Clinical trial NCT03515837
Conditions: Non-small Cell Lung Cancer
Keywords: PD1 PD-1 PDL1 PD-L1
Sponsor: Merck Sharp & Dohme LLC
Start date: 2018-06-29; Completion date: 2023-10-02
Enrollment: 492 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of pemetrexed plus platinum chemotherapy (carboplatin or cisplatin) with or without pembrolizumab (MK-3475; KEYTRUDA®) in the treatment of adults with the following types of tyrosine kinase inhibitor (TKI)-resistant, epidermal growth factor receptor (EGFR)-mutated, metastatic non-squamous non-small cell lung cancer (NSCLC) tumors: 1) TKI-failures (including osimertinib \[TAGRISSO®\] failure) with T790M-negative mutation tumors, 2) T790M-positive mutation tumors with prior exposure to osimertinib, and 3) first-line osimertinib failure regardless of T790M mutation status.

The primary study hypotheses are that the combination of pembrolizumab plus chemotherapy has superior efficacy compared to saline placebo plus chemotherapy in terms of: 1) Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) based on blinded independent central review, and 2) Overall Survival (OS). This study will be considered to have met its success criteria if the combination of pembrolizumab plus chemotherapy is superior to saline placebo plus chemotherapy in terms of PFS or OS.

Upon study completion, participants are discontinued and may be enrolled in a pembrolizumab extension study, if available.

Detailed description:

Arms: arm 1: Participants receive pembrolizumab (pembro) 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles PLUS pemetrexed 500 mg/m\^2 via IV infusion Q3W with no restrictions on the number of cycles PLUS platinum chemotherapy (chemo) (either carboplatin Area Under the Curve \[AUC\] 5 via IV infusion Q3W for 4 cycles \[Cycles 1-4\] or cisplatin 75 mg/m\^2 via IV infusion Q3W for 4 cycles \[Cycles 1-4\]). arm 2: Participants receive normal saline solution via IV infusion on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles PLUS pemetrexed 500 mg/m\^2 via IV infusion Q3W with no restrictions on the number of cycles PLUS platinum chemotherapy (chemo)(either carboplatin AUC 5 via IV infusion Q3W for 4 cycles \[Cycles 1-4\] or cisplatin 75 mg/m\^2 via IV infusion Q3W for 4 cycles \[Cycles 1-4\]).
Interventions: intervention 1: pembrolizumab intervention 2: pemetrexed intervention 3: carboplatin intervention 4: cisplatin intervention 5: saline solution
Intervention descriptions: intervention 1: IV infusion intervention 2: IV infusion intervention 3: IV infusion intervention 4: IV infusion intervention 5: IV infusion

Protocol documents:
Prot_SAP_001.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Randomized, Double-Blind, Phase 3 Study of Pemetrexed + Platinum 
Chemotherapy with or without Pembrolizumab (MK-3475) in TKI-
resistant EGFR-mutated Tumors in Metastatic Non-squamous Non-small 
Cell Lung Cancer (NSCLC) Participants (KEYNOTE-789)
NCT03515837 
24-July-2023


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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Randomized, Double-Blind, Phase 3 Study of Pemetrexed + Platinum 
Chemotherapy with or without Pembrolizumab (MK-3475) in TKI-resistant EGFR-mutated 
Tumors in Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC) Participants 
(KEYNOTE-789)
Protocol Number: 789-08
Compound Number: MK-3475
Sponsor Name and Legal Registered Address: 
Merck Sharp & Dohme LLC
(hereafter called the Sponsor or MSD)
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND NUMBER:   116,833
EudraCT NUMBER: 2017-004188-11 
Approval Date:  24 July 2023
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Trial 
File Binder (or equivalent). 
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
MK-3475-789-08
24-JUL-2023
Global amendment. To allow participants to rollover to the extension study (MK-3475-
587).
MK-3475-789-07
20-SEP-2022
Global amendment. To provide additional text to specify that IA3 will become the final 
analysis if the observed number of events at IA3 is too close to the target number of 
events at FA.
MK-3475-789-06
17-JUN-2021
Global amendment. To update the dose modification and toxicity management guidelines 
for immune-related adverse events (irAEs).
MK-3475-789-05
25-JAN-2021
Global amendment. The overall survival (OS) assumption of this protocol was based on 
the IMPRESS study, which comprised patients who failed only first-line gefitinib. In this 
population, the median OS was 19.5 months; however, a recent small retrospective study
showed a much lower median OS of 7.8 months in patients who failed osimertinib and 
switched to another therapy (primarily chemotherapy). Since KEYNOTE-789 includes a 
more heterogenous population, including those who failed first-line or second-line 
osimertinib or other first-line TKIs (if T790M-), the original assumption of OS will 
likely overestimate the survival in this study. Therefore, this amendment updates the OS 
design based on the characteristics of the population that was actually enrolled, changing
the control assumption of median OS from 19.5 months to 15 months. The number and 
timing of analyses has also been updated based on actual enrollment timing.
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Document
Date of Issue
Overall Rationale
MK-3475-789-04
23-MAR-2020
Global amendment. Based on better understanding of survival outcomes for this 
population, the initial hazard ratio (HR) assumption is likely to be too aggressive. To 
relax the HR for both OS and progression-free survival (PFS), and to maintain the same 
sample size, alpha allocation from objective response rate (ORR) needed to be 
redistributed. This amendment removes alpha from ORR and redistributes equally 
between PFS and OS, changes the assumption of the HR for PFS and OS from 0.65 to 
0.7, and from 0.7 to 0.72, respectively, and removes ORR-only interim analysis (IA)
reducing the number of IAs from 5 to 4. 
MK-3475-789-03
30-AUG-2018
Global amendment. To update the inclusion criteria regarding creatinine clearance in 
order to align with regulatory safety labeling for pemetrexed.
MK-3475-789-02
10-JUL-2018
Germany-specific amendment. Per the German Health Authority request, pregnancy 
testing must be conducted monthly, and testing for human immunodeficiency virus 
(HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) and tuberculosis (TB) at 
screening is required for residents of Germany.
MK-3475-789-01
16-MAY-2018
Sweden-specific amendment. Per the Swedish Health Authority request, the Health 
Authority must be notified in addition to the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) when the protocol is amended or terminated.
MK-3475-789-00
23-FEB-2018
Original protocol
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
1.1
Synopsis
Added text related to extension 
study enrollment.
To allow participants to 
rollover to the extension 
study (MK-3475-587).
'4.4
Beginning and End of the Trial
Added text related to extension 
study enrollment. 
To allow participants to 
rollover to the extension 
study (MK-3475-587) .
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
Throughout Document
Minor administrative, 
formatting, grammatical, and/or 
typographical changes were 
made throughout the document.
To ensure clarity and 
accurate interpretation of the 
intent of the protocol.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
SUMMARY OF CHANGES...................................................................................................5
1.
Protocol Summary .....................................................................................................16
Synopsis....................................................................................................................16
Schema .....................................................................................................................22
Schedule of Activities (SoA) ...................................................................................25
Schedule of Activities for Initial Treatment Phase..............................................25
Schedule of Activities for Crossover Treatment Phase .......................................40
Schedule of Activities for Second Course Retreatment Phase ............................47
2.
Introduction................................................................................................................50
Study Rationale .......................................................................................................50
PD1/PD-L1 Inhibitors in EGFR-mutant NSCLC ................................................52
Background..............................................................................................................53
Pharmaceutical and Therapeutic Background .....................................................53
Benefit/Risk Assessment.........................................................................................54
3.
Objectives/Hypotheses and Endpoints.....................................................................56
4.
Study Design...............................................................................................................58
Overall Design .........................................................................................................58
Scientific Rationale for Study Design....................................................................61
Rationale for Endpoints .......................................................................................61
Efficacy Endpoints........................................................................................61
RECIST 1.1............................................................................................62
Modified RECIST for Immune-based Therapeutics (iRECIST) ...........62
Safety Endpoints...........................................................................................62
Rationale for Patient Reported Outcomes.....................................................63
EORTC QLQ-C30 and EORTC QLQ-LC13.........................................63
EQ-5D-5L ..............................................................................................63
Planned Exploratory Biomarker Research....................................................63
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Future Biomedical Research.........................................................................65
Rationale for the Use of Comparator/Placebo .....................................................65
Justification for Dose ..............................................................................................66
Rationale for Pembrolizumab Dosing Regimen ..................................................66
Rationale for Chemotherapy Dosing Regimens...................................................67
Beginning and End of Study Definition ................................................................67
Clinical Criteria for Early Study Termination .....................................................67
5.
Study Population........................................................................................................67
Inclusion Criteria....................................................................................................68
Exclusion Criteria ...................................................................................................70
Lifestyle Considerations .........................................................................................73
Meals and Dietary Restrictions............................................................................73
Contraception.......................................................................................................73
Pregnancy.............................................................................................................73
Use in Nursing Women........................................................................................74
Screen Failures ........................................................................................................74
Participant Replacement Strategy.........................................................................74
6.
Treatments..................................................................................................................74
Treatments Administered.......................................................................................74
Preparation/Handling/Storage/Accountability ....................................................77
Dose Preparation..................................................................................................77
Handling, Storage and Accountability.................................................................78
Measures to Minimize Bias: Randomization and Blinding.................................78
Method of Treatment Assignment .......................................................................78
Stratification..................................................................................................79
Blinding................................................................................................................79
Treatment Compliance...........................................................................................79
Concomitant Therapy.............................................................................................79
Acceptable Concomitant Medications .................................................................79
Prohibited Concomitant Medications...................................................................80
Rescue Medications and Supportive Care ...........................................................81
Systemic Corticosteroid Use.........................................................................82
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Antiemetic Use..............................................................................................82
Colony-Stimulating Factors..........................................................................82
Pemetrexed Premedication............................................................................82
Cisplatin Premedication................................................................................83
Dose Modification (Escalation/Titration/Other)..................................................83
Dose Modification for Pembrolizumab............................................................84
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)..................................................................................................84
Dose Modification for Chemotherapy .................................................................91
Treatment After the End of the Study ..................................................................92
Clinical Supplies Disclosure...................................................................................92
7.
Discontinuation of Study Treatment and Participant Withdrawal ......................92
Discontinuation of Study Treatment.....................................................................92
Participant Withdrawal From the Study..............................................................94
Lost to Follow-up ....................................................................................................94
8.
Study Assessments and Procedures..........................................................................94
Administrative and General Procedures ..............................................................95
Informed Consent.................................................................................................95
General Informed Consent............................................................................95
Consent and Collection of Specimens for Future Biomedical 
Research........................................................................................................96
Inclusion/Exclusion Criteria ................................................................................96
Participant Identification Card.............................................................................96
Medical History ...................................................................................................96
Prior and Concomitant Medications Review .......................................................96
Prior Medications..........................................................................................96
Concomitant Medications.............................................................................97
Subsequent Anti-Cancer Therapy Status ......................................................97
Assignment of Screening Number.......................................................................97
Treatment Eligibility Assessment (TEA) Form............................................97
Assignment of Treatment/Randomization Number.............................................97
Treatment Administration....................................................................................98
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Timing of Dose Administration....................................................................98
Timing of Dose Administration of Pembrolizumab/Saline 
Placebo...................................................................................................98
Pemetrexed.............................................................................................99
Cisplatin.................................................................................................99
Carboplatin.............................................................................................99
Discontinuation and Withdrawal .........................................................................99
Withdrawal From Future Biomedical Research ...........................................99
Participant Blinding/Unblinding........................................................................100
Calibration of Equipment...................................................................................100
Efficacy Assessments.............................................................................................101
Tumor Imaging and Assessment of Disease......................................................101
Initial Tumor Imaging.................................................................................101
Tumor Imaging During the Study...............................................................102
End of Treatment and Follow-up Tumor Imaging......................................102
Second Course (Retreatment) and Crossover Tumor Imaging...................103
RECIST 1.1 Assessment of Disease...........................................................103
iRECIST Assessment of Disease................................................................104
Patient Reported Outcomes................................................................................106
Safety Assessments................................................................................................106
Physical Examinations.......................................................................................107
Vital Signs..........................................................................................................107
Electrocardiograms ............................................................................................107
Clinical Safety Laboratory Assessments............................................................107
Laboratory Safety Evaluations (Hematology, Chemistry, and 
Urinalysis)...................................................................................................108
Pregnancy Test............................................................................................108
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events .....................................................................................108
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ................................................................109
Method of Detecting AEs, SAEs, and Other Reportable Safety Events............111
Follow-up of AE, SAE and Other Reportable Safety Event Information..........111
Regulatory Reporting Requirements for SAE ...................................................111
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Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as AEs or SAEs................................................................................111
Pregnancy and Exposure During Breastfeeding ................................................112
Events of Clinical Interest (ECIs)......................................................................112
Treatment of Overdose.........................................................................................113
Pharmacokinetics..................................................................................................113
Pharmacodynamics...............................................................................................113
Biomarkers ............................................................................................................113
Future Biomedical Research Sample Collection................................................114
Medical Resource Utilization and Health Economics........................................114
Visit Requirements................................................................................................114
Screening............................................................................................................114
Initial Treatment Phase ......................................................................................115
Crossover Treatment Phase................................................................................115
Crossover Assessments and Procedures .....................................................116
Second Course Retreatment Phase.....................................................................116
Participants Discontinued From Study Intervention but Continuing to 
be Monitored in the Study..................................................................................117
Post-Study..........................................................................................................118
Safety Follow-up Visit................................................................................118
Follow-up Visits..........................................................................................118
Survival Follow-up Assessments................................................................118
Survival Status ...................................................................................................119
9.
Statistical Analysis Plan ..........................................................................................119
Statistical Analysis Plan Summary......................................................................120
Responsibility for Analyses/In-house Blinding...................................................122
Hypotheses/Estimation .........................................................................................122
Analysis Endpoints................................................................................................122
Efficacy Endpoints.............................................................................................122
Safety Endpoints ................................................................................................123
PRO Endpoints...................................................................................................123
Analysis Populations.............................................................................................123
Efficacy Analysis Populations ...........................................................................123
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Safety Analysis Populations ..............................................................................123
PRO Analysis Populations.................................................................................124
Statistical Methods................................................................................................124
Statistical Methods for Efficacy Analyses.........................................................124
Progression-free Survival (PFS) .................................................................124
Overall Survival (OS) .................................................................................126
Objective Response Rate (ORR) and Duration of Response (DOR)..........126
Analysis Strategy for Key Efficacy Endpoints...........................................127
Statistical Methods for Safety Analyses ............................................................128
Statistical Methods for PRO Analyses...............................................................130
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.............................................................................................................131
Demographic and Baseline Characteristics ................................................131
Interim Analyses ...................................................................................................131
Efficacy Interim Analyses..................................................................................131
Safety Interim Analyses.....................................................................................132
Multiplicity ............................................................................................................132
Objective Response Rate ...................................................................................133
Progression-Free Survival..................................................................................134
Overall Survival.................................................................................................135
Safety Analyses..................................................................................................136
Sample Size and Power Calculations ..................................................................137
Subgroup Analyses................................................................................................137
Extent of Exposure................................................................................................138
10.
Supporting Documentation and Operational Considerations.............................139
Appendix 1:  Regulatory, Ethical and Study Oversight Considerations .........139
Code of Conduct for Interventional Clinical Trials ...........................................139
Financial Disclosure...........................................................................................141
Data Protection...................................................................................................141
Confidentiality of Data ......................................................................................142
Confidentiality of Participant Records...............................................................142
Confidentiality of IRB/IEC Information............................................................142
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Committees Structure.........................................................................................142
Executive Oversight Committee.................................................................142
Data Monitoring Committee.......................................................................142
Publication Policy ..............................................................................................143
Compliance with Study Registration and Results Posting Requirements .........143
Compliance with Law, Audit, and Debarment ...........................................143
Data Quality Assurance ..............................................................................144
Source Documents......................................................................................145
Study and Site Closure................................................................................145
Appendix 2:  Collection and Management of Specimens for Future 
Biomedical Research.............................................................................................146
Appendix 3:  Contraceptive Guidance and Pregnancy Testing........................150
Definitions..........................................................................................................150
Contraception Requirements..............................................................................151
Pregnancy Testing..............................................................................................153
Appendix 4: Adverse Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting............................................154
Definition of AE ................................................................................................154
Definition of SAE ..............................................................................................155
Additional Events Reported in the Same Manner as SAE.................................156
Recording AE and SAE .....................................................................................156
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ..............................................................................................................160
Appendix 5:  Clinical Laboratory Tests..............................................................162
Appendix 6: Eastern Cooperative Oncology Group (ECOG) 
Performance Status...............................................................................................164
Appendix 7:  MASCC 2016 Guidelines...............................................................165
Appendix 8: Calculated Creatinine Clearance...................................................166
Appendix 9:  Abbreviations .................................................................................167
Appendix 10: Description of the iRECIST Process for Assessment of 
Disease Progression...............................................................................................171
Appendix 11: Common Terminology Criteria for Adverse Events 
V4.0 (CTCAE).......................................................................................................175
Appendix 12: Country-specific Requirements ...................................................176
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Sweden-specific Information......................................................................176
Germany-specific Information....................................................................177
Japan-specific Information .........................................................................177
11.
References.................................................................................................................179
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values......................................................70
Table 2
Study Treatment(s) ...............................................................................................75
Table 3
Dose Modifications for Study Medications..........................................................84
Table 4
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ....................................................................85
Table 5
Pembrolizumab Infusion Reaction Dose modification and Treatment 
Guidelines.............................................................................................................89
Table 6
Recommended Dose Modifications for Chemotherapy Hematological 
Toxicity.................................................................................................................91
Table 7
Recommended Dose Modifications for Chemotherapy Non-
Hematological Toxicity ........................................................................................91
Table 8
Imaging and Treatment after First Radiologic Evidence of Progressive 
Disease................................................................................................................105
Table 9
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events..........................................................................110
Table 10
Censoring Rules for Primary and Sensitivity Analyses of Progression-
free Survival........................................................................................................125
Table 11
Censoring Rules for DOR...................................................................................127
Table 12
Analysis Strategy for Key Efficacy Variables....................................................127
Table 13
Analysis Strategy for Safety Parameters ............................................................130
Table 14
Summary of Interim and Final Analyses Strategies ...........................................132
Table 15
Possible Alpha-levels and Approximate Objective Response Rate 
(ORR) Difference Required to Demonstrate Efficacy for ORR at 
Interim Analysis 1...............................................................................................134
Table 16
Efficacy Boundaries and Properties for Progression-free Survival 
Analyses..............................................................................................................134
Table 17
Efficacy Boundaries and Properties for Overall Survival Analyses...................136
Table 18
Highly Effective Contraception Methods...........................................................152
Table 19
Protocol-required Safety Laboratory Assessments.............................................162
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LIST OF FIGURES
Figure 1
Eligibility Diagram...............................................................................................22
Figure 2
Initial and Crossover Treatment Phases ...............................................................23
Figure 3
Initial/Crossover Treatment Phase – Progressive Disease Decision Flow 
Diagram ................................................................................................................24
Figure 4
Completion/Attainment of CR Decision Flow Diagram ......................................24
Figure 5
Imaging and Treatment for Clinically Stable Participants After First 
Radiologic Evidence of PD Assessed by the Investigator..................................106
Figure 6
Type I Error Reallocation Strategy.....................................................................133
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1. Protocol Summary
Synopsis
Protocol Title:
A Randomized, Double-Blind, Phase 3 Study of Pemetrexed + Platinum Chemotherapy 
with or without Pembrolizumab (MK-3475) in TKI-resistant EGFR-mutated Tumors in 
Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC) Participants 
(KEYNOTE-789)
Short Title:
Phase 3 Study of Pemetrexed + Platinum Chemotherapy with or without Pembrolizumab 
(MK-3475) in TKI-resistant EGFR-mutated Tumors in Metastatic Non-Squamous NSCLC
Objectives/Hypotheses and Endpoints:
In adult participants with TKI-resistant epidermal growth factor receptor (EGFR)-mutated
tumors in metastatic non-squamous NSCLC:
Objective/Hypothesis
Endpoint
Primary
Objective: To compare PFS per 
Response Evaluation Criteria in Solid 
Tumors 1.1 (RECIST 1.1) based on 
blinded independent central review 
(BICR) of the combinations of 
pembrolizumab + chemotherapy versus 
saline placebo + chemotherapy.
Hypothesis (H1): The combination 
of pembrolizumab + chemotherapy 
has superior PFS per RECIST 1.1 
based on BICR compared to saline 
placebo + chemotherapy
Progression-free survival (PFS) is the time 
from randomization to the first documented 
progressive disease (PD) or death due to 
any cause, whichever occurs first.
Objective: To compare overall survival 
(OS) of the combinations of 
pembrolizumab + chemotherapy versus 
saline placebo + chemotherapy.
Hypothesis (H2): The combination 
of pembrolizumab + chemotherapy 
has superior OS compared to saline 
placebo + chemotherapy.
OS is defined as the time from 
randomization to death due to any cause.
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This study will be considered to have met its success criteria if the combination of 
pembrolizumab + chemotherapy is superior to saline placebo + chemotherapy in PFS or 
OS.
Secondary
Objective: To compare objective 
response rate (ORR) per RECIST 1.1 
based on BICR of the combinations of 
pembrolizumab + chemotherapy versus 
saline placebo + chemotherapy.
Hypothesis (H3): The combination 
of pembrolizumab + chemotherapy 
has superior ORR per RECIST 1.1 
based on BICR compared to saline 
placebo + chemotherapy.

Objective response is a confirmed 
complete response (CR) or partial 
response (PR).
Objective: To evaluate duration of 
response (DOR) of the combinations of 
pembrolizumab + chemotherapy versus 
saline placebo + chemotherapy.

DOR is defined as the time from the 
earliest date of qualifying response until 
earliest date of disease progression or 
death from any cause, whichever comes 
first, per RECIST 1.1 based on BICR.
Objective: To evaluate the patient 
reported outcomes (PROs) mean score 
changes from baseline in global health 
status and quality of life scale between 
pembrolizumab + chemotherapy versus 
saline placebo + chemotherapy.

European Organization for Research and 
Treatment of Cancer (EORTC) Quality of 
Life Questionnaire-Core 30 items (QLQ-
C30) global health status (item 29) and 
quality of life scale (item 30).
Objective: To evaluate the PROs time 
to true deterioration (TTD) in the 
composite endpoint of cough, chest 
pain or dyspnea between 
pembrolizumab + chemotherapy versus 
saline placebo + chemotherapy.

TTD is the time from baseline to first 
onset of 10 points or more deterioration
from baseline with confirmation by the 
subsequent visit of 10 points or more 
deterioration from baseline of the 
composite endpoint of cough [EORTC 
QLQ-Lung Cancer Module 13 (LC13) 
item 1], chest pain [EORTC QLQ-LC13 
item 10], or dyspnea [EORTC QLQ-
LC30 item 8]. 
Objective: To evaluate the safety and 
tolerability of the combination of 
pembrolizumab + chemotherapy and 
saline placebo + chemotherapy.

