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Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et 
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metastatic melanoma. J Clin Oncol 2005;23(10):2346-57.
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Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. 
Treatment of metastatic melanoma with autologous CD4+ T cells against NY-
ESO-1. N Engl J Med 2008;358(25):2698-703.
[50]
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.
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Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev 
Immunol 2005;23:515-48.
[52]
Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and 
Tumor Responses with Lambrolizumab (Anti-PD-1) in Melanoma. N Engl J 
Med 2013;369(2):134-44.
[53]
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.
 
 
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Sandler AB, Nemunaitis J, Denham C, von Pawel J, Cormier Y, Gatzemeier U, 
et al. Phase III Trial of Gemcitabine Plus Cisplatin Versus Cisplatin Alone in 
Patients With Locally Advanced or Metastatic Non-Small-Cell Lung Cancer. J 
Clin Oncol 2000;18(1):122-30.
[55]
Zatloukal P, Petruzelka L, Zemanova M, Kolek V, Skrickova J, Pesek M, et al. 
Gemcitabine plus cisplatin vs. gemcitabine plus carboplatin in stage IIIb and IV 
non-small cell lung cancer: a phase III randomized trial. Lung Cancer 
2003;41(3):321-31.
[56]
Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, 
et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus 
pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell 
lung cancer. J Clin Oncol 2008;26(21):3543-51.
[57]
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.
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KEYTRUDA (pembrolizumab) Investigator's Brochure, Edition Number 10, 31-
AUG-2015.
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Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, et al. 
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, 
advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled 
trial. Lancet. 2016 Apr 9;387(10027):1540-50.
[60]
Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. 
Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung 
Cancer. N Engl J Med. 2016 Oct 8. [Epub ahead of print].
[61]
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.
[62]
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer 
statistics. CA Cancer J Clin 2011;61:69-90.
[63]
Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, et al. 
Phase III Trial of Cisplatin Plus Gemcitabine With Either Placebo or 
Bevacizumab As First-Line Therapy for Nonsquamous Non-Small-Cell Lung 
Cancer: AVAiL. J Clin Oncol 2009;27(8):1227-34.
[64]
Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. 
Paclitaxel-Carboplatin Alone or with Bevacizumab for Non-Small-Cell Lung 
Cancer. N Engl J Med 2006;355(24):2542-50.
 
 
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Nishie K, Kawaguchi T, Tamiya A, Mimori T, Takeuchi N, Matsuda Y, et al. 
Epidermal growth factor receptor tyrosine kinase inhibitors beyond progressive 
disease. J Thorac Oncol 2012;7(11):1722-7.
[66]
Camidge DR, Bang Y-J, Kwak EL, Lafrate AJ, Varella-Garcia M, Fox SB. 
Activity and safety of crizotinib in patients with ALK-positive non-small-cell 
lung cancer: updated results from a phase 1 study. Lancet Oncol 2012;13:1011-
9.
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Fukuoka M, Wu Y-L, Thongprasert S, Sunpaweravong P, Leong S-S, 
Sriuranpong V, et al. Biomarker analyses and final overall survival results from 
a phase III, randomized, open-label, first-line study of gefitinib versus 
Carboplatin/Paclitaxel in clinically selected patients with advanced non-small-
cell lung cancer in Asia (IPASS). J Clin Oncol 2011;29(21):2866-74.
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Akbay EA, Koyama S, Carretero J, Altabef A, Tchaicha JH, Christensen CL, et 
al. Activation of the PD-1 pathway contributes to immune escape in EGFR-
driven lung tumors. Cancer Discov. "in press" 2013.
[69]
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information time: biostatics technical report. Madison (WI): University of 
Wisconsin Clinical Cancer Center (US); 1988 May. 16 p. Report No.:44.
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Maurer W, Bretz F. Multiple testing in group sequential trials using graphical 
approaches. Stat Biopharm Res 2013;5(4):311-20.
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Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials 
using rank preserving structural failure time models. Commun Stat-Theor M 
1991;20(8):2609-31.
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Finkelstein DM. A proportional hazards model for interval-censored failure time 
data. Biometrics 1986;42:845-54.
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Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 
1985;4:213-26.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible.  Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name. 
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV.Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Collection and Management of Specimens for Future Biomedical Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease.  A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the 
influence of variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The DNA and tumor specimen(s) collected in the current trial will be used to study 
various causes for how subjects may respond to a drug/vaccine.  The DNA and tumor
specimen(s) will be stored to provide a resource for future trials conducted by Merck 
focused on the study of biomarkers responsible for how a drug/vaccine enters and is 
removed by the body, how a drug/vaccine works, other pathways a drug/vaccine may 
interact with, or other aspects of disease.  The specimen(s) may be used for future assay 
development and/or drug/vaccine development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by Merck or designees and research 
will be monitored and reviewed by a committee of our scientists and clinicians.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
 