Adverse events (AEs) and study drug 
discontinuation due to AEs.
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Overall Design:
Study Phase
Phase 3
Clinical Indication
Treatment of Metastatic Non-squamous Non-small Cell Lung 
Cancer
Population
Adult participants with TKI-resistant EGFR-mutated tumors in 
metastatic non-squamous NSCLC including:

TKI-failures (including osimertinib failure) with 
T790M-negative mutation tumors

T790M-positive mutation tumors with prior exposure 
to osimertinib

First-line osimertinib failure regardless of T790M 
mutation status
Study Type
Interventional
Type of Design
Randomized, active-control with placebo, parallel-group, 
multi-site, double-blind
Type of Control
Active control with placebo
Study Blinding
Double-blind
Estimated Duration 
of Study
The Sponsor estimates that the study will require 
approximately 7 years from the time the first participant 
provides documented informed consent until the last 
participant’s last study-related contact. 
Number of Participants:
Approximately 492 participants will be randomized.
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Treatment Groups and Duration:
Treatment Groups
There are 2 treatment arms:

Arm 1: Pembrolizumab (MK-3475) plus pemetrexed plus 
carboplatin or cisplatin

Arm 2: Saline placebo plus pemetrexed plus carboplatin 
or cisplatin
Duration of 
Participation
Each participant will participate in the study from the time the 
participant provides documented informed consent through the 
final protocol-specified contact.  
After a screening phase of up to 42 days, each eligible 
participant will be assigned to receive study treatment until 
reaching a discontinuation criterion (Section 7.1), examples of 
which include: disease progression is radiographically 
documented and verified by blinded independent central review 
(BICR), when clinically appropriate, confirmed by the site per 
modified Response Evaluation Criteria in Solid Tumors 1.1 for 
immune-based therapeutics (iRECIST), unacceptable adverse 
event(s) (AEs), intercurrent illness that prevents further 
administration of treatment, investigator’s decision to withdraw 
the participant, participant withdraws consent, pregnancy of 
participant, noncompliance with study treatment or procedure 
requirements or administrative reasons requiring cessation of 
treatment, or until the participant has received 35 administrations 
of pembrolizumab/saline placebo (approximately 2 years). 
Maintenance pemetrexed may continue for participants past 35 
cycles until reaching a discontinuation criterion (Section 7.1), as 
long as the participant is receiving benefit and per local 
regulations, whereas pembrolizumab/saline placebo are limited 
to 35 cycles.
At the time of documented disease progression as confirmed by 
BICR using RECIST 1.1 (Section 8.2.1), participants may have 
treatment assignment unblinded (Figure 3). Participants who 
received saline placebo in combination with chemotherapy per 
their randomized treatment assignment may be eligible to 
receive pembrolizumab monotherapy for a total of 35 
administrations in the Crossover Treatment Phase (Section 
8.11.3). Tumor imaging is to be re-baselined and RECIST 1.1 
criteria used for participant assessments (Sections 8.2.1.4 and 
8.2.1.5).
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Participants who received pembrolizumab in combination with 
chemotherapy, but are deemed to be benefiting clinically despite 
disease progression, may continue study treatment beyond 
progression and receive pembrolizumab monotherapy in the 
Crossover Treatment Phase (Section 8.11.3) to complete a total 
of up to 35 pembrolizumab administrations. Repeat imaging 
should occur at appropriate intervals per iRECIST criteria 
(Sections 8.2.1 and 10.10) until iRECIST confirmed PD (iCPD)
is established. 
Study treatment may continue until reaching a discontinuation 
criterion (Section 7.1).
Alternatively, participants may have treatment assignment 
remain blinded at the time of BICR-verified progression and 
may continue receiving the study treatment per their randomized 
treatment assignment as long as they continue to be clinically 
stable (Figure 3). 
Blinded study treatment can continue beyond verified 
progression at the Investigator’s discretion. Repeat imaging 
should occur at appropriate intervals per iRECIST criteria 
(Sections 8.2.1 and 10.10) until iCPD is established. Once iCPD 
is established, the participant may then have treatment 
assignment unblinded, but may not continue study treatment in 
the Crossover Treatment Phase (Section 8.11.3) as described 
above.
Participants on the pembrolizumab plus chemotherapy arm who 
have been on study treatment for ≥ 6 months and who attain a 
complete response (CR) may consider stopping study treatment. 
These participants, as well as those who stop study treatment 
after receiving 35 administrations of pembrolizumab for reasons 
other than disease progression or intolerability, may be eligible 
for up to 17 additional administrations of open-label 
pembrolizumab monotherapy (approximately 1 year) in the 
Second Course Retreatment Phase upon experiencing 
subsequent disease progression (Section 8.2.1). Second Course 
Retreatment Phase is at the discretion of the investigator 
according to the criteria in Section 8.11.4.
After the end of study treatment, each participant will be 
followed for a minimum of 30 days for the occurrence of AEs 
and for 120 days for spontaneously reported pregnancy, as 
described in Section 8.4. Serious adverse events will be collected 
for up to 90 days following cessation of the study treatment or 
30 days following the cessation of treatment if the participant 
initiates new anti-cancer therapy.
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Participants who complete the protocol-required cycles of study 
intervention or who discontinue for reasons other than 
radiographic disease progression will have post-treatment 
follow-up imaging for disease status until disease progression is 
documented radiographically per RECIST 1.1 and verified by 
BICR, the start of new anti-cancer treatment, pregnancy, 
participant withdraws consent, participant becomes lost to 
follow-up, participant death, or the end of the study. 
The Sponsor may request survival status to be assessed at 
additional time points and entered into the database during the 
course of the study. For example, survival status may be 
requested prior to, but not limited to, an external Data 
Monitoring Committee (eDMC) review.
All participants will be followed for overall survival until death, 
withdrawal of consent, or the end of the study. Survival status 
can be done in a variety of ways including phone, email, chart 
review, or review of public records. Survival status information 
(whether by telephone, review of public records, etc.) should be 
officially documented by the site. Upon study completion, 
participants are discontinued and may be enrolled in a 
pembrolizumab extension study, if available. 
Study Governance:
Study Governance 
Committees
Committee
Included in this study?
Steering Committee
N
Executive 
Oversight 
Committee
Y
Data Monitoring Committee
Y
Clinical 
Adjudication 
Committee
N
Study governance considerations are outlined in Section 
10.1.
A list of abbreviations used in this document can be found in Section 10.9.
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Schema
The Study Eligibility Diagram is depicted in Figure 1, Initial and Crossover Treatment 
Phases is depicted in Figure 2, Initial Treatment Phase – Progressive Disease Decision Flow 
Diagram is depicted in Figure 3. Completion/Attainment of CR Decision Flow Diagram is 
depicted in Figure 4.
Figure 1
Eligibility Diagram
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Figure 2
Initial and Crossover Treatment Phases
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Figure 3
Initial/Crossover Treatment Phase – Progressive Disease Decision Flow Diagram
Figure 4
Completion/Attainment of CR Decision Flow Diagram
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Schedule of Activities (SoA)
Schedule of Activities for Initial Treatment Phase
Details regarding the procedures listed in this table are outlined in Section 8. 
Study Period
Screening 
Phase
Treatment Cycles  (3-Week Cycles)
End of 
Treatment
(EOT)
Post Treatment Visits
Notes
Treatment Cycle
Screening 
(Visit 1)
1
2
3
4
5
6 to 
17
18 to 
35
36+
Discon
Safety 
Follow-
up1
Follow-
up2
Survival 
Follow-up
Scheduling Window
(Days):
-42 
to -1
-28 
to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At Time of 
Discon (+3)
30 Days 
Post 
Discon
(+14)
Every 
12 
Weeks    
(±7)
Every 12 
Weeks
(±14)
Administrative Procedures
Informed Consent Form 
(ICF) 3
X
ICF for Future Biomedical 
Research (FRB) (optional)
X
Documented 
informed 
consent for 
FBR is 
optional and is 
not required to 
participate in 
the study
Inclusion/Exclusion 
Criteria
X
Participant ID Card
X
Demographics and Medical 
History
X
Prior/Concomitant Meds
X
X
X
X
X
X
X
X
X
X
X
X4
Record all 
concomitant 
medications 
received within 
28 days before 
the first dose of 
study treatment
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Study Period
Screening 
Phase
Treatment Cycles  (3-Week Cycles)
End of 
Treatment
(EOT)
Post Treatment Visits
Notes
Treatment Cycle
Screening 
(Visit 1)
1
2
3
4
5
6 to 
17
18 to 
35
36+
Discon
Safety 
Follow-
up1
Follow-
up2
Survival 
Follow-up
Scheduling Window
(Days):
-42 
to -1
-28 
to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At Time of 
Discon (+3)
30 Days 
Post 
Discon
(+14)
Every 
12 
Weeks    
(±7)
Every 12 
Weeks
(±14)
NSCLC Disease Details 
and Prior Treatment
X
Treatment Eligibility 
Assessment (TEA)
X
The 
investigator 
must complete 
this form to 
document the 
rationale for 
the choice of 
carboplatin or 
cisplatin prior 
to 
randomization.
Obtain randomization 
number using IRT
X
Subsequent Anti-neoplastic 
Therapy Status
X
X
X
X
If participant 
discontinues 
study treatment 
for any reason 
other than PD, 
imaging should 
continue to be 
collected and 
sent to the 
central imaging 
vendor for 
possible 
retrospective 
review
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Study Period
Screening 
Phase
Treatment Cycles  (3-Week Cycles)
End of 
Treatment
(EOT)
Post Treatment Visits
Notes
Treatment Cycle
Screening 
(Visit 1)
1
2
3
4
5
6 to 
17
18 to 
35
36+
Discon
Safety 
Follow-
up1
Follow-
up2
Survival 
Follow-up
Scheduling Window
(Days):
-42 
to -1
-28 
to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At Time of 
Discon (+3)
30 Days 
Post 
Discon
(+14)
Every 
12 
Weeks    
(±7)
Every 12 
Weeks
(±14)
Survival Status
X
Upon Sponsor 
request, 
participants 
may be 
contacted for 
survival status 
at any time 
during the 
course of the 
study.
Clinical Procedures / Assessments
Review Adverse Events 
X
X
X
X
X
X
X
X
X
X
X
X
Report non-
serious AEs 
occurring 
within 30 days 
after the last 
dose of study 
treatment.
Report SAEs 
occurring 
within 90 days 
after the last 
dose of study 
treatment, or 
30 days after 
the last dose of 
study treatment 
if a new anti-
cancer therapy 
is initiated.
Full Physical Examination
X
X
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Study Period
Screening 
Phase
Treatment Cycles  (3-Week Cycles)
End of 
Treatment
(EOT)
Post Treatment Visits
Notes
Treatment Cycle
Screening 
(Visit 1)
1
2
3
4
5
6 to 
17
18 to 
35
36+
Discon
Safety 
Follow-
up1
Follow-
up2
Survival 
Follow-up
Scheduling Window
(Days):
-42 
to -1
-28 
to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At Time of 
Discon (+3)
30 Days 
Post 
Discon
(+14)
Every 
12 
Weeks    
(±7)
Every 12 
Weeks
(±14)
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
Vital Signs, Height, and 
Weight
X
X
X
X
X
X
X
X
X
X
X
Height at 
Screening only. 
BSA 
calculations 
required for 
chemo dosing.
12-Lead ECG
X
X
ECOG Performance Status
X
X5
X
X
X
X
X
X
X
X
X
At Screening, 
perform within 
7 days prior to 
first dose of 
study treatment 
but before 
randomization.
To be assessed 
prior to dosing 
at each cycle 
(Section 10.6)
Laboratory Procedures / Assessments: Analysis Performed by Local Laboratory
Pregnancy Test – Highly 
Sensitive Urine or Serum 
HCG
X
X
WOCBP 
require negative 
test within 72 
hours prior to 
Cycle 1. Test 
monthly if 
required by 
local 
regulations.
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Study Period
Screening 
Phase
Treatment Cycles  (3-Week Cycles)
End of 
Treatment
(EOT)
Post Treatment Visits
Notes
Treatment Cycle
Screening 
(Visit 1)
1
2
3
4
5
6 to 
17
18 to 
35
36+
Discon
Safety 
Follow-
up1
Follow-
up2
Survival 
Follow-up
Scheduling Window
(Days):
-42 
to -1
-28 
to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At Time of 
Discon (+3)
30 Days 
Post 
Discon
(+14)
Every 
12 
Weeks    
(±7)
Every 12 
Weeks
(±14)
Hepatitis B & C Serology
X
Testing for 
Hepatitis B and 
Hepatitis C is 
not required 
unless 
mandated by 
local health 
authority.
Refer to 
Section 10.12
for country-
specific 
requirements.
Hepatitis B 
surface 
antigen, HBV-
DNA, HCV-
RNA (or HCV 
antibody if 
HCV-RNA is 
not the local 
SOC). 
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Study Period
Screening 
Phase
Treatment Cycles  (3-Week Cycles)
End of 
Treatment
(EOT)
Post Treatment Visits
Notes
Treatment Cycle
Screening 
(Visit 1)
1
2
3
4
5
6 to 
17
18 to 
35
36+
Discon
Safety 
Follow-
up1
Follow-
up2
Survival 
Follow-up
Scheduling Window
(Days):
-42 
to -1
-28 
to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At Time of 
Discon (+3)
30 Days 
Post 
Discon
(+14)
Every 
12 
Weeks    
(±7)
Every 12 
Weeks
(±14)
HIV testing
X
Testing for 
HIV is not 
required unless 
mandated by 
local health 
authority.
Refer to 
Section 10.12 
for country-
specific 
requirements.
PT/INR and aPTT/PTT
X
Perform 
eligibility labs 
within 10 days 
prior to Cycle 1.
PT/INR and 
aPTT/PTT to be 
tested at 
Screening for all 
participants. 
Any participant 
receiving 
anticoagulant 
therapy should 
have 
coagulation 
factors 
monitored 
closely 
throughout the 
study.
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Study Period
Screening 
Phase
Treatment Cycles  (3-Week Cycles)
End of 
Treatment
(EOT)
Post Treatment Visits
Notes
Treatment Cycle
Screening 
(Visit 1)
1
2
3
4
5
6 to 
17
18 to 
35
36+
Discon
Safety 
Follow-
up1
Follow-
up2
Survival 
Follow-up
Scheduling Window
(Days):
-42 
to -1
-28 
to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At Time of 
Discon (+3)
30 Days 
Post 
Discon
(+14)
Every 
12 
Weeks    
(±7)
Every 12 
Weeks
(±14)
Hematology: CBC with 
Differential
X
X
X
X
X
X
X
X
X
X
Perform 
eligibility labs 
within 10 days 
prior to Cycle 
1. After Cycle 
1, may collect 
up to 3 days 
prior to dosing.
Chemistry Panel
X
X
X
X
X
X
X
X
X
X
Creatinine Clearance 
Calculation
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
Perform within 
10 days prior 
to Cycle 1, 
then every 2nd
cycle through 
Cycle 6, then 
every 6th cycle 
thereafter 
(Cycles 2, 4, 6, 
12, 18, etc.).
After Cycle 1, 
may collect up 
to 3 days prior 
to dosing.
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Study Period
Screening 
Phase
Treatment Cycles  (3-Week Cycles)
End of 
Treatment
(EOT)
Post Treatment Visits
Notes
Treatment Cycle
Screening 
(Visit 1)
1
2
3
4
5
6 to 
17
18 to 
35
36+
Discon
Safety 
Follow-
up1
Follow-
up2
Survival 
Follow-up
Scheduling Window
(Days):
-42 
to -1
-28 
to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At Time of 
Discon (+3)
30 Days 
Post 
Discon
(+14)
Every 
12 
Weeks    
(±7)
Every 12 
Weeks
(±14)
T3/FT3, FT4, and TSH
X
X
X
X
X
X
X
X
Perform within 
10 days prior 
to Cycle 1, 
then every 2nd
cycle (Cycles 
2, 4, 6, 8, etc.). 
May use
central lab only 
if local lab is 
not capable.
After Cycle 1, 
may collect up 
to 3 days prior 
to dosing.
Analysis Performed by Central 
Laboratory
Blood for Genetics 
Analysis
X
Collect pre-
dose. Do not 
collect if a 
documented 
law or 
regulation 
prohibits or 
local IRB/IEC 
does not 
approve.
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Study Period
Screening 
Phase
Treatment Cycles  (3-Week Cycles)
End of 
Treatment
(EOT)
Post Treatment Visits
Notes
Treatment Cycle
Screening 
(Visit 1)
1
2
3
4
5
6 to 
17
18 to 
35
36+
Discon
Safety 
Follow-
up1
Follow-
up2
Survival 
Follow-up
Scheduling Window
(Days):
-42 
to -1
-28 
to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At Time of 
Discon (+3)
30 Days 
Post 
Discon
(+14)
Every 
12 
Weeks    
(±7)
Every 12 
Weeks
(±14)
Blood for RNA Analysis
X
X
X
Collect pre-
dose
Blood for ctDNA Analysis
X
Blood for Serum/Plasma 
Biomarker Analysis
X
Tumor Tissue Collection
Newly Obtained or 
Archival  Tissue for PD-L1 
Analysis
X
May use an 
archival tissue
sample that 
was obtained 
prior to 
screening 
period as part 
of the 
participant’s 
standard care.
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Study Period
Screening 
Phase
Treatment Cycles  (3-Week Cycles)
End of 
Treatment
(EOT)
Post Treatment Visits
Notes
Treatment Cycle
Screening 
(Visit 1)
1
2
3
4
5
6 to 
17
18 to 
35
36+
Discon
Safety 
Follow-
up1
Follow-
up2
Survival 
Follow-up
Scheduling Window
(Days):
-42 
to -1
-28 
to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At Time of 
Discon (+3)
30 Days 
Post 
Discon
(+14)
Every 
12 
Weeks    
(±7)
Every 12 
Weeks
(±14)
Tissue/Plasma Collection 
after 1st disease 
progression for T790M 
Molecular Status
X
May send 
tumor tissue to 
central lab for 
T790M testing 
if status is 
unknown and 
cannot be 
determined 
locally.
Participants
with negative 
T790M mutati
on using 
plasma 
specimens will 
be required to 
have tissue 
biopsy
confirmation of 
negative 
T790M 
mutation prior 
to enrollment.
Participants 
with osimertinib 
treatment as 1st
line therapy are 
not required to 
have T790M 
status.
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Study Period
Screening 
Phase
Treatment Cycles  (3-Week Cycles)
End of 
Treatment
(EOT)
Post Treatment Visits
Notes
Treatment Cycle
Screening 
(Visit 1)
1
2
3
4
5
6 to 
17
18 to 
35
36+
Discon
Safety 
Follow-
up1
Follow-
up2
Survival 
Follow-up
Scheduling Window
(Days):
-42 
to -1
-28 
to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At Time of 
Discon (+3)
30 Days 
Post 
Discon
(+14)
Every 
12 
Weeks    
(±7)
Every 12 
Weeks
(±14)
Efficacy Measurements
Submission of Pre-trial 
Tumor Imaging
X
The site’s study 
team must have 
reviewed pre-trial 
images that are of 
diagnostic quality 
from at least 2 
dates to determine 
that radiographic 
progression has 
occurred per 
RECIST 1.1 
following 
initiation of the 
EGFR TKI. The 
central imaging 
vendor must have
received these 
scans and have 
confirmed that 
they are of 
acceptable 
diagnostic quality 
prior to 
randomization in 
this trial for a 
possible 
retrospective 
analysis of this 
eligibility 
criterion. The 
central vendor will 
not be confirming 
eligibility prior to
randomization.
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Study Period
Screening 
Phase
Treatment Cycles  (3-Week Cycles)
End of 
Treatment
(EOT)
Post Treatment Visits
Notes
Treatment Cycle
Screening 
(Visit 1)
1
2
3
4
5
6 to 
17
18 to 
35
36+
Discon
Safety 
Follow-
up1
Follow-
up2
Survival 
Follow-up
Scheduling Window
(Days):
-42 
to -1
-28 
to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At Time of 
Discon (+3)
30 Days 
Post 
Discon
(+14)
Every 
12 
Weeks    
(±7)
Every 12 
Weeks
(±14)
Tumor Imaging
X
X
X
X
X
X
X6
X6
Perform imaging at 
Baseline, and 6 
weeks after 
randomization, then 
Q9W through 51
weeks, and Q12W 
after randomization 
subsequently (all 
imaging after 
baseline has a ±7 
day window). 
Schedule should be 
followed regardless 
of treatment delays.
If participant 
discontinues study 
treatment for any 
reason other than 
PD, imaging should 
continue to be 
collected and sent 
to the central 
imaging vendor for 
possible retro-
spective review
If participant 
discontinues study 
treatment for PD, 
and imaging was 
obtained within 4 
weeks prior to DC, 
then a new scan at 
DC is not 
mandatory.
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Confidential
Study Period
Screening 
Phase
Treatment Cycles  (3-Week Cycles)
End of 
Treatment
(EOT)
Post Treatment Visits
Notes
Treatment Cycle
Screening 
(Visit 1)
1
2
3
4
5
6 to 
17
18 to 
35
36+
Discon
Safety 
Follow-
up1
Follow-
up2
Survival 
Follow-up
Scheduling Window
(Days):
-42 
to -1
-28 
to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At Time of 
Discon (+3)
30 Days 
Post 
Discon
(+14)
Every 
12 
Weeks    
(±7)
Every 12 
Weeks
(±14)
Brain MRI
X
Study Drug Administration – Per Randomized Assignment
Pembrolizumab (MK-3475) 
or Saline Placebo
X
X
X
X
X
X
X
Pemetrexed
X
X
X
X
X
X
X
X
Premedication 
should also be 
dosed per the 
approved 
product labels 
and as 
described in 
Section 6.5.3.
Carboplatin or Cisplatin
X
X
X
X
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Study Period
Screening 
Phase
Treatment Cycles  (3-Week Cycles)
End of 
Treatment
(EOT)
Post Treatment Visits
Notes
Treatment Cycle
Screening 
(Visit 1)
1
2
3
4
5
6 to 
17
18 to 
35
36+
Discon
Safety 
Follow-
up1
Follow-
up2
Survival 
Follow-up
Scheduling Window
(Days):
-42 
to -1
-28 
to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At Time of 
Discon (+3)
30 Days 
Post 
Discon
(+14)
Every 
12 
Weeks    
(±7)
Every 12 
Weeks
(±14)
Patient Reported Outcomes (PROs)
EQ-5D-5L
X
X
X
X
X
X
X
X
X
Perform every 
cycle through 
Cycle 7, then 
every 3rd cycle 
through Cycle 
19, then every 
4th cycle through 
Cycle 35 (eg, 
Cycles 1-7, 10, 
13, 16, 19, 23, 
27, 31 and 35.). 
PROs will also 
be obtained at the 
Treatment 
Discontinuation 
visit and 30-day 
Safety Follow-up 
visit. If the 
Treatment 
Discontinuation 
visit occurs 30 
days from the 
last dose of study 
treatment, at the 
time of the 
mandatory Safety 
Follow-up visit, 
PROs do not 
need to be 
repeated. 
Perform ePROs 
in the order listed 
in the SoA (EQ-
5D-5L first).
EORTC QLQ-C30
X
X
X
X
X
X
X
X
X
EORTC QLQ-LC13
X
X
X
X
X
X
X
X
X
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Protocol/Amendment No.: 789-08
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Study Period
Screening 
Phase
Treatment Cycles  (3-Week Cycles)
End of 
Treatment
(EOT)
Post Treatment Visits
Notes
Treatment Cycle
Screening 
(Visit 1)
1
2
3
4
5
6 to 
17
18 to 
35
36+
Discon
Safety 
Follow-
up1
Follow-
up2
Survival 
Follow-up
Scheduling Window
(Days):
-42 
to -1
-28 
to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At Time of 
Discon (+3)
30 Days 
Post 
Discon
(+14)
Every 
12 
Weeks    
(±7)
Every 12 
Weeks
(±14)
Notes: 
1. If Discontinuation visit occurs ≥30 days from last dose of study treatment, a Safety Follow-up Visit is not required.
2. Follow-Up visits may be scheduled to coincide with Follow-Up imaging (eg, 12 weeks from last imaging time point).
3. Informed consent must be obtained prior to sending any of the following: (a) plasma/tumor tissue samples to the central lab for PD-L1/EGFR T790M testing; (b) pretrial tumor 
imaging to the central imaging vendor for confirmation of diagnostic quality 
4. After the Safety Follow-up Visit, record all medications taken for SAEs and ECIs as defined in Section 10.4.
5. Does not have to be done if Screening ECOG was performed within 3 days prior to first dose of study treatment in Cycle 1.
6. For participants discontinuing for reasons other than BICR-verified PD, follow-up visits and imaging continue until BICR-verified PD (these images should continue to be sent 
to the central imaging vendor), the start of new anti-cancer treatment, withdrawing consent, or becoming lost to follow-up. Participants discontinuing treatment with BICR-
verified PD proceed directly to survival follow-up or Crossover Treatment Phase, if applicable. Follow-up Visits may be scheduled to coincide with Follow-up imaging (eg, 9 
weeks from last imaging time point through Week 51 or 12 weeks from last imaging if after Week 51).
Abbreviations: AE=adverse event; aPTT=activated partial thromboplastin time; BICR=blinded independent central (imaging) review; BSA=body surface area; CBC=complete 
blood count; ctDNA=circulating tumor deoxyribonucleic acid; CXDX=Cycle X Day X; d=days; DC/Discon=discontinuation; DNA = deoxyribonucleic acid; 
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EORTC=European Organisation for Research and Treatment of Cancer; EOT=end of treatment; 
ePRO=electronic patient reported outcome; EQ-5D-5L=EuroQol 5-dimension, 5-level Questionnaire; FRB=future biomedical research; FT4= free thyroxine; H/hr=hours; 
HBV/HCV=hepatitis B/C virus; HCG=human chorionic gonadotropin; HIV=human immunodeficiency virus; ICF=informed consent form; ID=identification; INR=international 
normalized ratio; IRB/IEC= Institutional Review Board/Independent Ethics Committee; min=minutes; IRT=interactive response technology; MRI=magnetic resonance imaging;
NSCLC=non-small cell lung cancer; PD=progressive disease; PD-L1=programmed cell death ligand 1; PRO=patient-reported outcome; PT=prothrombin time; PTT=partial 
thromboplastin time; Q=every; QLQ-C30=Quality of Life Questionnaire Core 30; QLQ-LC13=Quality of Life Questionnaire and Lung Cancer Module 13; RNA=ribonucleic acid; 
SAE=serious adverse event; SoA=schedule of activities; T3/FT3= free or total triiodothyronine; TSH= thyroid stimulating hormone; V=visit; W=weeks; WOCBP=woman of 
child-bearing potential.
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Schedule of Activities for Crossover Treatment Phase
Only applicable for participants that have BICR-verified progressive disease and are qualified for the Crossover Phase. Details 
regarding the procedures listed in this table are outlined in Section 8. 
Study Period
Treatment Cycles  (3-Week Cycles)
EOT
Post Treatment Visits
Notes
Treatment Cycle
1
2
3
4
5
6
7
8
9
10
11
12
13
14 
thru
35
Discon
Safety 
Follow-
up1
Follow-
up2
Survival 
Follow-
up
Scheduling 
Window (Days):
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At 
Time 
of 
Discon 
(+3)
30 Days 
Post 
Discon 
(+14)
Every 12 
Weeks     
(±7)
Every 12 
Weeks 
(±14)
Administrative Procedures
Eligibility Criteria
X
Prior/Concomitant 
Meds
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X3
Subsequent Anti-
neoplastic Therapy 
Status
X
X
X
X
Survival Status
X
Upon Sponsor 
request, 
participants 
may be 
contacted for 
survival status 
at any time 
during the 
course of the 
study.
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Protocol/Amendment No.: 789-08
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Study Period
Treatment Cycles  (3-Week Cycles)
EOT
Post Treatment Visits
Notes
Treatment Cycle
1
2
3
4
5
6
7
8
9
10
11
12
13
14 
thru
35
Discon
Safety 
Follow-
up1
Follow-
up2
Survival 
Follow-
up
Scheduling 
Window (Days):
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At 
Time 
of 
Discon 
(+3)
30 Days 
Post 
Discon 
(+14)
Every 12 
Weeks     
(±7)
Every 12 
Weeks 
(±14)
Clinical Procedures/Assessments
Review Adverse 
Events 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Report non-
serious AEs 
occurring 
within 30 days 
after the last 
dose of study 
treatment.
Report SAEs 
occurring 
within 90 days 
after the last 
dose of study 
treatment, or 
30 days after 
the last dose of 
study treatment 
if a new anti-
cancer therapy 
is initiated.
Full Physical 
Examination
X
X
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs and 
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
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Protocol/Amendment No.: 789-08
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Study Period
Treatment Cycles  (3-Week Cycles)
EOT
Post Treatment Visits
Notes
Treatment Cycle
1
2
3
4
5
6
7
8
9
10
11
12
13
14 
thru
35
Discon
Safety 
Follow-
up1
Follow-
up2
Survival 
Follow-
up
Scheduling 
Window (Days):
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At 
Time 
of 
Discon 
(+3)
30 Days 
Post 
Discon 
(+14)
Every 12 
Weeks     
(±7)
Every 12 
Weeks 
(±14)
ECOG Performance 
Status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
To be assessed 
prior to dosing 
at each cycle
(Section 10.6).
Laboratory Procedures / Assessments: Analysis Performed by Local Laboratory
Pregnancy Test –
Highly Sensitive 
Urine or Serum 
HCG
X
X
WOCBP 
require 
negative test 
within 72 hours
prior to 
Cycle 1. Test 
monthly if 
required by 
local
regulations.
Refer to 
Section 10.12 
for country-
specific 
requirements. 
Hematology: CBC  
with Differential
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Study Period
Treatment Cycles  (3-Week Cycles)
EOT
Post Treatment Visits
Notes
Treatment Cycle
1
2
3
4
5
6
7
8
9
10
11
12
13
14 
thru
35
Discon
Safety 
Follow-
up1
Follow-
up2
Survival 
Follow-
up
Scheduling 
Window (Days):
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At 
Time 
of 
Discon 
(+3)
30 Days 
Post 
Discon 
(+14)
Every 12 
Weeks     
(±7)
Every 12 
Weeks 
(±14)
PT/INR and 
aPTT/PTT 
X
PT/INR and 
aPTT/PTT to be 
tested at Cycle 1 
for all 
Crossover 
participants. 
Any Crossover 
participant 
receiving 
anticoagulant 
therapy should 
have 
coagulation 
factors 
monitored 
closely 
throughout the 
study.
Chemistry Panel
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
Perform prior to 
Cycle 1 and 
Cycle 2, then 
every 2nd cycle 
through Cycle 
6, then every 6th
cycle thereafter 
(Cycles 2, 4, 6, 
12, 18, etc.). 
After Cycle 1, 
may collect up 
to 3 days prior 
to dosing.
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Protocol/Amendment No.: 789-08
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Study Period
Treatment Cycles  (3-Week Cycles)
EOT
Post Treatment Visits
Notes
Treatment Cycle
1
2
3
4
5
6
7
8
9
10
11
12
13
14 
thru
35
Discon
Safety 
Follow-
up1
Follow-
up2
Survival 
Follow-
up
Scheduling 
Window (Days):
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At 
Time 
of 
Discon 
(+3)
30 Days 
Post 
Discon 
(+14)
Every 12 
Weeks     
(±7)
Every 12 
Weeks 
(±14)
T3/FT3, FT4, and 
TSH
X
X
X
X
X
X
X
X
X
X
Perform prior 
to Cycle 1 and 
Cycle 2, then 
every 2nd cycle 
(Cycles 2, 4, 6, 
8, etc.). May 
use central lab 
only if local 
lab is not 
capable. After 
Cycle 1, may 
collect up to 
3 days prior to 
dosing.
Efficacy Measurements
Brain MRI
X
Perform at time 
of crossover if 
participant has 
history of brain 
metastases.
Tumor Imaging
X
X
X
X
X
X
X
X
Blinded central 
review 
verifying 
progressive 
disease is 
required for 
crossover, 
without 
exception
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Protocol/Amendment No.: 789-08
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Study Period
Treatment Cycles  (3-Week Cycles)
EOT
Post Treatment Visits
Notes
Treatment Cycle
1
2
3
4
5
6
7
8
9
10
11
12
13
14 
thru
35
Discon
Safety 
Follow-
up1
Follow-
up2
Survival 
Follow-
up
Scheduling 
Window (Days):
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At 
Time 
of 
Discon 
(+3)
30 Days 
Post 
Discon 
(+14)
Every 12 
Weeks     
(±7)
Every 12 
Weeks 
(±14)
Study Drug Administration
Pembrolizumab 
(MK-3475)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Treatment with 
Pembro should 
not initiate 
until at least 21 
days after the 
last dose of 
chemo 
regardless of 
the time of 
progression.  
Participants 
originally 
assigned to 
pembro + 
chemo arm will 
complete up to 
a total of 35 
admin of 
pembro and 
participants 
from the saline 
placebo + 
chemo arm will 
receive up to 
35 admin of 
pembro
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Protocol/Amendment No.: 789-08
MK-3475-789-08 Final Protocol
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Study Period
Treatment Cycles  (3-Week Cycles)
EOT
Post Treatment Visits
Notes
Treatment Cycle
1
2
3
4
5
6
7
8
9
10
11
12
13
14 
thru
35
Discon
Safety 
Follow-
up1
Follow-
up2
Survival 
Follow-
up
Scheduling 
Window (Days):
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At 
Time 
of 
Discon 
(+3)
30 Days 
Post 
Discon 
(+14)
Every 12 
Weeks     
(±7)
Every 12 
Weeks 
(±14)
Notes: 
1. If Discontinuation visit occurs ≥30 days from last dose of study treatment, a Safety Follow-up Visit is not required.
2. Follow-Up visits may be scheduled to coincide with Follow-Up imaging (eg, 12 weeks from last imaging time point).
3. After the Safety Follow-up Visit, record all medications taken for SAEs and ECIs as defined in Section 10.4
Abbreviations: AE=adverse event; aPTT=activated partial thromboplastin time; CBC=complete blood count; CXDX=Cycle X Day X; d=days; DC/Discon=discontinuation; 
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOT=end of treatment;  FT4= free thyroxine; H/hr=hours; HCG=human chorionic gonadotropin; 
INR=international normalized ratio; min=minutes; MRI=magnetic resonance imaging; PD=progressive disease; PT=prothrombin time; PTT=partial thromboplastin time; Q=every; 
SAE=serious adverse event; SoA=schedule of activities; T3/FT3= free or total triiodothyronine; TSH= thyroid stimulating hormone;  V=visit; WOCBP=woman of child-bearing 
potential.
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Protocol/Amendment No.: 789-08
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Schedule of Activities for Second Course Retreatment Phase
Details regarding the procedures listed in this table are outlined in Section 8. Second course retreatment participants may receive up to 
17 cycles (approximately 1 year) of open-label pembrolizumab monotherapy.  
Study Period
Treatment Cycles (3-Week Cycles)
EOT
Post-Treatment Visits
Notes
Treatment Cycle:
1
2
3
4
5
6 to 17
Discon
Safety 
Follow-up1
Follow-
up2
Survival 
Follow-up
Scheduling Window (Days):
+3
± 3
± 3
± 3
± 3
± 3
At DC 
(+3) 
30 Days 
Post-DC 
(+14)
Every 12
Weeks
( ±7)
Every 12 
Weeks
(± 14)
Administrative Procedures
Eligibility Criteria
X
Concomitant Medication Review
X
X
X
X
X
X
X
X
Subsequent Anti-neoplastic 
Therapy Status
X
X
X
X
Survival Status 
X
Participants may be contacted for survival status 
at any time during the course of the study.
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
Report non-serious AEs occurring within 30 days 
after the last dose of study treatment. Report 
SAEs occurring within 90 days after the last dose 
of study treatment, or 30 days after the last dose 
of study treatment if a new anti-cancer therapy is
initiated.
Full Physical Examination
X
X
Directed Physical Examination
X
X
X
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
Perform within 7 days prior to SC Cycle 1.
To be assessed prior to dosing at each cycle.
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Study Period
Treatment Cycles (3-Week Cycles)
EOT
Post-Treatment Visits
Notes
Treatment Cycle:
1
2
3
4
5
6 to 17
Discon
Safety 
Follow-up1
Follow-
up2
Survival 
Follow-up
Scheduling Window (Days):
+3
± 3
± 3
± 3
± 3
± 3
At DC 
(+3) 
30 Days 
Post-DC 
(+14)
Every 12
Weeks
( ±7)
Every 12 
Weeks
(± 14)
Laboratory Procedures/Assessments: Analysis Performed by Local Laboratory
Pregnancy Test – Highly Sensitive 
Urine or Serum HCG
X
X
WOCBP require negative test within 72 hours
prior to Second Course (SC) Cycle 1. Test 
monthly if required by local regulations. Refer to 
Section 10.12 for country-specific requirements. 
PT/INR and aPTT/PTT 
X
PT/INR and aPTT/PTT to be tested at Cycle 1 for 
all Second Course participants. Any Second 
Course participant receiving anticoagulant 
therapy should have coagulation factors 
monitored closely throughout the study.
Hematology: CBC with Differential
X
X
X
X
X
X
X
X
Perform within 10 days prior to SC Cycle 1. After 
SC Cycle 1, may collect up to 3 days prior to 
dosing. 
Chemistry Panel
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
Every 2 cycles through SC Cycle 5, then every 6 
cycles (SC Cycles 1, 3, 5, 11, 17). After SC 
Cycle 1, may collect up to 3 days prior to dosing.
T3/FT3, FT4, TSH
X
X
X
X
X
X
Perform within 10 days prior to SC Cycle 1. 
Repeat every 2 cycles (SC Cycles 1, 3, 5, 7, etc.). 
May use central lab if local lab is not capable.
After SC Cycle 1, may collect up to 3 days prior 
to dosing.
Efficacy Measurements
Tumor Imaging
X
X
X
X
X
X3
SC baseline imaging within 28 days prior to SC 
Cycle 1. Perform imaging Q12W (±7 days) from 
SC Cycle 1 (after weeks 12, 24, 36, 48). Schedule 
should be followed regardless of treatment 
delays. If imaging was obtained within 4 weeks 
prior to DC, imaging at DC is not mandatory.
Brain MRI
X
Perform within 28 days prior to SC Cycle 1 if 
participant has history of brain metastases.
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Study Period
Treatment Cycles (3-Week Cycles)
EOT
Post-Treatment Visits
Notes
Treatment Cycle:
1
2
3
4
5
6 to 17
Discon
Safety 
Follow-up1
Follow-
up2
Survival 
Follow-up
Scheduling Window (Days):
+3
± 3
± 3
± 3
± 3
± 3
At DC 
(+3) 
30 Days 
Post-DC 
(+14)
Every 12
Weeks
( ±7)
Every 12 
Weeks
(± 14)
Study Drug Administration
Pembrolizumab (MK-3475)
X
X
X
X
X
X
Pembro can be administered for up to 17 
administrations (approximately 1 year).
Notes: 
1. If Discontinuation visit occurs ≥30 days from last dose of study treatment, a Safety Follow-up Visit is not required.
2. For participants discontinuing second course for reasons other than PD, follow-up visits and imaging continue until the start of new anti-cancer treatment, PD, withdrawal of 
consent, death or end of the study Participants discontinuing second course treatment with PD proceed directly to survival follow-up.
Abbreviations: AE=adverse events; aPTT=activated partial thromboplastin time; CBC=complete blood count; CXDX= Cycle X Day X; DC/Discon=discontinuation; 
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOT=end of treatment; FT4= free thyroxine; H/hr=hours; HCG=human chorionic gonadotropin; 
INR=international normalized ratio; PD=progressive disease; PT=prothrombin time; PTT=partial thromboplastin time; Q=every;  SAE=serious adverse event; SC=Second Course; 
SC C1D1=Second Course Cycle 1 Day 1; T3/FT3=free or total triiodothyronine; TSH=thyroid stimulating hormone; W=weeks; WOCBP=woman of child-bearing potential.
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2. Introduction
Study Rationale 
The global incidence of lung cancer was 1.8 million in 2012, resulting in an estimated 
1.6 million deaths [World Health Organization 2012]. In the United States, the 2016 
estimated incidence of new diagnoses was 224,400 and estimated number of deaths was 
158,100 [National Cancer Institute 2016]. Non-small cell lung cancer (NSCLC) represents 
approximately 80% to 85% of all lung cancers. Of the patients with NSCLC, tumor histology 
is approximately 40% to 60% adenocarcinoma, 10% to 15% squamous, 5% neuroendocrine, 
and the rest “not otherwise specified” [Sulpher, J. A., et al 2013]. 
Approximately 70% of patients with NSCLC have advanced disease not amenable to surgical 
resection at the time of diagnosis. The 5-year relative survival for patients with any lung 
cancer overall and metastatic lung cancer specifically has been reported to be 17.7% and 
4.3%, respectively [National Cancer Institute 2016].
The standard of care (SOC) for metastatic NSCLC has changed in recent years with the 
development of immunotherapy agents. In the Phase 3 study KEYNOTE-024, 
pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, showed statistically 
significant increases in overall survival (OS) and progression-free survival (PFS) compared 
to SOC platinum-based chemotherapy for treatment-naïve participants with metastatic 
NSCLC whose tumors expressed high levels of the programmed cell death ligand 1 (PD-L1) 
(tumor proportion score [TPS] ≥50%) with no epidermal growth factor receptor (EGFR) or 
anaplastic lymphoma kinase (ALK) genomic tumor aberrations, leading to regulatory 
approval for this indication in the US and other countries around the world. Approximately 
30% of patients with newly diagnosed, advanced NSCLC highly express PD-L1 to a TPS 
≥50% [Reck, M., et al 2016].
In the Phase 2 study KEYNOTE-021 Cohort G, pembrolizumab plus pemetrexed and 
carboplatin showed statistically significant increases in objective response rate (ORR) and 
PFS compared to pemetrexed and carboplatin alone in participants with non-squamous 
advanced NSCLC, regardless of PD-L1 status. These results established pembrolizumab plus 
chemotherapy as an efficacious option for first-line (1L) therapy in patients with NSCLC; 
these findings are being further evaluated in the ongoing Phase 3 studies KEYNOTE-189 
(non-squamous) and KEYNOTE-407 (squamous) (see the Investigator’s Brochure [IB]).
The EGFR is a transmembrane receptor with tyrosine kinase activity (TK) involved in the 
regulation of cell proliferation, survival, differentiation and other crucial processes through 
activation of multiple downstream signaling cascades, including PI3K/AKT, 
RAS/RAF/mitogen-activated protein kinase (MAPK) and STAT pathways. EGFR pathway is 
often deregulated in NSCLC. The overall prevalence for EGFR mutations in patients with 
NSCLC is 30%, ranging from 38% in China to 14% in Europe. The most common mutations 
are the in-frame exon 19 deletion and the exon 21 point mutation L858R (substitution from 
leucine to arginine at amino acid 858) accounting for about 90% of all mutations. Somatic 
activating mutations of EGFR are predominant in adenocarcinoma; the prevalence of EGFR
mutations is higher in never-smokers, females and patients of East Asian ethnicity [Zhang, Y. 
L., et al 2016].
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The first-generation, reversible EGFR tyrosine kinase inhibitors (TKIs), gefitinib and 
erlotinib, are orally bioavailable synthetic anilinoquinazolines designed to compete for 
adenosine triphosphate (ATP) binding to the catalytic site of the receptor, switch off survival 
signals, leading to tumor cell death, whereas the second-generation inhibitors, including 
afatinib and dacomitinib, are irreversible inhibitors with greater affinity for the EGFR kinase 
domain and can also inhibit and block signaling from other members of the ErbB family, thus 
providing enhanced EGFR blockade.
Iressa Pan-Asia Study (IPASS) was the first study demonstrating the superiority of gefitinib 
with a significantly longer PFS and ORR compared with chemotherapy in subgroup of 
patients with EGFR mutations NSCLC (hazard ratio [HR] for PFS, 0.48; 95% confidence 
interval (CI): 0.36, 0.64; p<0.001) thus leading to its approval [Mok, T. S., et al 2009].
Subsequent multiple, randomized Phase 3 trials, exclusively enrolling patients with EGFR-
mutated NSCLC, explored the use of gefitinib, erlotinib or afatinib as first-line treatment in 
comparison with standard platinum-based chemotherapy showed that EGFR TKIs improved 
ORRs ranging between 62% to 83%, and PFS (median PFS ranging between 9 to 
13 months), leading to approval of gefitinib, erlotinib, and afatinib, as upfront therapies in 
advanced NSCLC patients with EGFR mutations. Unfortunately, the vast majority of patients 
will later develop progressive disease, generally within 1 year of treatment, due to 
development of acquired resistance, limiting the long-term efficacy of these agents, multiple 
mechanisms are responsible for the acquired resistance have been identified such as: 1)
secondary mutation of the EGFR target gene, such as T790M mutation, which occurs in 
about 50% to 60% of EGFR TKI-resistant tumors, 2) bypass pathway activation such as 
amplification, overexpression of MET, HER2, and molecular alterations of downstream 
molecules of the PI3K/AKT/mammalian target of rapamycin (mTOR) or the 
RAS/RAF/MAPK pathways, and 3) histologic transformation, such as small cell lung cancer 
(SCLC) transformation and epithelial–mesenchymal transition [Morgillo, F., et al 2016].
The identification of EGFR T790M prompted the development of second-generation EGFR
TKIs such as afatinib and dacomitinib to overcome resistance; however, available clinical 
data have indicated a rather limited activity of these drugs in the setting of acquired 
resistance to first-generation TKIs. Subsequently, third-generation, mutant EGFR-selective 
TKIs have been developed, including rociletinib and osimertinib. Osimertinib was granted 
US FDA approval for the treatment of patients with metastatic EGFR T790M mutation-
positive NSCLC who have progressed on or after EGFR TKI therapy based on the AURA3 
study, which demonstrated improvement in PFS in patients treated with osimertinib versus 
chemotherapy, with an HR of 0.30 (95% CI: 0.23, 0.41; p<0.001) and median PFS of 10.1 
months versus 4.4 months [Mok, T. S., et al 2017]. Recently, the AURA3 study has been 
updated to report a median OS of 26.8 months in the osimertinib arm versus 22.5 months in 
the chemotherapy arm [Papadimitrakopoulou, V. A., et al 2020]. While these results are 
encouraging, most patients eventually progressed and will die of their disease. There is very 
little data on the survival of patients with T790M+ NSCLC who were treated with 
chemotherapy after failed osimertinib in the second-line setting. In a small retrospective 
study of 91 subjects with T790M+ NSCLC treated with osimertinib beyond progression or
switched to other therapies (primarily chemotherapy), the PFS and OS for those who 
switched therapies after progression on osimertinib were 4.7 months and 7.8 months,
respectively [Cortellini, A., et al 2020]. 
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The benefit of third-generation EGFR TKI is also evolving in the first-line setting. In the 
Phase 3 FLAURA study of osimertinib versus gefitinib/erlotinib, the PFS HR was 0.46 (95% 
CI: 0.37, 0.57, p <0.001) and the medians were 18.9 months versus 10.2 months, 
respectively, with comparable safety profiles of osimertinib to erlotinib/gefitinib, but with 
lower rates of Grade ≥3 AEs and a lower discontinuation rate [Ramalingam, S., et al 2017]. 
Recently, the FLAURA study was updated to report a longer median OS of 38.6 months for 
patients receiving first-line osimertinib versus 31.8 months in the erlotinib/gefitinib group, in 
which 47% of patients received osimertinib as the first subsequent therapy [Ramalingam, S. 
S., et al 2020].
Despite these developments in the treatment of EGFR mutant NSCLC, most patients still 
ultimately progress. Prolonged survival rates remain very low with median OS between 1 to 
2 years [Yu, H. A., et al 2013]. Systemic chemotherapy treatment generally represented by 
platinum-based doublet is currently considered the standard of care with only modest benefit 
of 20% to 30% response rate. Furthermore, the Phase 3 IMPRESS study failed to 
demonstrate long-term benefit combining gefitinib with chemotherapy (cisplatin and 
pemetrexed) compared with chemotherapy and placebo in patients who progressed on first-
line gefitinib. There was no difference in PFS between groups, with median PFS of 5.4 
months in both groups (95% CI: 4.5, 5.7 in the gefitinib group and 95% CI: 4.6, 5.5 in the 
placebo group), and the combination of gefitinib plus chemotherapy was detrimental to OS 
compared with chemotherapy alone, with median OS of 13.4 months versus 19.5 months 
(HR 1.44, 95% CI: 1.07, 1.94; p=0.016) [Soria, J. C., et al 2015] [Mok, T. S. K., et al 2017]. 
Alternative treatment strategies, including investigational drugs or novel combinations have 
been explored in clinical trials, but none of these has been approved as standard treatment in 
this setting, confirming the unmet medical need that exists in this patient population. Thus,
further development of new regimen and novel treatment strategies are urgently warranted. 
Recently, immune checkpoint inhibitors and anti-PD-1 (programmed death-1) and 
anti-PD-L1 (programmed death-ligand) antibodies demonstrated quite promising and durable 
response across broad range of solid tumors including NSCLC.
PD1/PD-L1 Inhibitors in EGFR-mutant NSCLC
Pembrolizumab monotherapy is one of the current standards of care (SOC) for the treatment 
of patients with good Eastern Cooperative Oncology Group (ECOG) performance status 
(ECOG 0 or 1) and previously treated, advanced, or metastatic NSCLC with a programmed 
cell death ligand 1 (PD-L1) tumor proportion score (TPS) ≥1%, including patients with 
EGFR mutation who have failed both prior EGFR TKI and platinum doublet chemotherapy. 
This is based on data from KEYNOTE-010 [IB Edition 15 2017]. KEYNOTE-010 was an 
open-label Phase 3, randomized, controlled study, compared pembrolizumab monotherapy to 
standard second-line docetaxel therapy in 1034 previously treated participants with advanced 
NSCLC and a PD-L1 TPS ≥1%, including patients with EGFR mutation who have failed 
both TKI and platinum doublet chemotherapy. Results from KEYNOTE-010 indicated a 
significant overall survival (OS) benefit for pembrolizumab over docetaxel therapy with an 
HR of 0.71 (p=0.00076) and 0.61 (p<0.00001) for pembrolizumab 2 mg/kg every 3 weeks 
(Q3W) and 10 mg/kg Q3W, respectively, compared to docetaxel. Pembrolizumab was 
superior to docetaxel in the strongly positive TPS ≥50% stratum with regard to PFS, with an 
HR of 0.58 (p=0.00009) and 0.59 (p=0.00007) for pembrolizumab 2 mg/kg Q3W and 
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10 mg/kg Q3W, respectively, compared to docetaxel. Although KEYNOTE-010 was not a 
study powered for distinguishing the effectiveness of pembrolizumab by EGFR mutational 
status from another, but was instead powered to demonstrate that selection of a group of 
subjects based on expression of the PD-L1 biomarker, irrespective of EGFR status, in a 
subgroup analysis of 54 patients with EGFR mutation, there was a trend toward improved OS 
favoring pembrolizumab 2mg /kg over standard of care docetaxel, with OS [HR] was 0.78 
(95% CI: 0.39, 1.60).
In addition, the Phase 3 study IMpower150, has shown that chemotherapy in combination 
with checkpoint inhibitor anti-PD-L1 (atezolizumab) with the addition of bevacizumab, 
reduces the risk of disease progression in advanced non-squamous NSCLC with an 
investigator assessed PFS [HR]=0.62; p<0.0001; 95 % CI: 0.52, 0.74 (patients with ALK and 
EGFR tumor mutations were excluded from the primary intent-to-treat [ITT] analysis). When 
the analysis was performed on the ITT population that included patients with mutant EGFR 
[108/800 (14%)] or ALK, the PFS [HR] was 0.59 (95 % CI: 0.37, 0.94), confirming the trend 
in improvement in PFS when a checkpoint inhibitors is added to chemotherapy in patients 
with EGFR mutations who has failed prior EGFR TKIs therapy [Reck, M., et al 2017] [Reck, 
M., et al 2017].  
Based on the potential beneficial role of pembrolizumab in previously treated (with EGFR
TKIs treatment followed by chemotherapy) patients with EGFR mutant metastatic NSCLC, 
and since chemotherapy combination with pembrolizumab or atezolizumab demonstrated
promising ORR and/or PFS in the first-line setting in non-squamous NSCLC as seen in 
KEYNOTE-021G and IMpower150, the combination of chemotherapy with pembrolizumab 
in patients who have failed EGFR TKIs previously warrants further exploration.
Background
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus 
inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell 
death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity 
and potent receptor blocking activity for PD-1. Pembrolizumab has an acceptable preclinical 
safety profile and is in clinical development as an IV immunotherapy for advanced 
malignancies. Keytruda® (pembrolizumab) is indicated for the treatment of patients across a 
number of indications. For more details on specific indications refer to the IB.
Refer to the IB/approved labeling for detailed background information on pembrolizumab.
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved 
prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and 
pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. 
Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable 
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objective tumor responses in cancers such as melanoma [Dudley, M. E., et al 2005] [Hunder, 
N. N., et al 2008].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an 
immunoglobulin (Ig) superfamily member related to cluster of differentiation 28 (CD28) and 
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
[Greenwald, R. J., et al 2005] [Okazaki, T., et al 2001].
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an Ig-variable–type (IgV-type) 
domain responsible for ligand binding and a cytoplasmic tail responsible for the binding of 
signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, 
an immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based 
switch motif. Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, 
SHP-1 and SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic 
tail, leading to the dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein 
kinase C-theta (PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are 
involved in the CD3 T-cell signaling cascade [Okazaki, T., et al 2001] [Chemnitz, J. M., et al 
2004] [Sheppard, K-A, et al 2004] [Riley, J. L. 2009]. The mechanism by which PD-1 down-
modulates T-cell responses is similar to, but distinct from, that of CTLA-4, because both 
molecules regulate an overlapping set of signaling proteins [Parry, R. V., et al 2005] 
[Francisco, L. M., et al 2010]. As a consequence, the PD-1/PD-L1 pathway is an attractive 
target for therapeutic intervention in NSCLC.
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and efficacy of an investigational medicine.
The beneficial effects of pembrolizumab have been observed in several NSCLC studies to 
date. A significantly positive benefit/risk ratio has been demonstrated for pembrolizumab in 
multiple randomized studies for NSCLC, both as a monotherapy (KEYNOTE-010, 
KEYNOTE-024) and in combination with chemotherapy (KEYNOTE-021G, KEYNOTE-
189).
KEYNOTE-010 included patients with PD-L1 TPS ≥1% and an EGFR mutation, who have
failed both a TKI and platinum doublet chemotherapy. Although KEYNOTE-010 was not a
study powered for distinguishing the effectiveness of pembrolizumab in participants with an
EGFR mutation, in a subgroup analysis of 54 patients with an EGFR mutation, there was a
trend toward improved OS favoring pembrolizumab 2 mg/kg over standard of care docetaxel
(HR=0.78; 95% CI: 0.39, 1.60). In addition, the Phase 3 study IMpower150 has shown that 
chemotherapy in combination with atezolizumab (a PD-L1 inhibitor) and bevacizumab 
reduced the risk of disease progression or death in advanced non-squamous NSCLC
[Reck, M., et al 2017] [Reck, M., et al 2017]. When the analysis was performed to include 
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patients with mutant EGFR (108/800 [14%)]) or rearranged ALK, an improved PFS was 
observed (HR=0.59; 95% CI: 0.37, 0.94). These data suggested that checkpoint inhibitors, 
either alone or in combination with chemotherapy, have clinical activity in patients with 
EGFR mutation after TKI failure. The most frequently reported AEs for patients treated with 
pembrolizumab (reported in ≥20% of patients) included fatigue, cough, nausea, pruritus, 
rash, decreased appetite, constipation, arthralgia and diarrhea. These were predominantly 
Grade 1 to 2, with fatigue being the only AE that occurred with a severity of Grade 3 or 
above in 5% of patients. Immune-related pneumonitis, colitis, hepatitis, hypophysitis, 
nephritis and thyroid abnormalities were seen at low frequency and were managed by 
holding or discontinuing the drug as described. 
Based on data from KEYNOTE-021G and KEYNOTE-189, the addition of pembrolizumab 
did not increase the frequency of AEs beyond what was expected with regimens involving 
pemetrexed and platinum doublet chemotherapy. Moreover, the incidence of most immune-
mediated AEs was not higher with pembrolizumab combination therapy than that previously 
observed with pembrolizumab monotherapy.
Despite the substantial improvement in ORR and PFS observed with different generation of 
EGFR TKIs treatment, most patients eventually have progressive disease. The current SOC 
chemotherapy does not improve outcomes. There remains a need to investigate new 
treatments which offer the prospect of added benefit for this patient population. The 
preliminary data showing potential benefits for patients with an EGFR mutation who 
progressed on a TKI, argues strongly for a comparison of the addition of pembrolizumab
with chemotherapy to the currently accepted standard of care, platinum doublet 
chemotherapy. Additional details regarding specific benefits and risks for participants 
participating in this clinical study may be found in the accompanying IB and Informed 
Consent documents.
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3. Objectives/Hypotheses and Endpoints
In adult participants with TKI-resistant EGFR-mutated tumors in metastatic non-squamous 
NSCLC:
Objective/Hypothesis
Endpoint
Primary
Objective: To compare PFS per Response 
Evaluation Criteria in Solid Tumors 1.1 
(RECIST 1.1) based on blinded 
independent central review (BICR) of the 
combinations of pembrolizumab + 
chemotherapy versus saline placebo + 
chemotherapy.
Hypothesis (H1): The combination of 
pembrolizumab + chemotherapy has 
superior PFS per RECIST 1.1 based on 
BICR compared to saline placebo + 
chemotherapy
Progression-free survival (PFS) is the time 
from randomization to the first 
documented progressive disease (PD) or 
death due to any cause, whichever occurs 
first.
Objective: To compare OS of the 
combinations of pembrolizumab + 
chemotherapy versus saline placebo + 
chemotherapy.