 
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present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  Information contained on the consent form alone cannot be traced 
to any specimens, test results, or medical information once the specimens have been 
rendered de-identified.
Subjects are not required to participate in the Future Biomedical Research sub-trial in 
order to participate in the main trial. Subjects who decline to sign the Future 
Biomedical Research informed consent will not have the specimen collected nor will 
they be discontinued from the main trial.
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.  Each consent will be assessed for 
appropriate specimen permissions.  
Each informed consent approved by an ethics committee is assigned a unique tracking 
number.  The tracking number on this document will be used to assign specimen 
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of both consent and acquisition of Future Biomedical Research 
specimens will be captured in the electronic Case Report Forms (eCRFs).  
Reconciliation of both forms will be performed to assure that only appropriately-
consented specimens are used for this sub-trial's research purposes. Any specimens 
for which such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Blood specimens for DNA or RNA isolation will usually be obtained at a time when 
the subject is having blood drawn for other trial purposes. Specimens like tissue and 
bone marrow will usually be obtained at a time when the subject is having such a 
procedure for clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where 
they will be processed (e.g., DNA or RNA extraction, etc) following the Merck 
approved policies and procedures for specimen handling and preparation.
If specimens are collected for a specific genotype or expression analysis as an 
objective to the main trial, this analysis is detailed in the main body of this protocol 
(Section 8.0 – Statistical Analysis Plan).  These specimens will be processed, 
analyzed, and the remainder of the specimen will be destroyed.  The results of these 
analyses will be reported along with the other trial results.  A separate specimen will 
be obtained from properly-consented subjects in this protocol for storage in the 
biorepository for Future Biomedical Research.
 
 
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4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, Merck has developed secure policies and procedures.  All 
specimens will be de-identified as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
This first code will be replaced with a second code at a Merck designated storage/lab 
facility.  The second code is linked to the first code via a second key. The specimen is 
now double coded.  Specimens with the second code are sometimes referred to as de-
identified specimens. The use of the second code provides additional confidentiality and 
privacy protection for subjects over the use of a single code.  Access to both keys would 
be needed to link any data or specimens back to the subject's identification.
The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the second 
code to the first code to allow clinical information collected during the course of the trial 
to be associated with the specimen.  This second key will be transferred under secure 
procedures by the Merck designated facility to an Entrusted Keyholder at Merck.  The 
second code will be logged into the primary biorepository database at Merck and, in this 
database, this identifier will not have identifying demographic data or identifying clinical 
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen 
will be stored in a designated biorepository site with secure policies and procedures for 
specimen storage and usage.
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by 
the Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would 
be directly linked to the full clinical data set would be those situations mandated by 
regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly 
transferred to the regulatory authority.
 
 
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5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the 
highly validated conditions usually associated with regulatory approval of diagnostics.  
The scope of research performed on these specimens is limited to the investigation of the 
variability in biomarkers that may correlate with a clinical phenotype in subjects.
Analyses utilizing the Future Biomedical Research specimens may be performed by 
Merck, or an additional third party (e.g., a university investigator) designated by Merck.  
The investigator conducting the analysis will be provided with double coded specimens. 
Re-association of analysis results with corresponding clinical data will only be conducted 
by the Merck Entrusted Keyholder.  Any contracted third party analyses will conform to 
the specific scope of analysis outlined in this sub-trial.  Future Biomedical Research 
specimens remaining with the third party after the specific analysis is performed will be 
returned to the sponsor or destroyed and documentation of destruction will be reported to 
Merck.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main 
trial are still available, the investigator will contact Merck using the designated mailbox 
 and a form will be provided by Merck to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. A letter 
will be sent from Merck to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from acquisition.  Specimens may be stored for longer if a 
regulatory or governmental authority has active questions that are being answered.  In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
 
 
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Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Merck designated biorepository.  The specimens will be stored under strict 
supervision in a limited access facility which operates to assure the integrity of the 
specimens.  Specimens will be destroyed according to Merck policies and procedures and 
this destruction will be documented in the biorepository database.
8. Data Security
Separate databases for specimen information and for results from the Future Biomedical 
Research sub-trial will be maintained by Merck.  This is done to separate the future 
exploratory test results (which include genetic data) from the clinical trial database 
thereby maintaining a separation of subject number and these results.  The separate 
databases are accessible only to the authorized Sponsor and the designated trial 
administrator research personnel and/or collaborators.  Database user authentication is 
highly secure, and is accomplished using network security policies and practices based in 
international standards (e.g., ISO17799) to protect against unauthorized access.  The 
Merck Entrusted Keyholder maintains control over access to all specimen data.  These 
data are collected for future biomedical research purposes only as specified in this sub-
trial will not be used for any other purpose.
9. Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
the trial participant.  Some guidelines advocate a proactive return of data in certain 
instances.  No information obtained from exploratory laboratory studies will be reported 
to the subject or family, and this information will not be entered into the clinical database 
maintained by Merck on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation and absence of good clinical practice standards in 
exploratory research typically used for diagnostic testing.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information as 
to how to offer clinical diagnostic  testing (paid for by Merck) to subjects enrolled and 
will be advised that counseling should be made available for all who choose to participate 
in this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, Merck will publish the results without revealing specific 
subject information, inform all trial sites who participated in the Merck clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for 
public access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
 