Hypothesis (H2): The combination of 
pembrolizumab + chemotherapy has 
superior OS compared to saline placebo +
chemotherapy.
OS is defined as the time from 
randomization to death due to any cause.
This study will be considered to have met its success criteria if the combination of 
pembrolizumab + chemotherapy is superior to saline placebo + chemotherapy in PFS or OS.
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Objective/Hypothesis
Endpoint
Secondary
Objective: To compare objective response 
rate (ORR) per RECIST 1.1 based on 
BICR of the combinations of 
pembrolizumab + chemotherapy versus 
saline placebo + chemotherapy.
Hypothesis (H3): The combination of 
pembrolizumab + chemotherapy has 
superior ORR per RECIST 1.1 based on 
BICR compared to saline placebo + 
chemotherapy.

Objective response is a confirmed 
complete response (CR) or partial 
response (PR).

Objective:
To evaluate
DOR of the 
combinations 
of 
pembrolizumab 
+ 
chemotherapy versus saline placebo + 
chemotherapy.

DOR is defined as the time from the 
earliest date of qualifying response until 
earliest date of disease progression or 
death from any cause, whichever comes 
first, per RECIST 1.1 based on BICR.

Objective: To evaluate the patient 
reported outcomes (PROs) mean score 
changes from baseline in global health 
status and quality of life scale between 
pembrolizumab + chemotherapy versus 
saline placebo + chemotherapy.

European Organization for Research and 
Treatment of Cancer (EORTC) Quality of 
Life Questionnaire-Core 30 items (QLQ-
C30) global health status (item 29) and 
quality of life scale (item 30).

Objective: To evaluate the PROs time to 
true deterioration (TTD) in the composite 
endpoint of cough, chest pain or dyspnea 
between pembrolizumab + chemotherapy 
versus saline placebo + chemotherapy.

TTD is the time from baseline to first 
onset of 10 points or more deterioration
from baseline with confirmation by the 
subsequent visit of 10 points or more 
deterioration from baseline of the 
composite endpoint of cough [EORTC 
QLQ-Lung Cancer Module 13 (LC13) 
item 1], chest pain [EORTC QLQ-LC13 
item 10], or dyspnea [EORTC QLQ-C30 
item 8].

Objective: To evaluate the safety and 
tolerability of the combination of 
pembrolizumab + chemotherapy and 
saline placebo + chemotherapy.

Adverse events (AEs) and study drug 
discontinuation due to AEs.
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Objective/Hypothesis
Endpoint
Tertiary/Exploratory

Objective: To compare the PFS and ORR 
per Modified RECIST 1.1 for Immune-
based Therapeutics (iRECIST) of the 
combinations of pembrolizumab + 
chemotherapy versus saline placebo + 
chemotherapy.
PFS is defined as the time from 
randomization to the first documented PD 
per iRECIST as assessed by the 
Investigator or death due to any cause, 
whichever occurs first. 
ORR is defined as the proportion of 
participants who have a confirmed CR or 
PR per iRECIST as assessed by the 
Investigator.

Objective: To evaluate changes in health-
related quality of life assessments from 
baseline in the overall study population 
using the EORTC QLQ-C30 and EORTC
QLQ-LC13

Change from baseline in health-related 
quality of life evaluated using the multi-
item and single-item scales of EORTC 
QLQ-C30 and EORTC QLQ-LC13.

Objective: To characterize utilities using 
the European Quality of Life Five-
dimension Five-level Scale Questionnaire 
(EQ-5D-5L).

Health utilities assessed using the EQ-
5D-5L.
4. Study Design 
Overall Design 
This is a worldwide, randomized, active-control with placebo, parallel-group, multi-site, 
double-blind study of IV pembrolizumab (also known as MK-3475) combined with 
pemetrexed plus platinum chemotherapy versus saline placebo combined with pemetrexed 
plus platinum chemotherapy in participants with TKI-resistant EGFR-mutated tumors in 
metastatic non-squamous NSCLC. Approximately 492 participants will be enrolled in this 
trial to examine the efficacy of pembrolizumab combined with chemotherapy compared to 
chemotherapy alone. Participants will be randomized 1:1 to either receive pembrolizumab 
200 mg combined with pemetrexed and platinum chemotherapy (investigator’s choice of 
carboplatin or cisplatin), or saline placebo plus pemetrexed and platinum chemotherapy
(investigator’s choice of carboplatin or cisplatin) as indicated below:
CCI
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
Arm 1: Pembrolizumab 200 mg + pemetrexed 500 mg/m2 (with vitamin 
supplementation) + carboplatin AUC 5 mg/mL•min OR cisplatin 75 mg/m2, all on 
Day 1 every 3 weeks (Q3W) for 4 cycles followed by pembrolizumab 200 mg + 
pemetrexed 500 mg/m2 Q3W for up to an additional 31 cycles (up to 35 total 
cycles), followed by pemetrexed 500 mg/m2 Q3W maintenance until progression 
or unacceptable toxicity.

Arm 2: Saline placebo + pemetrexed 500 mg/m2 (with vitamin supplementation) 
+ carboplatin AUC 5 mg/mL•min OR cisplatin 75 mg/m2, all on Day 1 Q3W for 4 
cycles followed by saline placebo + pemetrexed 500 mg/m2 Q3W for up to an 
additional 31 cycles (up to 35 total cycles), followed by pemetrexed 500 mg/m2
Q3W maintenance until progression or unacceptable toxicity.
Participants who received adjuvant or neoadjuvant therapy are permitted onto the study if the
therapy was completed at least 6 months prior to the development of metastatic disease.
Participants will be stratified by PD-L1 expression: TPS ≥50% versus <50%; treatment 
history: osimertinib versus no osimertinib; and geographic region of the enrolling site: East 
Asia versus Non-East Asia, prior to randomization.
Treatment with pembrolizumab or saline placebo will continue until reaching a 
discontinuation criterion (Section 7.1), examples of which include: administration of 
35 study treatments, documented disease progression, unacceptable adverse event(s), 
intercurrent illness that prevents further administration of treatment, investigator’s decision 
to withdraw the participant, participant withdraws consent, pregnancy of the participant, 
noncompliance with study treatment or procedure requirements, or administrative reasons.
Maintenance pemetrexed may continue for participants past 35 cycles until reaching a 
discontinuation criterion (Section 7.1), as long as the participant is receiving benefit and per 
local regulations, whereas pembrolizumab/saline placebo are limited to 35 cycles.
Participants will be evaluated at 6 weeks (42 + 7 days) and then every 9 weeks (63 ± 7 days) 
with radiographic imaging to assess response to treatment for the first 51 weeks and every 
12 weeks (84 ± 7 days) subsequently; treatment-based decisions should be based on the
iRECIST criteria. All imaging obtained on study during the initial treatment phase will be 
submitted without indication of treatment assignment to a central imaging review vendor, ie, 
blinded independent central review (BICR), who will assess the images using RECIST 1.1
for determination of PFS and ORR (Section 8.2.1).
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 (Section 10.11).
At the time of documented disease progression as confirmed by BICR using RECIST 1.1
(Section 8.2.1), participants may have treatment assignment unblinded (Figure 3). 
Participants who received saline placebo in combination with chemotherapy may be eligible 
to receive pembrolizumab monotherapy for a total of 35 administrations in the Crossover 
Treatment Phase (Section 8.11.3). Tumor imaging is to be re-baselined and RECIST 1.1 
criteria used for participant assessments (Sections 8.2.1.4 and 8.2.1.5).
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Participants who received pembrolizumab in combination with chemotherapy, but are 
deemed to be benefiting clinically despite disease progression, may continue study treatment
beyond progression and receive pembrolizumab monotherapy in the Crossover Treatment 
Phase (Section 8.11.3) to complete a total of up to 35 pembrolizumab administrations. Repeat 
imaging should occur at appropriate intervals per iRECIST criteria (Sections 8.2.1 and 10.10) 
until iCPD is established.
Study treatment may continue until participant reaches a discontinuation criterion (Section 
7.1), examples of which include subsequent documented progression, unacceptable adverse 
event(s), intercurrent illness that prevents further administration of treatment, investigator’s 
decision to withdraw the participant, participant withdraws consent, pregnancy of the
participant, noncompliance with study treatment or procedure requirements, or for 
administrative reasons.
Alternatively, participants may have treatment assignment remain blinded at the time of 
BICR-verified progression and may continue receiving the study treatment per their 
randomized treatment assignment as long as they continue to be clinically stable (Figure 3).
Clinical Stability is defined in Section 7.1. 
Blinded study treatment can continue beyond verified progression at the Investigator’s 
discretion. Repeat imaging should occur at appropriate intervals per iRECIST criteria 
(Sections 8.2.1 and 10.10) until iCPD is established. Once iCPD is established, the 
participant may then have treatment assignment unblinded, but may not continue study 
treatment in the Crossover Treatment Phase (Section 8.11.3) as described above.
Participants who attain a confirmed complete response (CR) per RECIST 1.1 criteria may 
consider stopping study treatment. These participants, as well as participants randomized to 
the pembrolizumab plus chemotherapy arm that stop study treatment after 35 treatment 
administrations may be eligible for the Second Course Phase (Figure 4). 
Participants randomized to the saline placebo plus chemotherapy arm who complete 35 
treatment administrations and subsequently experience progressive disease will not be 
eligible for Second Course Phase but may continue into the Crossover Treatment Phase 
instead (Section 8.11.3). 
The Second Course Phase is re-treatment with open-label pembrolizumab monotherapy after 
Initial Treatment Phase completion or the attainment of a CR and upon subsequent 
radiographic disease progression. Second Course Phase is only available to participants 
randomized to the pembrolizumab plus chemotherapy arm. Participation is at the discretion 
of the investigator according to defined criteria in Section 8.11.4. Response or progression in 
the Second Course Phase will not count toward the PFS and ORR endpoints in this trial.
After the end of treatment, each participant will be followed for a minimum of 30 days for 
the occurrence of AEs and spontaneously reported pregnancy as described in Section 8.4. 
Serious adverse events will be collected for up to 90 days following cessation of the study 
treatment, or 30 days following the cessation of treatment if the participant initiates new anti-
cancer therapy. 
Participants who discontinue for reasons other than radiographic disease progression will 
have post-treatment follow-up imaging for disease status until disease progression is 
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documented radiographically per RECIST 1.1 and verified by BICR, the start of new 
anti-cancer treatment, pregnancy, participant withdraws consent, participant becomes lost to 
follow-up, participant death, or the end of the study.
The Sponsor may request survival status to be assessed at additional time points and entered 
into the database during the course of the study. For example, survival status may be 
requested prior to, but not limited to, an external Data Monitoring Committee (eDMC) 
review.
All participants will be followed for overall survival until death, withdrawal of consent, or 
the end of the study. Survival status can be done in a variety of ways including phone, email, 
chart review, or review of public records. Survival status information (whether by telephone, 
review of public records, etc.) should be officially documented by the site.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the Schedule of Activities (SoA), Section 1.3. 
Details of each procedure are provided in Section 8.
Scientific Rationale for Study Design 
Rationale for Endpoints
Efficacy Endpoints
This study will use PFS based on RECIST 1.1 criteria as assessed by BICR and overall 
survival (OS) as the co-primary endpoints. 
Progression-free survival is an acceptable measure of clinical benefit for a late stage study
that demonstrates superiority of a new antineoplastic therapy, especially if the magnitude of 
the effect is large and the therapy has an acceptable risk/benefit profile. The use of BICR and 
RECIST 1.1 to assess PFS is typically considered acceptable by regulatory authorities. 
Images will be read by a central imaging vendor blinded to treatment assignment to minimize 
bias in the response assessments. In addition, the final determination of radiologic 
progression will be based on the central assessment of progression, rather than a local site 
investigator/radiology assessment. Real time verification of radiologic progression when 
requested by the local site investigator/radiology assessment as assessed by BICR will be 
communicated to the site and sponsor.
Overall survival (OS) has been recognized as the gold standard for the demonstration of 
superiority of a new antineoplastic therapy in randomized clinical studies.
ORR by RECIST 1.1 criteria as assessed by BICR is considered preliminary evidence of
efficacy and is a secondary endpoint for this study.
DOR by RECIST 1.1 criteria and assessed by BICR is a commonly accepted endpoint by
both regulatory authorities and the oncology community.
The BICR consists of a group of highly qualified radiologists contracted by the central
imaging vendor who are otherwise not involved in the study. The methodology of the BICR
is described in the imaging review charter.
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RECIST 1.1
RECIST 1.1 will be used by the BICR when assessing images for efficacy measures and by
the local site when determining eligibility. Although traditional RECIST 1.1 references a
maximum of 5 target lesions in total and 2 per organ, this protocol has implemented an
adjustment to RECIST 1.1 to allow a maximum of 10 target lesions in total and 5 per organ. 
This will be termed as RECIST 1.1 throughout the protocol. Further details are found in
Section 8.2.1.5.
Modified RECIST for Immune-based Therapeutics (iRECIST)
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
following treatment with pembrolizumab (Section 8.2.1.6). Immunotherapeutic agents such 
as pembrolizumab may produce antitumor effects by potentiating endogenous cancer-specific 
immune responses. The response patterns seen with such an approach may extend beyond the 
typical time course of responses seen with cytotoxic agents, and participants treated with 
pembrolizumab may manifest a clinical response after an initial increase in tumor burden or 
even the appearance of new lesions. Thus, standard RECIST 1.1 may, not provide an 
accurate response assessment of immunotherapeutic agents such as pembrolizumab. Based 
on an analysis of participants with melanoma enrolled in KEYNOTE-001 (KN001), 7% of 
evaluable participants experienced delayed or early tumor pseudo-progression. Of note, 
participants who had progressive disease (PD) by RECIST 1.1 but not by the immune-related 
response criteria [Wolchok, J. D., et al 2009] had longer overall survival than participants 
with PD by both criteria [Hodi, F. S., et al 2014]. Additionally, the data suggest that RECIST 
1.1 may underestimate the benefit of pembrolizumab in approximately 15% of participants. 
These findings support the need to apply a modification to RECIST 1.1 that takes into 
account the unique patterns of atypical responses in immunotherapy and enables treatment 
beyond initial radiographic progression, if the participant is clinically stable. 
Modified RECIST 1.1 for immune-based therapeutics (iRECIST) assessment has been 
developed and published by the RECIST Working Group, with input from leading experts 
from industry and academia, along with participation from the US Food and Drug 
Administration and the European Medicines Agency [Seymour, L., et al 2017]. The 
unidimensional measurement of target lesions, qualitative assessment of non-target lesions, 
and response categories are identical to RECIST 1.1, until progression is seen by RECIST 
1.1. However, if a participant is clinically stable, additional imaging may be performed to 
confirm radiographic progression. iRECIST will be used by Investigators to assess tumor 
response and progression and make treatment decisions as well as for exploratory efficacy 
analyses where specified.
Safety Endpoints
The incidence of AE/serious AEs (SAEs) (including fatal SAEs), immune-related AEs, 
laboratory abnormalities, and rates of dose interruption and discontinuation due to AEs are 
important endpoints for safety and tolerability evaluations.
Refer to Section 10.12 for country-specific requirements. 
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Rationale for Patient Reported Outcomes
Symptomatic improvement is considered a clinical benefit and accepted by health authorities. 
As part of the analyses for this study, participants will provide information regarding their 
health-related quality of life (HRQoL) via the following assessment tools: European 
Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC 
QLQ-LC13, and EQ-5D-5L questionnaires. 
EORTC QLQ-C30 and EORTC QLQ-LC13
EORTC QLQ-C30 is the most widely used cancer specific health related quality of life 
(QoL) instrument, which contains 30 items and measures 5 functional dimensions (physical, 
role, emotional, cognitive, and social), 3 symptom items (fatigue, nausea/vomiting, and pain), 
6 single items (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial 
impact), and a global health and QoL scale [Aaronson, N. K., et al 1993]. The EORTC QLQ-
C30 is a psychometrically and clinically validated instrument appropriate for assessing QoL 
in oncology studies [Aaronson, N. K., et al 1993].
The EORTC Quality of Life Questionnaire and Lung Cancer Module 13 (QLQ-LC13), a 
supplemental lung cancer-specific module used in combination with QLQ-C30, comprises 
multi-item and single-item measures of lung cancer-associated symptoms (cough, 
hemoptysis, dyspnea, and site specific pain) and treatment-related symptoms (sore mouth, 
dysphagia, peripheral neuropathy and alopecia) [Bergman, B., et al 1994]. It is scored on a 4 
point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much) and has been translated and 
validated into more than 60 languages. 
EQ-5D-5L
The EuroQol 5-dimension, 5-level questionnaire (EQ-5D-5L) is a standardized instrument 
for use as a measure of health outcome and will provide data to develop health utilities or 
quality-adjusted life-years for use in health economic analyses [Rabin, R. and de Charro, F. 
2001]. The 5 health state dimensions in the EQ-5D-5L include the following: mobility, self-
care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is rated on a 5 
point scale from 1 (no problem) to 5 (unable to/extreme problems). The EQ-5D-5L also 
includes a graded (0 to 100) vertical visual analog scale on which the participant rates his or 
her general state of health at the time of the assessment. This instrument has been used 
extensively in cancer studies and published results from these studies support its validity and 
reliability [Pickard, A. S., et al 2007].
Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents. 
However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating patients. Thus, to aid future patients, it is important to investigate the determinants 
of response or resistance to cancer immunotherapy and other treatments administered, as well 
as determinants of AEs in the course of our clinical studies. These efforts may identify novel 
predictive/PD biomarkers and generate information that may better guide single-agent and 
combination therapy with immuno-oncology drugs. To identify novel biomarkers, 
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biospecimens (ie, blood components, tumor material) will be collected to support analyses of 
cellular components (eg, protein, DNA, RNA, metabolites) and other circulating molecules. 
Investigations may include but are not limited to:
Germline (blood) genetic analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing)
This research may evaluate whether genetic variation within a clinical study 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. Furthermore, it is important to evaluate germline DNA variation across 
the genome in order to interpret tumor-specific DNA mutations. Finally, microsatellite 
instability (MSI) may be evaluated as this is an important biomarker for some cancers (ie, 
colorectal cancer).
Genetic (DNA) analyses from tumor
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (ie, mutations, methylation 
status, microsatellite instability). Key molecular changes of interest to immuno-oncology 
drug development include the mutational burden of tumors and the clonality of T-cells in the 
tumor microenvironment. Increased mutational burden (sometimes referred to as a ‘hyper-
mutated’ state) may generate neo-antigen presentation in the tumor microenvironment. To 
conduct this type of research, it is important to identify tumor-specific mutations that occur 
across all genes in the tumor genome. Thus, genome-wide approaches may be used for this 
effort. Note that in order to understand tumor-specific mutations, it is necessary to compare 
the tumor genome with the germline genome. Microsatellite instability may also be evaluated 
as this is an important biomarker for some cancers (ie, colorectal cancer). Circulating tumor 
DNA and/or RNA may also be evaluated from blood samples.
Tumor and/or blood RNA analyses
Both genome-wide and targeted messenger RNA (mRNA) expression profiling and 
sequencing in tumor tissue and/or in blood may be performed to define gene signatures that 
correlate to clinical response to treatment with immunotherapies and/or other treatments 
administered. Immunotherapies induce a response in tumors that likely reflects an 
inflamed/immune phenotype. Specific immune-related gene sets (ie, those capturing 
interferon-gamma transcriptional pathways) may be evaluated and new signatures may be 
identified. Individual genes related to the immune system may also be evaluated (eg, IL-10). 
MicroRNA profiling may also be pursued as well as exosomal profiling.
Proteomics and immunohistochemistry (IHC) using blood and/or tumor
Tumor and/or blood samples from this study may undergo proteomic analyses (eg, PD-L1 
IHC). PD L1 protein level in tumor sections, assessed by IHC, has been shown to correlate 
with response to immunotherapy in patients with NSCLC, and an in vitro diagnostic (IVD) 
device has been developed for use with immunotherapy in NSCLC. Preliminary data 
indicates that this association may also be true in additional cancer types (ie, triple negative 
breast cancer, head and neck, and gastric). Additional tumor or blood-derived proteins may 
also correlate with response to immunotherapy. Therefore, tumor tissue may be subjected to 
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proteomic analyses using a variety of platforms that could include but are not limited to 
immunoassays and liquid chromatography/mass spectrometry. This approach could identify 
novel protein biomarkers that could aid in patient selection for immunotherapy and/or 
treatments.
Other biomarkers
In addition to expression on the tumor tissue, PD-L1 and other tumor derived proteins can be 
shed from tumor and released into the blood. Assays such as enzyme-linked immunosorbent 
assay (ELISA) that measure proteins may also be evaluated from blood samples. Correlation 
of these biomarkers with response to immunotherapy and/or treatments may identify new 
approaches for predictive biomarkers in blood, representing a major advance from today’s 
reliance on assessing tumor biomarkers. This research would serve to develop such assays for 
future clinical use. 
Other molecular changes of interest include the subtype of T-cells in the tumor 
microenvironment. The T-cell repertoire from tumor tissue and blood components may be 
evaluated.
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics (serum, plasma) 
and/or the measurement of other analytes, depending on which specimens are consented for 
future biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of future biomedical research are presented in Section 10.2.
Rationale for the Use of Comparator/Placebo
Platinum doublet chemotherapy remains the most widely accepted approach, and currently 
considered the standard of care for treating Stage IV NSCLC in patients with EGFR mutation 
who has failed either 1st or 2nd generation EGFR TKI (eg, erlotinib/afatinib/gefitinib), and has 
not develop T790M mutation as a TKIs-resistant mechanism. Platinum doublet 
chemotherapy is also considered the standard of care for patient who has developed T790M 
mutation and has failed 3rd generation EGFR TKI osimertinib. The most commonly used 
platinum doublet is pemetrexed in combination with cisplatin or carboplatin. In a non-
inferiority, Phase 3 trial, overall survival in 1725 subjects with previously untreated NSCLC 
was found to be non-inferior after treatment with cisplatin and pemetrexed compared to 
cisplatin combined with gemcitabine (median survival 10.3 months versus 10.3 months; HR, 
0.94; 95% CI: 0.84%, 1.05%) [Scagliotti, G. V., et al 2008]. However, in a planned subgroup 
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analysis, cisplatin and pemetrexed was found to be superior in subjects with non-squamous
NSCLC (n=1000; HR 0.81; 95% CI: 0.7, 0.94; p = 0.005). Pemetrexed and platinum therapy 
has become a significant treatment of choice for advanced non-squamous NSCLC. 
Continuation of pemetrexed after initial 4 cycles of pemetrexed cisplatin demonstrated a 
survival benefit in a randomized double-blind, placebo-controlled study: median overall 
survival 13.9 months (95% CI: 12.8, 16.0) for pemetrexed compared to 11.0 months (95%
CI: 10.0, 12.5) for placebo and a HR of 0.78 (95% CI: 0.64, 0.96) [Paz-Ares, L. G., et al 
2013]. Pemetrexed in combination with either cisplatin or carboplatin is therefore an 
appropriate control arm treatment in this Phase 3 trial.  
The use of pembrolizumab matching placebo in combination with platinum doublet 
chemotherapy will ensure the objectivity of the local investigators’ treatment decision and 
AE causality assessments, while still providing participants the SOC treatment.
Justification for Dose 
Rationale for Pembrolizumab Dosing Regimen
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based 
on the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab for adults across all indications and regardless of tumor 
type. As outlined below, this dose is justified by:

Clinical data from 8 randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W), 

Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications, and

Pharmacology data showing full target saturation in both systemic circulation 
(inferred from pharmacokinetic [PK] data) and tumor (inferred from physiologically-
based PK [Physiological Based Pharmacokinetics (PBPK)] analysis) at 200 mg Q3W
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and non-small cell lung cancer (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 studies compared 
2 mg/kg Q3W versus 10 mg/kg Q3W (KN001 Cohort B2, KN001 Cohort D, KN002, 
KN010, and KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W 
(KN001 Cohort B3, KN001 Cohort F2 and KN006). All of these studies demonstrated flat 
dose- and exposure-response relationships across the doses studied representing an 
approximate 5- to 7.5-fold difference in exposure. The 2 mg/kg (or 200 mg fixed-dose) Q3W 
provided similar responses to the highest doses studied. Subsequently, flat dose-exposure-
response relationships were also observed in other tumor types including head and neck 
cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 200 mg 
Q3W as the appropriate dose independent of the tumor type. These findings are consistent 
with the mechanism of action of pembrolizumab, which acts by interaction with immune 
cells, and not via direct binding to cancer cells.
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Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition (TMDD) 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 of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that the fixed-dosing 
provides similar control of PK variability as weight based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. 
Supported by these PK characteristics, and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across all pembrolizumab protocols.
Rationale for Chemotherapy Dosing Regimens
The dosing regimens of chemotherapy represent the SOC per the approved product labels. 
Chemotherapy may be reduced, interrupted, or discontinued at the Investigator’s discretion 
using the guidance provided in Section 6.6. (Note: Guidance in Section 6.6 should serve as a 
guide and do not replace investigator judgment and applicable local label recommendations if 
more stringent.)
Beginning and End of Study Definition
The overall study begins when the first participant provides documented informed consent.
The overall study ends when the last participant completes the last study-related contact, 
withdraws consent or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study, if available. 
Clinical Criteria for Early Study Termination
The clinical trial may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the trial population as 
a whole is unacceptable. In addition, further recruitment in the trial or at (a) particular trial 
site(s) may be stopped due to insufficient compliance with the protocol, Good Clinical 
Practice (GCP) and/or other applicable regulatory requirements, procedure-related problems 
or the number of discontinuations for administrative reasons is too high.
5. Study Population
As stated in the Code of Conduct for Clinical Trials (Appendix 1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the Investigational Medical Product (IMP) under investigation.
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Male/female participants with TKI-resistant EGFR-mutated tumors in metastatic NSCLC
who are at least 18 years of age will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Type of Participant and Disease Characteristics
1. Have histologically or cytologically confirmed diagnosis of Stage IV (AJCC Version 
8 or current version as applicable) non-squamous NSCLC.
2. Have documentation of tumor activating EGFR mutation, specifically either DEL19
or L858R.
3. Have investigator determined radiographic disease progression per RECIST 1.1 after 
treatment with an EGFR TKI therapy:
a) Participants previously treated with 1st or 2nd generation EGFR TKI (eg,
erlotinib/afatinib/gefitinib) are required to have confirmed documented 
absence of EGFR T790M mutation. Note: Participants with negative EGFR
T790M mutation using plasma specimens will be required to have tissue 
biopsy confirmation of negative T790M mutation prior to 
enrollment/confirmation of eligibility.
b) Participants with confirmed acquired T790M mutation after 1st or 2nd
generation EGFR TKI (eg, erlotinib/afatinib/gefitinib) are required to have 
osimertinib TKI treatment failure prior to enrollment. Note: Participants must 
have documentation of acquired T790M mutation (using plasma or tissue 
biopsy specimens) after 1st disease progression prior to osimertinib treatment. 
c) Participants previously failed osimertinib TKI treatment as 1st line therapy are 
eligible regardless of their EGFR T790M mutation status.
Note: TKI washout period for all participants is 1 week or 2 half-lives after last 
treatment dose, whichever is longer. TKI washout should be completed prior to the 
first dose of study medication.
Note: The site’s study team must have reviewed pre-trial images that are of 
diagnostic quality from at least 2 dates to determine that radiographic progression has 
occurred per RECIST 1.1 following initiation of the EGFR TKI. The central imaging 
vendor must have received these scans and have confirmed that they are of acceptable 
diagnostic quality prior to randomization in this trial for a possible retrospective 
analysis of this eligibility criterion. The central vendor will not be confirming 
eligibility prior to randomization.
4. Have measurable disease per RECIST 1.1 as assessed by the local site 
investigator/radiology. Lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions.
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5. Have provided archival tumor tissue sample or newly obtained (no anti-neoplastic 
therapy since biopsy) core or excisional biopsy of a tumor lesion not previously 
irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to 
slides. Newly obtained biopsies are preferred to archival tissue.
Note: If site is sending unstained slides, we strongly recommend that sites freshly cut 
sections and send out to the pathology laboratory within 7 days from sectioning in 
order for samples to be received within 14 days of site slide-cutting date.
Demographics
6. Be ≥18 years of age on the day of signing informed consent.
7. Have a life expectancy of at least 3 months.
8. Have an ECOG performance status of 0 or 1 within 7 days prior to the first dose of 
study treatment but before randomization.
Male participants:
9. A male participant must agree to use contraception as detailed in Section 10.3 of this 
protocol during the treatment period and for at least 120 days after the last dose of 
pembrolizumab and up to 180 days after last dose of chemotherapeutic agents.
Female participants:
10. A female participant is eligible to participate if she is not pregnant (see Section 10.3), 
not breastfeeding, and at least one of the following conditions applies:
a.
Not a woman of childbearing potential (WOCBP) as defined in Appendix 3
OR
b. A WOCBP who agrees to follow the contraceptive guidance in Section 10.3 during 
the treatment period and for at least 120 days after the last dose of pembrolizumab 
and up to 180 days after the last dose of chemotherapeutic agents.
Informed Consent
11. The participant provides written informed consent for the study.
12. Have adequate organ function as defined in the following table (Table 1). Specimens 
must be collected within 10 days prior to the start of study treatment.
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Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/L1
Renal
Creatinine OR
Measured or calculated2 creatinine clearance
(GFR can also be used in place of creatinine or 
CrCl)
≤1.5 × ULN OR
≥50 mL/min for participant with creatinine 
levels >1.5 × institutional ULN
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels 
>1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN 
Coagulation
International normalized ratio (INR) OR 
prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT is 
within therapeutic range of intended use of 
anticoagulants
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit 
of normal.
1 Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion 
within last 2 weeks.
2 Creatinine Clearance should be calculated using the Cockcroft-Gault Method: Refer to Section 10.8 for the 
appropriate calculation.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of specific 
chemotherapies.
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Has predominantly squamous cell histology NSCLC. Mixed tumors will be 
categorized by the predominant cell type; if small cell elements are present, the 
participant is ineligible.
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2. Has symptomatic ascites or pleural effusion. A participant who is clinically stable 
following treatment for these conditions (including therapeutic thoraco- or 
paracentesis) is eligible.
3. A WOCBP who has a positive urine pregnancy test within 72 hours prior to 
randomization (see Section 10.3). If the urine test is positive or cannot be confirmed 
as negative, a serum pregnancy test will be required. 
Note:  In the event that 72 hours have elapsed between the screening pregnancy test 
and the first dose of study treatment, another pregnancy test (urine or serum) must be 
performed and must be negative in order for participant to start receiving study 
medication
Prior/Concomitant Therapy
4. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or 
with an agent directed to another stimulatory or co-inhibitory T-cell receptor 
(eg, CTLA-4, OX-40, CD137).
5. Has received prior systemic cytotoxic chemotherapy or investigational agent(s), 
excluding EGFR TKIs, for metastatic NSCLC.
Note: Prior 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 metastatic NSCLC.
Note: If participant received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting study
treatment.
Note: Prior exposure to traditional medicine(s) is allowed as long as therapy was 
discontinued at least 4 weeks prior to the first dose of study treatment.
6. Has received prior radiotherapy within 2 weeks of start of study treatment or has 
received lung radiation therapy of >30 Gy within 6 months before the first dose of 
study treatment. Participants must have recovered from all radiation-related toxicities, 
not require corticosteroids, and not have had radiation pneumonitis. A 1-week 
washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central 
nervous system (CNS) disease.
7. Has received a live vaccine within 30 days prior to the first dose of study treatment. 
Examples of live vaccines include, but are not limited to, the following:  measles, 
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, bacillus 
Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed; however, intranasal 
influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
Prior/Concurrent Clinical Study Experience
8. Is currently participating in or has participated in a study of an investigational agent 
or has used an investigational device within 4 weeks prior to the first dose of study
treatment.
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Note:  Participants who have entered the follow-up phase of an investigational study 
may participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
Diagnostic Assessments
9. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of study treatment.
10. Has a known additional malignancy that is progressing or has required active 
treatment within the past 5 years.  
Note:  Participants with basal cell carcinoma of the skin, squamous cell carcinoma of 
the skin, superficial bladder cancer, or carcinoma in situ (eg, breast carcinoma, 
cervical cancer in situ) that have undergone potentially curative therapy are not 
excluded.
11. Has known active untreated CNS metastases and/or carcinomatous meningitis. 
Participants with previously treated brain metastases may participate provided they 
are radiologically stable, ie, without evidence of progression for at least 4 weeks by 
repeat imaging (note that the repeat imaging should be performed during study 
screening),  clinically stable and without requirement of steroid treatment for at least 
14 days prior to first dose of study treatment. 
12. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its 
excipients.
13. Has a known sensitivity to any component of cisplatin, carboplatin, or pemetrexed.
14. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(ie, with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency) is not considered a form of 
systemic treatment and is allowed.
15. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis.
16. Has an active infection requiring systemic therapy.
17. Has a known history of human immunodeficiency virus (HIV) infection. No HIV 
testing is required unless mandated by local health authority.
18. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] 
reactive or HBV-DNA detected) or known active Hepatitis C virus (defined as HCV 
RNA [qualitative] is detected or HCV antibody reactive, if HCV-RNA is not the local 
SOC) infection.
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local 
health authority.
19. Has a known history of active tuberculosis (TB; Bacillus tuberculosis)
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20. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant's 
participation for the full duration of the study, or is not in the best interest of the 
participant to participate, in the opinion of the treating investigator.
21. Has known psychiatric or substance abuse disorder that would interfere with 
cooperating with the requirements of the study.
Other Exclusions
22. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 120 days 
after the last dose of pembrolizumab and up to 180 days after the last dose of 
chemotherapeutic agents.
Refer to Section 10.12 for country-specific requirements regarding exclusion criteria.
Lifestyle Considerations
Meals and Dietary Restrictions
Participants 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. Refer to Section 10.3 for 
approved methods of contraception.
Participants 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, participants of childbearing potential must adhere to the contraception 
requirement (Section 10.3) from the day of study medication initiation (or 14 days prior to 
the initiation of study medication for oral contraception) throughout the study period up to 
120 days after the last dose of pembrolizumab and up to 180 days after the last dose of 
chemotherapeutic agents. If there is any question that a participant of childbearing potential 
will not reliably comply with the requirements for contraception, that participant should not 
be entered into the study. 
Pregnancy
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
participant will be immediately discontinued from study treatment. The site will contact the 
participant at least monthly and document the participant’s status until the pregnancy has 
been completed or terminated. The outcome of the pregnancy will be reported to the Sponsor 
without delay and within 24 hours if the outcome is a serious adverse experience (eg, death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn). The study Investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
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Sponsor. If a male participant impregnates his female partner, the study personnel at the site 
must be informed immediately and the pregnancy must be reported to the Sponsor and 
followed as described in Section 10.3.
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, participants who are breastfeeding are not eligible for enrollment.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards 
of Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any AEs or serious adverse events (SAEs) meeting reporting 
requirements as outlined in the data entry guidelines.
Participant Replacement Strategy
A participant who discontinues from study treatment or withdraws consent will not be 
replaced.
6. Treatments
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo,
or medical device(s) intended to be administered to a study participant according to the study 
protocol.
Clinical supplies [study treatment(s) provided by the Sponsor] will be packaged to support 
enrollment. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
Treatments Administered
The treatments to be used in this study are outlined below in Table 2.
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Table 2
Study Treatment(s)
Arm 
Name
Arm 
Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/ 
Treatment 
Period
Use
IMP or 
NIMP/
AxMP
Sourcing
Arm 1
Experi-
mental
Pembrolizumab 
(MK-3475)
Biological/ 
Vaccine
Solution for 
Infusion
100 mg/ 
vial
200 mg 
IV Infusion
Q3W
Test Product
IMP
Provided centrally 
by the Sponsor
Arm 1
Experi-
mental
Pemetrexed
Drug
Lyophilized 
Powder
500 mg / 
vial
500 
mg/m2
IV Infusion
Q3W
Background 
Treatment
NIMP/ 
AxMP
Provided locally by 
the study site, 
subsidiary, or 
designee. OR 
Provided centrally 
by the Sponsor
Arm 1
Experi-
mental
Carboplatin
Drug
Solution for 
Infusion
10 mg/mL 
vial
AUC 5 
mg/mL•
min
IV Infusion
Q3W for 
4 cycles 
(Cycles 1-
4)
Background 
Treatment
NIMP/ 
AxMP
Provided locally by 
the study site, 
subsidiary, or 
designee. OR 
Provided centrally 
by the Sponsor
Arm 1
Experi-
mental
Cisplatin
Drug
Solution for 
Infusion
1 mg/mL 
vial
75 
mg/m2
IV Infusion
Q3W for 
4 cycles 
(Cycles 1-
4)
Background 
Treatment
NIMP/ 
AxMP
Provided locally by 
the study site, 
subsidiary, or 
designee. OR 
Provided centrally 
by the Sponsor
Arm 2
Placebo 
Com-
parator
Saline Placebo
Drug
Solution for 
Infusion
NA
NA
IV Infusion
Q3W
Placebo
IMP
Provided locally by 
the study site, 
subsidiary, or 
designee
Arm 2
Placebo 
Com-
parator
Pemetrexed
Drug
Lyophilized 
Powder
500 mg / 
vial
500 
mg/m2
IV Infusion
Q3W
Background 
Treatment
NIMP/ 
AxMP
Provided locally by 
the study site, 
subsidiary, or 
designee. OR 
Provided centrally 
by the Sponsor
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Arm 
Name
Arm 
Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/ 
Treatment 
Period
Use
IMP or 
NIMP/
AxMP
Sourcing
Arm 2
Placebo 
Com-
parator
Carboplatin
Drug
Solution for 
Infusion
10 mg/mL 
vial
AUC 5
mg/mL•
min
IV Infusion
Q3W for 
4 cycles 
(Cycles 1-
4)
Background 
Treatment
NIMP/ 
AxMP
Provided locally by 
the study site, 
subsidiary, or 
designee. OR 
Provided centrally 
by the Sponsor
Arm 2
Placebo 
Com-
parator
Cisplatin
Drug
Solution for 
Infusion
1 mg/mL 
vial
75 
mg/m2
IV Infusion
Q3W for 
4 cycles 
(Cycles 1-
4)
Background 
Treatment
NIMP/ 
AxMP
Provided locally by 
the study site, 
subsidiary, or 
designee. OR 
Provided centrally 
by the Sponsor
AUC=area under the curve; EEA=European Economic Area; IMP=investigational medicinal product; IV=intravenous; NA=not applicable; NIMP/AxMP=noninvestigational/
auxiliary medicinal product; Q3W=every 3 weeks.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with 
respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
In this protocol, placebo for pembrolizumab is diluent alone (normal saline and/or dextrose); diluent is used for blinding purposes and does not contain active ingredients.
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For pemetrexed plus platinum chemotherapy, the investigator will select one of the following 
regimens prior to randomization:

Pemetrexed 500 mg/m2 + carboplatin AUC 5 mg/mL•min Q3W for 4 cycles followed 
by pemetrexed 500 mg/m2 Q3W

Pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 for 4 cycles followed by pemetrexed 
500 mg/m2 Q3W
Maintenance pemetrexed may continue for participants past 35 administrations until reaching 
a discontinuation criterion (Section 7.1), as long as the participant is receiving benefit and per 
local regulations, whereas pembrolizumab/saline placebo are limited to 35 administrations.
All study treatments will be administered on an out-patient basis.
All products indicated in Table 2 will be provided centrally by the Sponsor or locally by the 
study site, subsidiary or designee, depending on local country operational or regulatory 
requirements with the exception of saline placebo, which will be provided locally by the 
study site, subsidiary or designee.
For any commercially available product that is provided by the study site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number.  
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
All supplies indicated in Table 2 will be provided per the ‘Sourcing’ row depending upon 
local country operational requirements. Every attempt should be made to source these 
supplies from a single lot/batch number where possible (eg, not applicable in the case where 
multiple lots or batches may be required due to the length of the study, etc.).
Refer to Section 8.1.8 for details regarding administration of the study treatment.
Preparation/Handling/Storage/Accountability
Dose Preparation
Pembrolizumab: the dose amount required to prepare the pembrolizumab infusion solution 
will be based on a fixed dose of 200 mg. Details on the dose calculation, preparation and 
administration are provided in the Pharmacy Manual.
Chemotherapeutic agents will be prepared and administered as per the approved product 
label at the doses indicated below:

Pemetrexed: 500 mg/m2

Cisplatin: 75 mg/m2
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
Carboplatin: AUC 5 mg/mL•min (using Calvert formula). Carboplatin dose not to 
exceed 750 mg
Calvert Formula
Total Dose (mg) = (target AUC) x (CrCl*+25)
The estimated GFR used in the Calvert formula should not exceed 125 mL/min
Maximum carboplatin dose (mg) = target AUC 5 (mg/mL•min) x (125+25) = 
5x150 mL/min = 750 mg
*CrCl should be calculated using the Cockcroft-Gault Method: Refer to Section 10.8 for the 
appropriate calculation.
Handling, Storage and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment. All study treatments must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of study 
treatments in accordance with the protocol and any applicable laws and regulations.
Measures to Minimize Bias: Randomization and Blinding
Method of Treatment Assignment 
Treatment allocation/randomization will occur centrally using an interactive response 
technology (IRT) system. There are 2 study treatment arms. Participants will be assigned 
randomly in a 1:1 ratio to pembrolizumab plus pemetrexed plus platinum chemotherapy or 
saline placebo plus pemetrexed plus platinum chemotherapy, respectively.
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Stratification
Treatment allocation/randomization will be stratified according to the following factors:
1. PD-L1 expression: Tumor Proportion Score (TPS) ≥50% or TPS <50%;
2. Treatment history: osimertinib or no osimertinib;
3. Geographic region of the enrolling site: East Asia versus Non-East Asia
Blinding 
This is a double-blinded trial; therefore, the participant, the Investigator and Sponsor 
personnel or delegate(s) who are involved in the treatment administration or clinical 
evaluation of the participants are unaware of the group assignments. The chemotherapy 
agents will be open-label. The Sponsor, investigator and participant will not know whether 
the treatment administered contains pembrolizumab or saline placebo. The study site’s 
unblinded pharmacist will obtain each participant’s study identification number and study 
treatment assignment from the interactive voice response system (IVRS)/interactive web 
response system (IWRS) and prepare the solutions for infusion. The unblinded pharmacist 
will provide the investigative staff with ready-to-use blinded pembrolizumab/saline placebo 
infusion solutions, packaged identically in order to maintain the blinding, for administration 
at scheduled infusion. The unblinded pharmacist should have no involvement in study 
assessments.
See Section 8.1.10 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
Treatment Compliance
Administration of study medication(s) will be monitored by the Investigator and/or study
staff. The total volume of study medication infused will be compared with the total volume 
prepared to determine compliance with each dose administered.
Interruptions from the protocol-specified treatment plan for more than 12 weeks between 
study treatment doses for nondrug-related or administrative reasons require consultation 
between the Investigator and the Sponsor and written documentation of the collaborative 
decision on participant management.
Concomitant Therapy
Acceptable Concomitant Medications
Palliative and supportive care is permitted during the course of the study for underlying 
medical conditions and management of symptoms. Surgery for tumor control is not permitted 
during the study. Palliative radiotherapy is permitted to a limited number of lesions if 
considered medically necessary by the treating physician as long as the lesions are NOT a 
RECIST 1.1-defined target lesion. Study therapy should be held during the course of 
palliative radiotherapy, and study therapy should be resumed no earlier than the next 
scheduled administration of study therapy. The specifics of the radiation treatment, including 
the location, will be recorded.
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All concomitant medications received within 28 days before the first dose of study 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 10.4.
If a participant enters into second course therapy, all concomitant medications received 
within 28 days before the first dose of second course treatment should be recorded. 
Following second course therapy Safety Follow-up Visit, record all medications taken for 
SAEs and ECIs as defined in Section 10.4.
Prohibited Concomitant Medications
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study. If there is a clinical indication for any medication or vaccination
specifically prohibited, discontinuation from study intervention may be required. The 
investigator is to discuss prohibited medication/vaccination with the Sponsor’s Clinical 
Director. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician. However, the decision to continue the 
participant on study treatment requires the mutual agreement of the investigator, the Sponsor 
and the participant.
Listed below are specific restrictions for concomitant therapy or vaccination during the 
course of the study:

Antineoplastic systemic chemotherapy or biological therapy 

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab/saline placebo

Radiation therapy 
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the Investigator’s discretion. 

Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study. Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, 
and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed; however, intranasal influenza vaccines (eg, 
FluMist®) are live attenuated vaccines and are not allowed. 
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, replication-
incompetent adenoviral vaccines, or inactivated vaccines. These vaccines will be 
treated just as any other concomitant therapy.
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are 
not allowed.
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
Systemic glucocorticoids for any purpose other than those described in Section 
6.5.3.1 are prohibited. The use of physiologic doses of corticosteroids may be 
approved after consultation with the Sponsor.
Replacement doses of steroids (for example, prednisone 10 mg daily) are permitted 
while on study, as is the use of local steroid injections and topical steroids.

Phenytoin during therapy with cisplatin/carboplatin.
Participants who, in the assessment of the Investigator, require the use of any of the 
aforementioned treatments for clinical management should be discontinued from study
treatment.  
All treatments that the Investigator considers necessary for a participant’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 eCRF including all 
prescription, over-the-counter (OTC) products, herbal supplements, and IV medications and 
fluids. If changes occur during the study period, documentation of drug dosage, frequency, 
route, and date should also be included on the eCRF.
All concomitant medications received within 28 days prior to the first dose of study treatment 
and up to 30 days after the last dose of study treatment should be recorded. Concomitant 
medications administered 30 days after the last dose of study treatment should be recorded 
for SAEs and events of clinical interest (ECIs) as defined in Section 10.4.
If a participant enters into second course therapy, all concomitant medications received 
within 28 days before the first dose of second course treatment should be recorded. 
Following second course therapy Safety Follow-up Visit, record all medications taken for 
SAEs and ECIs as defined in Section 10.4.
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 6.6.
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the Investigator does not need to follow the treatment guidance. Refer to Table 4 in Section 
6.6 for guidelines regarding dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
For supportive care guidelines for chemotherapy agents, please refer to current version of the 
SmPC for cisplatin, carboplatin, and pemetrexed for details.
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Systemic Corticosteroid Use
Systemic corticosteroids are permitted in the following situations:

To modulate symptoms of an AE that is suspected to have an immunologic etiology
as guided in Table 4.

For the prevention of emesis and other chemotherapy-related AEs.

To premedicate for IV contrast allergies.

To treat asthma or chronic obstructive pulmonary disease (COPD) exacerbations 
(only short-term oral or IV use in doses >10 mg/day prednisone equivalent).

For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent.
In addition, the following corticosteroid use is allowed:

Topical use or ocular use

Intraarticular joint use

Inhalation in the management of asthma or COPD
Antiemetic Use
For participants receiving chemotherapy, antiemetic therapy should follow Multinational 
Association of Supportive Care in Cancer (MASCC) or appropriate local guidelines 
(Section 10.7) and should, for the first 4 cycles, include a 5-HT3 receptor antagonist, 
dexamethasone (or equivalent), and aprepitant (or equivalent NK-1 receptor antagonist) as 
per the guideline followed.
Colony-Stimulating Factors
For participants receiving chemotherapy, the American Society of Clinical Oncology 
(ASCO) guidelines for use of colony-stimulating factors (CSFs), or local equivalent, should 
be used for patient management [Smith, T. J., et al 2015].
Pemetrexed Premedication
All participants must receive the appropriate supplementation of vitamin B12 and folic acid 
and corticosteroid prophylaxis as listed below or as per local label:

Folic acid 350 to 1000 μg oral: at least 5 doses of folic acid must be taken during the 
7 days preceding the first dose of pemetrexed, and folic acid dosing must continue 
during the full course of therapy and for 21 days after the last dose of pemetrexed.

Vitamin B12 1000 μg IM injection in the week preceding the first dose of pemetrexed 
and once every 3 cycles thereafter. Subsequent vitamin B12 injections may be given 
the same day as pemetrexed administration.