 
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10. Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on Merck clinical 
trials for future biomedical research.  When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens 
from subjects and controls to represent the ethnic and gender population representative of 
the disease under current investigation.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. Risks include 
those associated with venipuncture to obtain the whole blood specimen. This specimen 
will be obtained at the time of routine blood specimens drawn in the main trial. 
Merck has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, 
age, toxicities, etc.) to be re-associated to double coded specimens at the time of data 
analysis.  These subject data will be kept in a separate, secure Merck database, and all 
specimens will be stripped of subject identifiers.  No information concerning results 
obtained from future biomedical research will be entered into clinical records, nor will it 
be released to outside persons or agencies, in any way that could be tied to an individual 
subject.
12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.
13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
14. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff
 
 
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ECOG Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(e.g., light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% of 
waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair.
5
Dead.
* As published in Am J Clin Oncol:  Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET,
Carbone PP. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 
1982;5:649-55. Eastern Cooperative Oncology Group, Robert Comis MD, Group Chair.
 
 
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Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting
(http://ctep.cancer.gov/reporting/ctc.html).
 
 
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Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 Criteria for 
Evaluating Response in Solid Tumors
A modification to RECIST version 1.1* will be used in this study for patient management. 
While either CT or MRI may be used utilized, as per RECIST 1.1, CT is the preferred 
imaging technique in this study. Details are provided in the Image Acquisition Guidelines..
* As published in the European Journal of Cancer:
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. 
Lacombe, J. Verweij. New response evaluation criteria in solid tumours: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47.
 
 
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List of Abbreviations
Abbreviation/Term
Definition
1L
First line
AE
Adverse event
ADA
Anti-Drug Antibodies
ALT
Alanine aminotransferase
ALK
Anaplastic lymphoma kinase
ANC
Absolute neutrophil count
aPTT
Activated partial thromboplastin time
AUC
Area under curve
AST
Aspartate aminotransferase
β-HCG
Beta-human chorionic gonadotropin
BSC
Best supportive care
CBC
Complete blood count
CI
Confidence interval
CNS
Central nervous system
CR
Complete response
CrCl
Calculated creatinine clearance
CRF
Case report form
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Toxicity Criteria for Adverse Events
DLT
Dose limiting toxicity
DNA
Deoxyribonucleic acid
DMC
Data Monitoring Committee 
ECIs
Events of clinical interest
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EGFR
Epidermal growth factor receptor 
EMA
European Medicines Agency
ERC
Ethics review committee
FBR
Future Biomedical Research
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
Hb
Hemoglobin
HBV
Hepatitis B
HCV
Hepatitis C
HIV
Human immunodeficiency virus
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Conference on Harmonization
IHC
Immunohistochemistry
INR
International normalized ratio
irAEs
Immune-related adverse events
IRB
Institutional Review Board
ITT
Intent-to-treat 
IV
Intravenous
kg
Kilogram
LDH
Lactate dehydrogenase
mcL
Millimeters
MEL
Melanoma 
 
 
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Abbreviation/Term
Definition
MG
Milligram
mg/kg
Milligram per kilogram
MRI
Magnetic resonance imaging
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
MTD
Maximum tolerated dose
NA or N/A
Not applicable
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NHANES
National Health and Nutrition Examination Survey
NSCLC
Non-small cell lung cancer
ORR
Objective response rate
OS
Overall survival
OTC
Over-the-counter
PD
Progressive disease
PET
Positron emission tomography
PFS
Progression free survival
PFS2
Next line of therapy PFS2
PGt
Pharmacogenetic
PK
Pharmacokinetic
PK-PD
Pharmacokinetic-Pharmacodynamic
P
Protocol 
PRO
Patient reported outcome 
PR
Partial response
PT
Prothrombin time
Q2W
Every 2 weeks
Q3W
Every 3 weeks
Q-TWiST
Quality-adjusted Time without Symptoms or Toxicity 
RCC
Renal cell carcinoma 
RNA
Ribonucleic acid
RECIST
Response Evaluation Criteria in Solid Tumors Version 1.1
RR
Response rate
SAE
Serious adverse events
SAP
Statistical Analysis Plan
SFU
Survival follow-up
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SOC
Standard of care
TIL
Tumor-infiltrating lymphocytes
TKI
Tyrosine kinase inhibitors
TPS
Tumor proportion score
TSH
Thyroid stimulating hormone
TTP
Time to progression
ULN
Upper limit of normal
WHO
World Health Organization
wt
Wild type
 
 
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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 7.2 – 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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