Dexamethasone prophylaxis 4 mg, orally twice per day (or equivalent). Taken the day 
before, day of, and day after pemetrexed administration. Higher or additional doses 
are permitted for antiemetic prophylaxis during Cycles 1 through 4 but not to exceed 
doses in MASCC guidelines (or local equivalent).
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Cisplatin Premedication
Hydration is necessary to cause sufficient diuresis during and after treatment with cisplatin. 
All participants should receive adequate hydration from 2 to 12 hours prior to administration 
until minimum 6 hours after the administration of cisplatin per the local label. 
Dose Modification (Escalation/Titration/Other)
If appropriate, the investigator may attribute each toxicity event to cisplatin/carboplatin, 
pemetrexed or pembrolizumab alone or to the combination and use a stepwise dose reduction 
according to Table 3 to Table 7. Dose modifications must be based on the maximum toxicity 
experienced during a cycle. Toxicity needs to resolve to Grade ≤1 or baseline prior to 
resuming subsequent cycle. For individual participants requiring a dose modification, 
treatment for each new cycle may be delayed if the scheduled off-drug periods are not 
adequate to allow for recovery to Grade ≤1 or the baseline status of the participant. 
Pembrolizumab dose reductions are not permitted. Pembrolizumab treatment may be 
interrupted or discontinued due to toxicity. If a dose reduction for toxicity occurs with any 
agent, the dose may not be re-escalated. Participants can have a maximum of 2 dose 
modifications (if applicable) to each of the components of study therapy throughout the 
course of the study for toxicities. If a participant experiences several toxicities and there are 
conflicting recommendations, the most conservative dose adjustment recommended should 
be followed (dose reduction appropriate to the most severe toxicity). Participants who require 
a 3rd dose modification to any particular component will have that agent discontinued.
Reduction of 1 chemotherapy agent and not the other agent is appropriate if, in the opinion of 
the investigator, the toxicity is clearly related to one of the treatments. If, in the opinion of 
the investigator, the toxicity is related to the combination of both chemotherapy agents, both 
drugs should be reduced according to recommended dose modifications. If the toxicity is 
related to the combination of 3 agents, all 3 agents should be reduced (if applicable), 
interrupted or discontinued according to the recommended dose modifications. 
Participants may have chemotherapy discontinued and continue on pembrolizumab/saline 
placebo alone. Similarly participants may discontinue pembrolizumab/saline placebo and 
continue on chemotherapy alone if appropriate.
Chemotherapy may be interrupted for a maximum of 6 weeks from last dose; pembrolizumab 
may be interrupted for a maximum of 12 weeks from last dose.
The Common Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0) must be 
used to grade the severity of adverse events. All dose modifications should be based on the 
AE requiring the greatest dose modification. Dose modifications are detailed in Table 3
through Table 7.
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Table 3
Dose Modifications for Study Medications
Dose Level 0
Dose Level -1
Dose Level -2
Dose Level -3
Cisplatin
75 mg/m2
56 mg/ m2
38 mg/ m2
Discontinue
Carboplatin
Area under curve (AUC) 5
Maximum dose 750mg
AUC 3.75
Maximum dose 
562.5mg
AUC 2.5
Maximum dose 
375mg
Discontinue
Pemetrexed
500mg/m2
375 mg/m2
250 mg/m2
Discontinue
Pembrolizumab/
Saline placebo
200 mg fixed dose
Dose reductions 
are not permitted
Dose reductions 
are not permitted
Dose reductions 
are not permitted
Dose Modification for Pembrolizumab
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 4. 
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Table 4
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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Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 5. 
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Table 5
Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the investigator.
None
Grade 2
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping drug infusion, the infusion may 
be restarted at 50% of the original infusion rate (eg, from 100 mL/hr to 50 
mL/hr). Otherwise dosing will be held until symptoms resolve and the 
participant should be premedicated for the next scheduled dose.
Participants who develop Grade 2 toxicity despite adequate premedication 
should be permanently discontinued from further study drug treatment
Participant may be premedicated 1.5h (± 
30 minutes) prior to infusion of 
pembrolizumab with:
Diphenhydramine 50 mg po (or equivalent 
dose of antihistamine).
Acetaminophen 500-1000 mg po (or 
equivalent dose of analgesic).
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NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (eg, renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy may include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be used immediately.
Participant is permanently discontinued from further study drug 
treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at http://ctep.cancer.gov
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Other allowed dose interruption for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Participants should 
be placed back on study therapy within 12 weeks of the scheduled interruption, unless 
otherwise discussed with the Sponsor. The reason for interruption should be documented in 
the participant's study record.
Dose Modification for Chemotherapy
Recommended dose modifications for key chemotherapy toxicities are outlined in Table 6
and Table 7. These serve as a guide and do not replace investigator judgment and applicable 
local label recommendations if more stringent.
Table 6
Recommended Dose Modifications for Chemotherapy Hematological Toxicity
Pemetrexed
Cisplatin/Carboplatin
Platelets
ANC
Dose level (DL) from Table 3
≥50,000/mcL  AND
≥ 500/mcL
DL 0
DL 0
≥50,000/mcL  AND
< 500/mcL
DL -1
DL -1
<50,000/mcL without bleeding 
AND
ANY
DL -1
DL -1
<50,000/mcL with Grade ≥ 2 
bleeding AND
ANY
DL -2
DL -2
ANY AND
< 1,000/mcL + fever ≥ 
38.5°C (101°F)
DL -1
DL -1
Table 7
Recommended Dose Modifications for Chemotherapy Non-Hematological 
Toxicity
Pemetrexed
Cisplatin
Carboplatin
Event
CTC Grade
Dose level (DL) from Table 3
Nausea or vomiting
Grade 3 or 4
DL 0
DL 0
DL 0
Diarrhea
Grade 3 or 4
DL -1
DL -1
DL 0
Mucositis
Grade 3 or 4
DL -2
DL 0
DL 0
Neurotoxicity
Grade 2
DL 0
DL -2
DL 0
Grade 3 or 4
DL -1
Discontinue
DL -1
Transaminase elevation
Grade 3
DL -1
DL -1
DL -1
Grade 4
Discontinue
Discontinue
Discontinue
Other non-hematological
toxicity
Grade 3 or 4
DL -1
DL -1
DL -1
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Creatinine clearance (CrCl):
CrCl will be based original weight-based Cockcroft and Gault formula in Section 10.8. CrCl 
must be ≥45 mL/min prior to the administration on the day of chemotherapy. Pemetrexed 
and/or platinum may be delayed for up to 42 days to allow the participant time to recover 
from the toxicity. If a participant’s CrCl value has not returned to ≥45 mL/min within 
42 days after the previous dose, platinum and/or pemetrexed must be discontinued.
Treatment After the End of the Study 
There is no study-specified treatment following the end of the study.
Clinical Supplies Disclosure
This study is blinded but supplies are provided open label; therefore, an unblinded 
pharmacist or qualified study site personnel will be used to blind supplies. Study treatment 
identity (name, strength or potency) is included in the label text; random code/disclosure 
envelopes or lists are not provided.
The emergency unblinding call center will use the treatment/randomization schedule for the 
study to unblind participants and to unmask study treatment identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.10). In the 
event that the emergency unblinding call center is not available for a given site in this study, 
the central electronic treatment allocation/randomization system (IRT) should be used in 
order to unblind participants and to unmask study treatment identity. The Sponsor will not 
provide random code/disclosure envelopes or lists with the clinical supplies.
See Section 8.1.10 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
7. Discontinuation of Study Treatment and Participant Withdrawal
Discontinuation of Study Treatment 
Discontinuation of study treatment does not represent withdrawal from the study.
As certain data on clinical events beyond study treatment discontinuation may be important 
to the study, they must be collected through the participant’s last scheduled follow-up, even 
if the participant has discontinued study treatment. Therefore, all participants who 
discontinue study treatment prior to completion of the protocol-specified treatment period
will still continue to participate in the study as specified in Section 1.3 and Section 8.11.5
unless the participant has withdrawn from the study (Section 7.2).
Participants may discontinue study treatment at any time for any reason or be discontinued
from the study treatment at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study treatment by the investigator 
or the Sponsor if study treatment is inappropriate, the study plan is violated, or for 
administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study treatment discontinuation are provided in Section 8.1.9.
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A participant must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons:
○
The participant or participant’s legally acceptable representative requests to discontinue 
study treatment.
o
The participant’s treatment assignment has been unblinded by the investigator for reasons 
other than BICR-verified radiographic disease progression, by MSD subsidiary or 
through the emergency unblinding call center.
o
Any prolonged interruption of study intervention beyond the permitted periods, for irAE 
management or other allowed dose interruptions, as noted in Section 6.6.1 require 
Sponsor consultation prior to restarting treatment. If treatment will not be restarted, the 
participant will continue to be monitored in the study and the reason for discontinuation 
of study intervention will be recorded in the medical record.
o
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study treatment.
o
The participant has a confirmed positive serum pregnancy test.
o
BICR-verified disease progression as outlined in Section 8.2.1 AND the participant is 
clinically unstable.
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 (eg, cord compression) requiring urgent alternative medical 
intervention.
o
Any progression or recurrence of any malignancy, or occurrence of another malignancy 
that requires active treatment
o
Noncompliance with study treatment or procedure requirements
o
Unacceptable adverse experiences.
Completion of pembrolizumab Q3W monotherapy consists of 35 treatments (approximately 
2 years). Discontinuation of treatment may be considered for participants who have attained a 
confirmed CR and have been treated for at least 8 cycles (at least 24 weeks), receiving 2 
doses of pembrolizumab beyond the date when the initial CR was declared. These 
participants may be eligible for second course treatment described in Section 8.11.4.
For participants who are discontinued from study treatment but continue to be monitored in 
the study, all visits and procedures, as outlined in the SoA, should be completed.
Participants may be allowed to begin study treatment again if deemed medically appropriate
for Second Course Retreatment Phase if the participant meets all eligibility criteria in Section 
8.11.4.
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Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant decides not to continue receiving study intervention, the participant is to be 
encouraged to continue visits in the study for follow-up, imaging, and vital status assessment.
Participants who withdraw consent during the study
If the participant or participant’s legally acceptable representative withdraws consent, the 
participant must be withdrawn from the study.
Section 8.1.9 delineates the specific procedures performed at the time of withdrawal and
withdrawal from future biomedical research. Survival Follow-up Procedures are outlined in 
Section 8.11.6.3. Any AEs that are present at the time of withdrawal should be followed in 
accordance with the safety requirements outlined in Section 8.4. The procedures to be 
performed should a participant repeatedly fail to return for scheduled visits and/or if the 
study site is unable to contact the participant are outlined in Section 7.3.
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
●
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
●
The investigator or designee must make every effort to regain contact with the 
participant at each missed visit (eg, telephone calls and/or a certified letter to the 
participant’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the participant’s medical record.
●
Note:  A participant is not considered lost to follow-up until the last scheduled visit 
for the individual participant. The missing data for the participant will be managed 
via the prespecified statistical data handling and analysis guidelines.
8. Study Assessments and Procedures
●
Study procedures and their timing are summarized in the SoA. 
●
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
●
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training and experience) staff. Delegation of 
study site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
●
All study-related medical (or dental) decisions must be made by an investigator who 
is a qualified physician (or dentist when appropriate).
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●
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
●
Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.
●
Additional evaluations/testing may be deemed necessary by the investigator and or 
the Sponsor for reasons related to participant safety. In some cases, such 
evaluation/testing may be potentially sensitive in nature (eg, HIV, Hepatitis C, etc.), 
and thus local regulations may require that additional informed consent be obtained 
from the participant. In these cases, such evaluations/testing will be performed in 
accordance with those regulations.
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 participant can be found in the Procedures Manual.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
Administrative and General Procedures
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or future biomedical 
research. If there are changes to the participant’s status during the study (eg, health or age of 
majority requirements), the investigator or medically qualified designee must ensure the 
appropriate documented informed consent is in place. 
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the trial protocol number, trial 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant 
before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant's willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
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captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
Specifics about the study and the study population are to be included in the study informed 
consent form. 
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, or the participant’s legally acceptable representative, answer all of 
his/her questions, and obtain documented informed consent before performing any procedure 
related to future biomedical research. A copy of the informed consent will be given to the 
participant before performing any procedure related to future biomedical research.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator who is a qualified 
physician to ensure that the participant qualifies for the study.
Participant Identification Card
All participants will be given a Participant Identification Card identifying them as 
participants in a research study. The card will contain study site contact information 
(including direct telephone numbers) to be utilized in the event of an emergency. The 
investigator or qualified designee will provide the participant with a Participant Identification 
Card immediately after the participant provides documented informed consent. At the time of 
treatment allocation/randomization, site personnel will add the treatment/randomization 
number to the Participant Identification Card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
treatment in emergency situations where the investigator is not available.
Medical History
A medical history will be obtained by the investigator or qualified designee.
Prior and Concomitant Medications Review
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before first dose of study medication.
Prior anti-cancer treatment for NSCLC will be recorded separately and not listed as a prior 
medication. The investigator or qualified designee will review and record all prior anti-
cancer treatments including systemic treatments, radiation, and surgeries, regardless of the 
time prior to first dose of study treatment.
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Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the Safety Follow-up Visit. In addition, new medications started 
during the Crossover Phase and Second Course through the Crossover Safety Follow-up Visit 
and Second Course Safety Follow-up Visit should be recorded.
All medications related to reportable SAEs and ECIs should be recoded as defined in 
Sections 8.4 and 10.4.
Subsequent Anti-Cancer Therapy Status
The investigator or qualified designee will review all new anti-cancer therapy initiated after 
the last dose of study treatment. If a participant initiates a new anti-cancer therapy within 30 
days after the last dose of study treatment, the 30 day Safety Follow-up visit must occur 
before the first new dose of the new therapy. Once new anti-cancer therapy has been initiated 
the participant will move into survival follow-up.
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only one screening number. Screening numbers must not be re-used for 
different participants.
Any participant 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 8.11.1. 
Treatment Eligibility Assessment (TEA) Form
A TEA form is included in this study to document the investigators’ choice of carboplatin or 
cisplatin and the rationale. These data may be required to support reimbursement efforts for 
pembrolizumab.  
The investigator must complete this form to document the rationale for the choice of 
carboplatin or cisplatin prior to randomization. 
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
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Treatment Administration
Administration of study medication will be monitored by the investigator and/or study staff.
Study interventions will be administered by the investigator and/or study staff according to 
the specifications within the pharmacy manual. The total volume of pembrolizumab infused 
will be compared to the total volume prepared to determine compliance to each dose of 
pembrolizumab administered.
The instructions for preparing and administering pembrolizumab will be provided in the 
Pharmacy Manual. Premedication should also be dosed per the approved product labels and 
as described in Section 6.5.3.
Study treatment should begin on the day of treatment allocation/randomization or as close as 
possible to the date on which the participant is allocated/assigned.
Timing of Dose Administration
Participants will receive blinded pembrolizumab 200 mg or saline placebo together with 
pemetrexed 500 mg/m2 (with vitamin supplementation) + cisplatin 75 mg/m2 OR carboplatin 
AUC 5 mg/mL•min all on Day 1 Q3W for 4 cycles followed by blinded pembrolizumab 
200 mg or saline placebo together with pemetrexed 500 mg/m2 Q3W on Day 1 of each 
subsequent cycle until BICR-verified disease progression, study completion, or any 
discontinuation criteria are met per Sections 7.1 and 8.1.9.
Study treatment should be administered on Day 1 of each cycle after all procedures / 
assessments have been completed (Section 1.3). Study treatment can be administered 3 days
before or after of the targeted Day 1 for each cycle, except Cycle 1 Day 1 (C1D1), where 
study treatment can only be administered + 3 days from randomization.
All study treatments will be administered on an outpatient basis.
Timing of Dose Administration of Pembrolizumab/Saline Placebo
Pembrolizumab/saline placebo will be administered as a dose of 200 mg using a 30-minute 
IV infusion prior to administration of chemotherapy agents. Sites should make every effort to 
target infusion timing to be as close to 30 minutes as possible. However, given the variability 
of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (ie, 
infusion time is 30 minutes -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for pembrolizumab reconstitution, 
preparation of the infusion fluid, and administration.
For participants who experience disease progression, investigators may elect to interrupt 
treatment by deferring the decision to continue/discontinue treatment in the trial until 
confirmation of disease progression per RECIST 1.1 at least 28 days from the date of 
imaging demonstrating disease progression confirmed through blinded central imaging 
vendor review. Participants for whom disease progression is not confirmed on subsequent 
imaging may resume treatment. Please see Section 7 for other exceptions.
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Pemetrexed
Pemetrexed 500 mg/m2 will be administered as an IV infusion over 10 minutes Q3W until 
progression or unacceptable toxicity. All participants should receive the appropriate 
supplementation of vitamin B12 and folic acid and corticosteroid prophylaxis as described in 
Section 6.5 and/or according to local practice and labels.
Cisplatin
Cisplatin 75 mg/m2 will be administered as an IV infusion over a recommended time of 60
minutes. However, cisplatin may be administered over 30 to 150 minutes to accommodate 
local SOC. Treatment will be administered after pemetrexed on Day 1 of the 21 day cycle, 
for a maximum of 4 administrations.
Cisplatin administration should be immediately preceded and followed by hydration 
procedures described in Section 6.6 and administered according to local practice and labels. 
Carboplatin
Carboplatin AUC 5 mg/mL•min will be administered as an IV infusion over 30 to 60 
minutes. Treatment will be administered after pemetrexed on Day 1 of the 21 day cycle, for a 
maximum of 4 administrations. The dose of carboplatin will be calculated using the Calvert 
Formula as described in Section 6.2.
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.
Discontinuation and Withdrawal
Participants who withdraw consent from the study should be encouraged to complete all 
applicable activities scheduled for the final study visit at the time of withdrawal.
Once the participant moves to survival follow-up, he/she shall not be allowed to restart study 
treatment, but overall survival information will still be collected.
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the principal investigator for the main study. If 
medical records for the main study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@MSD.com). 
Subsequently, the participant's consent for future biomedical research will be withdrawn. A 
letter will be sent from the Sponsor to the investigator confirming the withdrawal. It is the 
responsibility of the investigator to inform the participant of completion of withdrawal. Any 
analyses in progress at the time of request for withdrawal or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
study data and results. No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
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or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
Participant Blinding/Unblinding
STUDY TREATMENT IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the drug used by a participant and/or the dosage 
administered, he/she will contact the emergency unblinding call center by telephone and 
make a request for emergency unblinding. As requested by the investigator or medical 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s treatment assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity/toxicity grade of the AEs observed, the relation to study drug, the reason thereof, 
etc., in the medical chart etc., in the medical chart. If it is not possible to record this 
assessment in the chart prior to the unblinding, the unblinding should not be delayed.
For studies that require non-emergency unblinding as part of the study design (BICR-verified 
radiographic disease progression) to support treatment decisions, instructions in Section 8.11
should be followed. The emergency unblinding center should not be used for this purpose.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician should continue to be monitored in the 
study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. In the event that the 
emergency unblinding call center is not available for a given site in this study, the IRT
system should be used for emergency unblinding in the event that this is required for 
participant safety.
Study treatment identification information is to be unmasked ONLY if necessary for the 
welfare of the participant. Every effort should be made not to unblind the participant unless 
necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible. Once an emergency unblinding has 
taken place, the principal investigator, site personnel, and Sponsor personnel may be
unblinded so that the appropriate follow-up medical care can be provided to the participant.
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
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calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
Efficacy Assessments 
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the central imaging vendor can be 
found in the Site Imaging Manual. CT scans are preferred over other tumor imaging methods. 
For the abdomen and pelvis, contrast-enhanced magnetic resonance imaging (MRI) may be 
used when CT with iodinated contrast is contraindicated, or when mandated by local 
practice. MRI is the strongly preferred modality for imaging the brain. The same type of
scan, ideally the same scanner, and the use of contrast should be used in a participant 
throughout the study to optimize the reproducibility of the assessment of existing and new 
tumor burden and improve the accuracy of the response assessment. Note: for the purposes of 
assessing tumor imaging, the term “Investigator” refers to the local investigator at the site 
and/or the radiological reviewer located at the site or at an offsite facility.
Brain MRI will be done for all participants at screening. If MRI is medically contraindicated, 
then CT with contrast is an acceptable alternative.
Participant eligibility will be determined using local assessment (Investigator assessment) 
based on RECIST 1.1. All scheduled images for all study participants from the sites will be 
submitted to the central imaging vendor. In addition, images (including via other modalities) 
that are obtained at an unscheduled time point to determine disease progression, as well as 
imaging obtained for other reasons, but which demonstrate radiologic progression, should 
also be submitted to the central imaging vendor.
When the Investigator identifies radiographic progression per RECIST 1.1, the central 
imaging vendor will perform expedited verification of radiologic PD and communicate the 
results to the study site and Sponsor (See Section 8.2.1.5 and Figure 3). Treatment should 
continue until PD has been verified. Regardless of whether PD is verified, if the Investigator 
considers the participant has progressed, but elects to implement iRECIST, the Investigator 
will assess for confirmation of progression by iRECIST at subsequent time points (Section 
1.2, Figure 3). Images should continue to be submitted to the central imaging vendor. 
Initial Tumor Imaging
The site’s study team must have reviewed pre-trial images from at least 2 dates to confirm 
that radiographic progression has occurred per RECIST 1.1 confirming disease progression 
after TKI treatment failure. The central imaging vendor must have received these scans prior 
to randomization in this trial for a possible retrospective analysis of this eligibility 
criterion. The central imaging vendor must also confirm that pre-trial scans are of diagnostic 
quality prior to randomization. 
Initial tumor imaging at Screening must be performed within 28 days prior to the date of 
randomization. The site study team must review screening images to confirm the participant 
has measurable disease per RECIST 1.1. 
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The screening images must be submitted to the central imaging vendor for retrospective 
review.
Tumor imaging performed as part of routine clinical management is acceptable for use as 
screening tumor imaging if it is of diagnostic quality and performed within 28 days prior to 
the date of randomization and can be assessed by the central imaging vendor.  
When brain imaging is performed, MRI should be used if possible. If MRI is medically 
contraindicated, then CT with contrast is an acceptable alternative.
Tumor Imaging During the Study
The first on-study imaging assessment should be performed at 6 weeks (42 days +7 days) 
from the date of randomization. Subsequent tumor imaging should be performed every 9
weeks (63 days ±7 days) or more frequently if clinically indicated. After 51 weeks, 
participants who remain on treatment will have imaging performed every 12 weeks (84 days 
±7 days). Imaging timing should follow calendar days and should not be adjusted for delays 
in cycle starts. Imaging should continue to be performed until disease progression is 
identified by the Investigator and verified by the central imaging vendor (unless the 
Investigator elects to continue treatment and follow iRECIST), the start of a new anti-cancer 
treatment, pregnancy, withdrawal of consent, death, or the end of the study. All imaging must 
be submitted to the central imaging vendor. 
Objective response should be confirmed by a repeat imaging assessment. Tumor imaging to 
confirm PR or CR should be performed at least 4 weeks after the first indication of a 
response is observed. Participants will then return to regular scheduled imaging, starting with 
the next scheduled imaging time point. Participants who receive additional imaging for 
confirmation do not need to undergo the next scheduled tumor imaging if it is less than 4 
weeks later; tumor imaging may resume at the subsequent scheduled imaging time point. 
Note:  Response does not typically need to be verified in real time by the central imaging 
vendor.
On-study brain or bone imaging should be performed if clinically indicated or to confirm CR
(if other lesions indicate CR and brain or bone lesions existed at baseline).
Per iRECIST (Section 8.2.1.6), disease progression should be confirmed by the site 4 to 
8 weeks after central verification of site-assessed first radiologic evidence of PD in clinically 
stable participants. Participants, who have unconfirmed disease progression may continue on 
their assigned study treatment at the discretion of the Investigator until progression is 
confirmed by the site (Section 1.2, Figure 3) and provided they have met the conditions 
detailed in Section 8.2.1.6. Participants who receive confirmatory imaging do not need to 
undergo the next scheduled tumor imaging if it is less than 4 weeks later; tumor imaging may 
resume at the subsequent scheduled imaging time point, if clinically stable. Participants, who 
have confirmed disease progression by iRECIST, as assessed by the site, will discontinue 
study treatment. Exceptions are detailed in Section 8.2.1.6.
End of Treatment and Follow-up Tumor Imaging
For participants who discontinue study treatment, tumor imaging should be performed at the 
time of treatment discontinuation (±4 week window). If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation 
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is not mandatory. For participants who discontinue study treatment due to documented 
disease progression, this is the final required tumor imaging if the Investigator elects not to 
implement iRECIST.
For participants who discontinue study treatment without documented disease progression, 
tumor imaging using the same imaging schedule used while on treatment (every 9 weeks in 
Year 1 or every 12 weeks after Year 1) or according to local standard of care imaging 
intervals should be used to monitor disease status until the start of new anti-cancer treatment, 
disease progression, pregnancy, death, withdrawal of consent, or the end of the study, 
whichever occurs first.
Second Course (Retreatment) and Crossover Tumor Imaging
Tumor imaging must be performed within 28 days prior to starting/restarting treatment with 
pembrolizumab. The Investigator, working with local radiology will be used to determine 
eligibility. Imaging should be submitted to the central imaging vendor for quality control, 
storage, and possible retrospective review.
The first on-study imaging assessment should be performed at 12 weeks (±7 days) after the 
restart of treatment. Subsequent tumor imaging should be performed every 12 weeks 
(±7 days) or more frequently, if clinically indicated.
Per iRECIST (Section 8.2.1.6), if tumor imaging shows initial PD, tumor assessment should 
be repeated 4 to 8 weeks later in order to confirm PD with the option of continuing treatment 
while awaiting radiologic confirmation of progression. Participants who obtain confirmatory 
imaging do not need to undergo scheduled tumor imaging if it is less than 4 weeks later and 
may wait until the next scheduled imaging time point, if clinically stable.
Imaging should continue to be performed until disease progression, the start of a new anti-
cancer treatment, pregnancy, withdrawal of consent, death, or the end of the study, whichever 
occurs first. In clinically stable participants, disease progression may be confirmed by the 
investigator using iRECIST 4 to 8 weeks after the first tumor imaging indicating PD.
For participants who discontinue Second Course study treatment, tumor imaging should be 
performed at the time of treatment discontinuation (±4 week window). If previous imaging 
was obtained within 4 weeks prior to the date of discontinuation, then imaging at treatment 
discontinuation is not mandatory. For participants who discontinue study treatment due to 
documented disease progression, this is the final required tumor imaging.
For participants who discontinue Second Course study treatment without documented disease 
progression, radiologic tumor imaging using the same imaging schedule used while on 
treatment (ie, every 12 weeks ±7 days) or according to local standard of care imaging 
intervals should be used to monitor disease status until the start of new anti-cancer treatment, 
disease progression, pregnancy, death, withdrawal of consent, or the end of the study, 
whichever occurs first.
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used by BICR as the primary measure for assessment of tumor response, 
date of disease progression, and as a basis for all protocol guidelines related to disease status 
(eg, discontinuation of study treatment). Although RECIST 1.1 references a maximum of 
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5 target lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions 
in total and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden. 
Initial tumor imaging showing site-assessed PD should be submitted immediately for BICR 
verification of PD. The site will be notified if the BICR verifies PD using RECIST 1.1.  
Figure 5 illustrates the imaging flow involving verification of PD for clinically stable 
participants.
iRECIST Assessment of Disease
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the Investigator, working with local 
radiology to assess tumor response and progression, and make treatment decisions. When 
clinically stable, participants should not be discontinued until progression is confirmed by the 
Investigator, working with local radiology, according to the rules outlined in Section 10. This 
allowance to continue treatment despite initial radiologic PD takes into account the 
observation that some participants can have a transient tumor flare in the first few months 
after the start of immunotherapy, and then experience subsequent disease response. This data 
will be captured in the clinical database.
Clinical stability is defined in Section 7.1.
Any participant deemed clinically unstable should be discontinued from study treatment at 
central verification of site-assessed first radiologic evidence of PD, and is not required to 
have repeat tumor imaging for confirmation of PD by iRECIST.
If the Investigator decides to continue treatment, the participant may continue to receive 
study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per Investigator assessment. Images should continue to be sent in to the 
central imaging vendor for potential retrospective BICR. 
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
If a participant has confirmed radiographic progression (iCPD) as defined in Section 10, 
study treatment should be discontinued; however, if the participant is achieving a clinically 
meaningful benefit, an exception to continue study treatment may be considered following 
consultation with the Sponsor. In this case, if study treatment is continued, tumor imaging 
should continue to be performed following the intervals as outlined in Section 1.3 and 
submitted to the central imaging vendor. 
A description of the adaptations and iRECIST process is provided in Section 10, with 
additional details in the iRECIST publication [Seymour, L., et al 2017]. A summary of 
imaging and treatment requirements after first radiologic evidence of progression is provided 
in Table 8 and illustrated as a flowchart in Figure 5.
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Table 8
Imaging and Treatment after First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic evidence of 
PD by RECIST 1.1 that has 
been verified by BICR
Repeat imaging at 4 to 
8 weeks to confirm PD.
May continue study treatment at 
the Investigator’s discretion 
while awaiting confirmatory 
tumor imaging by site by 
iRECIST.
Repeat imaging at 4 to 
8 weeks to confirm PD per 
Investigator’s discretion 
only.
Discontinue treatment
Repeat tumor imaging 
confirms PD (iCPD) by 
iRECIST per Investigator 
assessment
No additional imaging 
required.
Discontinue treatment 
(exception is possible upon 
consultation with Sponsor).
No additional imaging 
required.
Not applicable
Repeat tumor imaging 
shows iUPD by iRECIST 
per Investigator assessment
Repeat imaging at 4 to 
8 weeks to confirm PD. 
May occur at next 
regularly scheduled 
imaging visit.
Continue study treatment at the 
Investigator’s discretion.
Repeat imaging at 4 to 
8 weeks to confirm PD per 
Investigator’s discretion 
only.
Discontinue treatment
Repeat tumor imaging 
shows iSD, iPR, or iCR by 
iRECIST per Investigator 
assessment.
Continue regularly 
scheduled imaging 
assessments.
Continue study treatment at the 
Investigator’s discretion.
Continue regularly 
scheduled imaging 
assessments.
May restart study treatment if 
condition has improved and/or 
clinically stable per Investigator’s 
discretion. Next tumor imaging 
should occur according to the 
regular imaging schedule.
iCPD=iRECIST confirmed progressive disease; iCR=iRECIST complete response; iRECIST=modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics; iSD=iRECIST stable disease; iUPD=iRECIST unconfirmed progressive disease; PD=progressive disease; RECIST 1.1=Response Evaluation Criteria in Solid Tumors 
1.1; VOP=verification of progression
Note:  If progressive disease (PD) has been centrally verified, further management is by the site, based on iRECIST. Any further imaging should still be submitted to the central 
imaging vendor, but no real-time review will occur. If RECIST 1.1 disease progression has not been centrally verified, ideally the site should continue treatment. Whether or not 
treatment continues, imaging should be collected and submitted to the central imaging vendor with VOP request until RECIST 1.1 progression is verified by BICR.
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Figure 5
Imaging and Treatment for Clinically Stable Participants After First Radiologic 
Evidence of PD Assessed by the Investigator
Patient Reported Outcomes
The EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ-LC13 questionnaires will be 
administered by trained site personnel and completed electronically by participants in the 
following order: EQ-5D-5L first, then EORTC QLQ-C30, then EORTC QLQ-LC13. The 
questionnaires should be administered prior to dosing at every cycle through Cycle 7, then 
every 3rd cycle through Cycle 19, then every 4th cycles through Cycle 35 (eg, Cycles 1-7, 
10, 13, 16, 19, 23, 27, 31, and 35), at the Treatment Discontinuation Visit, and at the 30-day 
Safety Follow-up Visit.
If the Treatment Discontinuation visit occurs 30 days from the last dose of study treatment, at 
the time of the mandatory Safety Follow-up visit, PROs do not need to be repeated.
It is best practice and strongly recommended that electronic patient reported outcomes 
(ePROs) are administered to randomized participants prior to drug administration, adverse 
event evaluation, and disease status notification. If the participant does not complete the 
ePROs at a scheduled time point, the MISS_MODE form must be completed to capture the 
reason the assessment was not performed.
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below.
Planned time points for all safety assessments are provided in the SoA.
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Physical Examinations
A complete (full) physical examination will be conducted by an investigator or medically 
qualified designee (consistent with local requirements) as per institutional standard during 
the Screening period and at Discontinuation. 
For cycles that do not require a full physical examination, a brief directed physical 
examination will be conducted as per institutional standard. 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
Vital Signs
Vital signs will be collected at Screening, prior to the administration of each dose of study 
treatment, EOT/Discontinuation and/or 30 days after the last dose of study treatment (follow-
up) as outlined in the SoA in Section 1.3. Vital signs measurements include temperature, 
pulse, respiratory rate, weight, and blood pressure. Height will be measured at Screening
only. Refer to Section 10.12 for country-specific requirements. 
Electrocardiograms
A single 12-lead electrocardiogram (ECG) will be obtained and reviewed by an investigator 
or medically qualified designee (consistent with local requirements) at Screening and at 
EOT/Discontinuation using local standard procedures as outlined in the SoA in Section 1.3. 
Clinically significant abnormal findings at Screening should be recorded as medical history. 
Additional ECGs may be performed as clinically necessary.
Clinical Safety Laboratory Assessments
Refer to Section 10.5 for the list of clinical laboratory tests to be performed and to the SoA 
for the timing and frequency. 
●
The investigator or medically qualified designee (consistent with local requirements)
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected 
for the participant's condition.
●
All protocol-required laboratory assessments, as defined in Section 10.5, must be 
conducted in accordance with the laboratory manual and the SoA Section 1.3.
●
If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in study participant management or 
are considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
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●
For any laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 30 days after the last dose of study 
treatment, every attempt should be made to perform repeat assessments until the 
values return to normal or baseline or if a new baseline is established as determined 
by the investigator. 
Details regarding specific laboratory procedures/assessments to be performed in this study 
are provided below. The total amount of blood/tissue to be drawn/collected over the course 
of the study (from pre-study to post-study visits), including approximate blood/tissue 
volumes drawn/collected by visit and by sample type per participant can be found in the 
Procedures Manual. Refer to the SoA in Section 1.3 for the timing of laboratory assessments.
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Section 10.5.
Pregnancy Test
●All women who are being considered for participation in the study, and who are not 
surgically sterilized or postmenopausal, must be tested for pregnancy within 72 hours 
of the first dose of study treatment. If a urine test is positive or not evaluable, a serum 
test will be required. Participants must be excluded/discontinued from the study in the 
event of a positive test result. Repeated Pregnancy test (such as monthly testing) may 
be conducted if required by local regulations. 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events 
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Section 10.4, Appendix 4.
Progression of the cancer under study is not considered an AE as described in Section 8.4.5 
and Section 10.4.
AE, SAEs, and other reportable safety events will be reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events.
Investigators remain responsible for following up AE, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
Adverse events will not be collected for participants during the prescreening period (for 
determination of archival tissue status) as long as that participant has not undergone any 
protocol-specified procedure or intervention. If the participant requires a blood draw, fresh 
tumor biopsy etc., the participant is first required to provide consent to the main study and 
AEs will be captured according to guidelines for standard AE reporting.
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Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent but before treatment allocation/randomization must be 
reported by the investigator if the participant is receiving placebo run-in or other run-in 
treatment, if the event causes the participant to be excluded from the study, or is the result of 
a protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, or a procedure. 

All AEs from the time of treatment allocation/randomization through 30 days 
following cessation of study treatment must be reported by the investigator. 

All AEs meeting serious criteria, from the time of treatment allocation/randomization 
through 90 days following cessation of study treatment, or 30 days following 
cessation of study treatment if the participant initiates new anticancer therapy, 
whichever is earlier must be reported by the investigator. 

All pregnancies and exposure during breastfeeding, from the time of treatment 
allocation/randomization through 120 days following cessation of study treatment, or 
30 days following cessation of study treatment if the participant initiates new 
anticancer therapy must be reported by the investigator. 

Additionally, any SAE brought to the attention of an investigator at any time outside 
of the time period specified above must be reported immediately to the Sponsor if the 
event is considered to be drug-related.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator
considers the event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 9.
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Table 9
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Time Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to 
SPONSOR:
Consent to 
Randomization/ 
Allocation
Randomization/ 
Allocation through 
Protocol-Specified 
Follow-up Period
After the Protocol 
Specified Follow-
up Period
Non-Serious Adverse 
Event (NSAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse 
Event (SAE)
including Cancer and 
Overdose
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine 
related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if 
participant has 
been exposed to 
any protocol-
specified 
intervention (eg, 
procedure, 
washout or run-in 
treatment 
including placebo 
run-in)
Report all
Previously reported 
– Follow to 
completion/terminat
ion; report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- Potential drug-
induced liver injury 
(DILI)
- Require regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (Do not 
require regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- non-DILI ECIs and 
those not requiring 
regulatory reporting
Not required
Within 5 
calendar days
of learning of 
event
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Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AE and/or SAE and other reportable 
safety events. Open-ended and nonleading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.
Follow-up of AE, SAE and Other Reportable Safety Event Information 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE, SAE, and other reportable safety events 
including pregnancy and exposure during breastfeeding, ECIs, Cancer and Overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Section 10.4.
Regulatory Reporting Requirements for SAE

Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is 
essential so that legal obligations and ethical responsibilities toward the safety of 
participants and the safety of a study treatment under clinical investigation are met. 

The Sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study treatment under clinical 
investigation. All AEs will be reported to regulatory authorities, IRB/IECs and 
investigators in accordance with all applicable global laws and regulations, ie, per 
ICH Topic E6 (R2) Guidelines for GCP.

Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy 
and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file 
it along with the IB and will notify the IRB/IEC, if appropriate according to local 
requirements.
Disease-related Events and/or Disease-related Outcomes Not Qualifying as AEs 
or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 8.4.1. 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will ensure that unblinded aggregated efficacy endpoint events and safety data
are monitored to safeguard the participants in the study. 
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Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Any pregnancy complication will be reported as an AE or SAE. 
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus. 
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
Events of Clinical Interest (ECIs)
Selected nonserious and serious adverse events are also known as ECIs and must be reported 
to the Sponsor.
Events of clinical interest for this study include: 
1. an overdose of Sponsor's product, as defined in Section 8.5, 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 study site guidance for 
assessment and follow-up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent).
ECIs that occur after the participant provides documented informed consent, but before 
treatment randomization, must be reported by the investigator to Sponsor if the event caused 
the participant to be excluded from the study or is the result of a protocol-specified 
intervention.
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All ECIs that occur from the time of treatment randomization through 30 days following 
cessation of study treatment must be reported by the investigator to Sponsor in accordance 
with the reporting time period described in Table 9.
Treatment of Overdose
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater (≥5 times the indicated dose). 
No specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious 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 electronic data collection (EDC) data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Pharmacokinetics
PK parameters will not be evaluated in this study.
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
Biomarkers
To identify novel biomarkers, the following biospecimens to support exploratory analyses of 
cellular components (eg, protein, RNA, DNA, metabolites) and other circulating molecules 
will be collected from all participants in this study as specified in the SoA:

Blood for ctDNA, Genetics, and RNA Analyses

Blood for Serum and Plasma Analyses

Archival tumor specimen
Sample collection, storage and shipment instructions for the exploratory biomarker 
specimens will be provided in the laboratory manual.
The sample for genetic analysis should be drawn for planned exploratory biomarker research. 
This sample will not be collected at the site if there is either a local law or regulation 
prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for 
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these purposes. If the sample is collected, leftover extracted DNA will be stored for future 
biomedical research if the participant provides documented informed consent for future 
biomedical research. If the genetic sample collection is not approved, but future biomedical 
research is approved and consent is given, this sample will be collected for the purpose of 
future biomedical research.
Future Biomedical Research Sample Collection 
If the participant provides documented informed consent for the biomedical research, the 
following specimens will be obtained as part of future biomedical research:

Leftover DNA for future research

Leftover main study tumor stored for future research

Leftover main study serum/plasma from biomarker analyses stored for future 
research

Leftover main study RNA stored for future research

Leftover plasma or derivative for ctDNA
Medical Resource Utilization and Health Economics
All-cause hospitalizations and emergency department visits must be reported in the eCRF, 
from the time of treatment allocation/randomization through 90 days following cessation of 
study treatment, or 30 days following cessation of study treatment, if the participant initiates 
new anti-cancer therapy, whichever is earlier.
Visit Requirements
Screening
Within 42 days prior to treatment allocation/randomization, potential participants will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 5. 
Screening procedures may be repeated after consultation with the Sponsor.
Documented informed consent must be obtained prior to performing any protocol-specific 
procedure. Results of a test performed prior to the participant providing documented 
informed consent as part of routine clinical management are acceptable in lieu of a screening 
test if performed within the specified time frame. Screening procedures are to be completed 
within 42 days prior to the first dose of study treatment except for the following:

Laboratory tests are to be performed within 10 days prior to the first dose of study 
treatment. An exception is hepatitis and/or HIV (if required by local SOC) testing 
which may be done up to 28 days prior to the first dose of study treatment.

Evaluation of ECOG is to be performed within 7 days prior to the first dose of 
study treatment but before randomization (see Section 10.6).

For women of reproductive potential, a urine or serum pregnancy test will be 
performed within 72 hours prior to the first dose of study treatment. If urine 
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pregnancy results cannot be confirmed as negative, a serum pregnancy test will be 
required (performed by the local study site laboratory).

Archival tumor sample collection is not required to be obtained within 42 days 
prior to the first dose of study treatment. Newly obtained tumor tissue may be 
obtained within 90 days of treatment initiation.
Participants may be rescreened after initially failing to meet the inclusion/exclusion 
criteria. Results from assessments during the initial screening period are acceptable in 
lieu of a repeat screening test if performed within the specified time frame and the 
corresponding inclusion/exclusion criteria is met. Participants who are rescreened will 
retain their original screening number.
Initial Treatment Phase 
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.1.
Crossover Treatment Phase
Participants who experience BICR-verified disease progression and are unblinded (Section 
1.2, Figure 3) will have the opportunity to crossover to receive pembrolizumab monotherapy. 
At the time of documented disease progression as confirmed by BICR using RECIST 1.1 
(Section 8.2.1), participants may have treatment assignment unblinded (Figure 3). 
Participants who received saline placebo in combination with chemotherapy may be eligible 
to receive pembrolizumab monotherapy for a total of 35 administrations in the Crossover 
Treatment Phase. 
Participants who received pembrolizumab in combination with chemotherapy, but are 
deemed to be benefiting clinically despite disease progression, may continue study treatment 
beyond progression and receive pembrolizumab monotherapy in the Crossover Treatment 
Phase to complete a total of up to 35 pembrolizumab administrations. 
Study treatment may continue until participant reaches a discontinuation criterion (Section 
7.1), examples of which include subsequent documented progression, unacceptable adverse 
event(s), intercurrent illness that prevents further administration of treatment, investigator’s
decision to withdraw the participant, participant withdraws consent, pregnancy of the 
participant, noncompliance with study treatment or procedure requirements, or for 
administrative reasons.
Crossover Qualifications:
Participants will be considered for crossover to pembrolizumab monotherapy after
documented, progressive disease assessed based on RECIST 1.1 verified by central imaging 
vendor BICR. Participants who permanently discontinue chemotherapy due to an adverse 
event, withdraw consent, or for any reason other than progressive disease, will not be eligible 
for crossover. Crossover participants must not initiate treatment with pembrolizumab any
earlier than 21 days after their last dose of chemotherapy regardless of the time of 
progression.
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Crossover is optional and is at the discretion of the Investigator and with Sponsor 
consultation. Participants who meet the following criteria are eligible for crossover:

Documented verification of progressive disease by BICR;

Adverse events (except alopecia) due to therapy must have improved to CTCAE 
(Version 4.0) ≤Grade 1;

ECOG Performance Status 0-1

Participant has not received any other cytotoxic anticancer therapies other than the
chemotherapy administered during the initial treatment phase;

If required, completed palliative radiotherapy (30 Gy or less) ≥7 days before
the first dose of crossover study treatment.

Participant has adequate organ function as indicated by the laboratory values in 
Section 5.1 (Inclusion Criteria).
If progressive disease is centrally verified but participant does not qualify for Crossover per 
the above listed criteria, unblinding may be considered after consulting with Sponsor.
NOTE: If a participant is clinically unstable as a result of a new or progressing CNS 
metastasis(es) the participant will not be eligible for crossover.
Crossover Assessments and Procedures
Crossover participants must not initiate treatment with pembrolizumab any earlier than
21 days after their last dose of chemotherapy regardless of the time of progression. The
participant will then start the Crossover Phase as outlined in Crossover Treatment Phase SoA 
in Section 1.3.2. Crossover entry procedures need to be completed within 28 days of 
confirmed progressive disease (or up to 42 days from last dose if recovering from adverse 
event). All procedures and assessments completed at the time of withdrawal from the Initial 
Treatment Phase may be used as appropriate for the start of the Crossover Treatment Phase
of the study. The tumor image used to determine progressive disease can be used as the
new baseline image for the Crossover Phase if: 1) 28 days prior to receiving the first
dose of pembrolizumab monotherapy and 2) No study treatment between the image and
first dose of pembrolizumab monotherapy, otherwise a new baseline image must be
performed prior to pembrolizumab monotherapy treatment.
Participants entering the Crossover Treatment Phase will be treated with pembrolizumab 
monotherapy. Chemotherapy will not be dosed in the Crossover Treatment Phase.
Pembrolizumab monotherapy will be dosed every 21 days ± 3 days (1 cycle). Treatment may 
continue until a discontinuation criterion is met (Section 7.1).
Second Course Retreatment Phase
Second Course Phase visit requirements are outlined in the SoA (Section 1.3.3). Specific 
procedure-related details are provided in Section 8.1.
Participants who stop study treatment with a SD or better may be eligible for up to an 
additional 17 cycles (approximately 1 year) of pembrolizumab monotherapy treatment if they 
progress after stopping study treatment from the Initial Treatment Phase. This retreatment is 
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termed Second Course Phase and is only available if the study remains open and the 
participant meets the following conditions:
Either

Stopped initial treatment with study treatment after attaining an investigator-
determined confirmed CR based on RECIST 1.1, and
o Was treated with at least 8 cycles of study treatment before discontinuing
treatment, and
o Received at least 2 treatments with pembrolizumab beyond the date when the 
initial CR was declared
OR

Had SD, PR, or CR and stopped study treatment after completion of 35 
administrations (approximately 2 years) of study treatment for reasons other than 
disease progression or intolerability
AND, regardless of what is true above

Experienced an investigator-determined radiographic disease progression by
RECIST 1.1 after stopping initial treatment, and
o Upon unblinding at the time of centrally verified disease progression were 
found to have been treated on the pembrolizumab plus chemotherapy arm, and
o No new anti-cancer treatment was administered after the last dose of study 
treatment, and
o The participant meets all of the safety parameters listed in the inclusion criteria 
and none of the safety parameters listed in the exclusion criteria, and 
o The study is ongoing.
Participants who enter the Second Course Phase will be retreated with open-label 
pembrolizumab monotherapy. Chemotherapy will not be dosed in Second Course Phase.
Pembrolizumab will be dosed every 21 days (1 cycle) for up to 17 administrations
(approximately 1 year). Treatment may continue until a discontinuation criterion is met 
(Section 7.1).
An objective response or progression of disease that occurs during the Second Course Phase 
for a participant will not be counted as an event in the primary analyses in this trial.
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
All participants who discontinue study treatment prior to completion of the protocol-
specified treatment period will still continue to participate in the study as specified in Section 
1.3. 
Descriptions of the study follow-up visits including required procedures are provided in 
Section 8.11.6.
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Post-Study
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study treatment and before the initiation of a new anti-cancer treatment. 
Participants who are eligible for crossover and/or retreatment with pembrolizumab 
monotherapy may have up to 2 safety follow-up visits; 1 after the Initial Treatment Period, 
and 1 after either the Crossover Phase or after the Second Course Treatment.
Follow-up Visits
Participants who complete the protocol-required cycles of study intervention or who
discontinue study treatment for a reason other than BICR-verified disease progression will 
move into the Follow-Up Phase and should be assessed at least every 12 weeks ± 7 days to 
monitor disease status, including tumor imaging. Follow-up Visits may be scheduled to 
coincide with Follow-up imaging (eg, 9 weeks from last imaging time point through Week 
51 or 12 weeks from last imaging if after Week 51). Follow-up visits and imaging continue 
until BICR-verified PD, the start of new anti-cancer treatment, pregnancy, participant 
withdraws consent, participant becomes lost to follow-up, participant death, or end of the 
study. Participants who completed all efficacy assessments and/or will not have further 
efficacy assessments must enter the Survival Follow-up Phase.
Participants discontinuing treatment with BICR-verified PD proceed directly to survival 
follow-up or Crossover Treatment Phase, if applicable. 
The Sponsor may request survival status to be assessed at additional time points during the 
course of the study (not to exceed approximately 12 weeks). Every effort should be made to 
collect information regarding disease status until disease progression, death, end of study or 
if the participant begins Second Course Retreatment Phase with pembrolizumab as detailed 
in Section 8.11.4. Information regarding post-study anticancer treatment will be collected if 
new treatment is initiated.
Participants who are eligible to receive retreatment with pembrolizumab according to the 
criteria in Section 8.11.4 will move from the Follow-Up Phase to the Second Course Phase 
when they experience disease progression. Details are provided in the Study Flow Chart 
(Section 1.2) for retreatment with pembrolizumab.
Survival Follow-up Assessments
Participants who experience BICR-verified disease progression will move into the Survival 
Follow-Up Phase and should be contacted by telephone approximately every 12 weeks to 
assess for survival status until death, withdrawal of consent, or the end of the trial, whichever 
occurs first. Survival status can be done in a variety of ways including phone, email, chart 
review, or review of public records. Survival status information (whether by telephone, 
review of public records, etc.) should be officially documented by the site.
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Participant survival follow-up status will be assessed approximately every 12 weeks until 
death, withdrawal of consent, or the end of the study, whichever occurs first.
The first survival follow-up assessment should be scheduled as described below: 
For participants who discontinue treatment intervention and who will not enter the efficacy 
follow-up phase, the first survival follow-up assessment will be scheduled 12 weeks after the 
discontinuation visit and/or safety follow-up visit (whichever is last).  
For participants who completed assessments in the efficacy follow-up phase, the first 
survival follow-up assessment will be scheduled 12 weeks after the last efficacy assessment 
follow-up visit has been performed.
Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to but not limited to an external Data 
Monitoring Committee (eDMC) review, interim and/or final analysis. Upon Sponsor 
notification, all participants who do not/will not have a scheduled study visit or study contact 
during the Sponsor defined time period will be contacted for their survival status (excluding 
participants that have a previously recorded death event in the collection tool). Survival 
status can be done in a variety of ways including phone, email, chart review, or review of 
public records. Survival status information (whether by telephone, review of public records, 
etc.) should be officially documented by the site.
9. Statistical Analysis Plan 
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, changes made to primary and/or key secondary hypotheses, or the statistical 
methods related to those hypotheses, then the protocol will be amended (consistent with ICH 
Guideline E-9). Changes to exploratory or other non-confirmatory analyses made after the 
protocol has been finalized, will be documented in a supplemental Statistical Analysis Plan
(sSAP) and referenced in the Clinical Study Report (CSR) for the study. Post hoc exploratory 
analyses will be clearly identified in the CSR. Separate analysis plans (ie, separate 
documents from the sSAP) may be developed to detail other planned analyses (ie, those 
specific to the analysis of patient-reported outcomes and future biomedical research). 
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Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 to 9.11.  
Study Design Overview
A Randomized, Double-Blind, Phase 3 Study of Pemetrexed + Platinum 
Chemotherapy with or without Pembrolizumab (MK-3475) in TKI-
resistant EGFR-mutated Tumors in Metastatic Non-squamous Non-small 
Cell Lung Cancer (NSCLC) Participants (KEYNOTE-789)
Treatment Assignment
Participants will be randomized in a 1:1 ratio to receive pembrolizumab 
or saline placebo in combination with pemetrexed plus platinum 
chemotherapy, with pemetrexed maintenance. Stratification factors are in 
Section 6.3.1.1. This is a randomized double-blinded study.
Analysis Populations
Efficacy: Intention to Treat (ITT)
Safety: All Participants as Treated (APaT)
Primary Endpoint(s)
1)
Progression-free Survival (PFS) per RECIST 1.1 assessed by
BICR
2)
Overall survival (OS)
Key Secondary Endpoints
1)
Objective response rate (ORR) per RECIST 1.1 assessed by BICR
Statistical Methods for Key 
Efficacy Analyses
The dual primary hypotheses on PFS and OS will be evaluated by 
comparing pembrolizumab to saline placebo in combination with platinum 
and pemetrexed using a stratified Log-rank test. The HR will be estimated 
using a stratified Cox regression model. Event rates over time will be 
estimated within each treatment group using the Kaplan-Meier method. 
The stratified M&N method with sample size weights will be used for 
analysis of ORR.
Statistical Methods for Key 
Safety Analyses
The analysis of safety results will follow a tiered approach. There are no 
Tier 1 safety parameters in this trial. All safety parameters are considered 
either Tier 2 or Tier 3. Tier 2 parameters will be assessed via point 
estimates with 95% confidence intervals provided for between-group 
comparisons; only point estimates by treatment group are provided for 
Tier 3 safety parameters. The between-treatment difference will be 
analyzed using the Miettinen and Nurminen method.
In the primary safety comparison, participants who crossover to 
pembrolizumab monotherapy are censored at time of crossover (ie, AEs 
occurring during treatment with pembrolizumab are excluded for 
control-arm participants). Additional safety summary may be conducted 
for the crossover population including all safety events starting from the 
date of the first dose of pembrolizumab. Safety data from the Second 
Course Treatment Phase will be summarized separately and will not be 
included in the primary safety comparison.
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Interim Analyses
Three interim analyses will be performed in this study. Results will be 
reviewed by an external data monitoring committee. The primary purpose 
of the interim analyses is to demonstrate superior efficacy. Safety data will 
also be reviewed at each planned interim analysis to assess the overall risk: 
benefit. These interim analyses and the FA are summarized below. Details 
are provided in Section 9.7. 

IA 1: 
o
Timing: To be performed at approximately 6 months after the 
last participant has been randomized (estimated ~30 months 
after the first participant randomized)
o
Testing: 1) To demonstrate superiority of pembrolizumab in 
combination with platinum and pemetrexed in PFS; 2) To 
demonstrate superiority of pembrolizumab in combination 
with platinum and pemetrexed in OS.

IA 2 (Final PFS analysis):
o
Timing: To be performed ~16 months after the last 
participant has been randomized AND approximately
414 PFS events have been observed (estimated ~40 months 
after the first participant randomized).
o
Testing: 1) To demonstrate superiority of pembrolizumab in 
combination with platinum and pemetrexed in PFS; 2) To 
demonstrate superiority of pembrolizumab in combination 
with platinum and pemetrexed in OS.

IA 3:
o
Timing: To be performed at ~29 months after the last 
participant has been randomized (estimated ~53 months after 
the first participant randomized).
o
Testing: To demonstrate superiority of pembrolizumab in 
combination with platinum and pemetrexed in OS.

FA:
o
Timing: To be performed at ~42 months after the last 
participant has been randomized AND approximately
423 deaths have occurred (estimated ~66 months after the 
first participant randomized).
o
Testing: To demonstrate superiority of pembrolizumab in 
combination with platinum and pemetrexed in OS.

Note that for the FA, if the OS events accrue slower than expected
such that the targeted number of events cannot be reached in the 
anticipated timeframe, the Sponsor may conduct the analysis with 
approximately 2 additional months of follow-up, or when the specified 
number of events is observed, whichever occurs first. If the observed 
number of OS events at the time of IA3 is very close to the target 
number of events at FA (if more than ~98% information fraction, ie,
~415 OS events), then IA3 will become the FA using the remaining 
alpha that has not been spent at the earlier analyses, and will be 
performed at ~29 months after the last participant has been 
randomized and approximately 423 deaths have occurred.
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Multiplicity
The study uses an extension of the graphical method of Maurer and Bretz 
[Maurer, W. and Bretz, F. 2013] to control multiplicity for multiple 
hypotheses as well as interim analyses. According to this approach, study 
hypotheses may be tested more than once, and when a particular null 
hypothesis is rejected, the alpha allocated to that hypothesis can be 
reallocated to other hypothesis tests. The overall type I error is controlled 
at 0.025 (one-sided) for the hypothesis testing of ORR, PFS and OS. The 
pre-allocated alpha is 0, 0.0125 and 0.0125 for ORR, PFS, and OS, 
respectively.
Sample Size and Power 
The planned sample size is 492 participants assuming 24 months of 
enrollment. The FA will occur after approximately 423 deaths have been 
observed. With 492 participants, the study has ~86% power to detect a 
HR of 0.72 on OS at 0.0125 (one-sided) alpha-level, and ~91% power to 
detect a HR of 0.7 on PFS at 0.0125 (one-sided) alpha-level.
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The Sponsor will generate the randomized allocation schedule(s) for study treatment
assignment for this protocol, and the randomization will be implemented in IVRS.
This trial is double blinded with a Crossover Phase. At the time of documented progression, 
participants may have treatment assignment unblinded and be able to continue therapy in the 
Crossover Phase (please refer to Section 4, Study Design for details). In addition, the BICR
will be performed by the central imaging vendor without knowledge of treatment assignment.
Blinding issues related to the planned interim analyses are described in Section 9.7.  
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below.
Efficacy Endpoints
Dual Primary
Progression-free survival (PFS) – RECIST 1.1 assessed by BICR
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 central 
imaging vendor review or death due to any cause, whichever occurs first. See Section 9.6.1
for the censoring rules.
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Overall Survival
Overall Survival (OS) is defined as the time from randomization to death due to any cause. 
Participants without documented death at the time of analysis will be censored at the date of 
last known contact. 
Secondary
Objective response rate (ORR) – RECIST 1.1 assessed by BICR
Objective response rate (ORR) is defined as the proportion of participants who have a CR or 
a partial response (PR). Responses are based on confirmed assessments by the BICR by the 
central imaging vendor per RECIST 1.1.
Duration of Response (DOR) – RECIST 1.1 assessed by BICR
For participants who demonstrated CR or PR, duration of response (DOR) is defined as the 
time from first documented evidence of CR or PR until disease progression or death. 
Response duration for participants who have not progressed or died at the time of analysis 
will be censored at the date of their last tumor assessment. Response duration will be 
calculated for RECIST 1.1 based on BICR by the imaging vendor.
Safety Endpoints
Safety measurements are described in Section 4.2.1.2.
PRO Endpoints
The secondary patient-reported outcome (PRO) endpoints include the global health 
status/quality of life scale of the QLQ-C30 (items 29 and 30) and TTD in the composite 
endpoint of cough (LC13 Q1), chest pain (LC13 Q10) or dyspnea (C30 Q8). The TTD is
defined as the time from baseline to first onset of 10 points or more deterioration from 
baseline with confirmation by the subsequent visit of 10 points or more deterioration from 
baseline in any of the 3 items.  
Additional scales of EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-5L are exploratory 
PRO endpoints as described in Section 3 and will also be evaluated. Details will be provided 
in the sSAP.
Analysis Populations
Efficacy Analysis Populations
The Intention-to-Treat (ITT) population will serve as the population for primary efficacy 
analysis. All randomized participants will be included in this population. Participants will be 
included in the treatment group to which they are randomized.
Safety Analysis Populations
The All Participants as Treated (APaT) population will be used for the analysis of safety data 
in this study. The APaT population consists of all randomized participants who received at 
least one dose of study treatment. Participants will be included in the treatment group 
corresponding to the study treatment they actually received for the analysis of safety data 
using the APaT population. For most participants this will be the treatment group to which 
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they are randomized. Participants who take incorrect study treatment for the entire treatment 
period will be included in the treatment group corresponding to the study treatment actually 
received. Any participant who receives the incorrect study medication for one cycle but 
receives the correct treatment for all other cycles will be analyzed according to the 
participant’s randomized treatment group and a narrative will be provided for any events that 
occur during the cycle for which the participant was incorrectly dosed. 
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
PRO Analysis Populations
The PRO analyses are based on the PRO full analysis set (FAS) population, defined as 
participants who have at least one PRO assessment available and have received at least one 
dose of study medication.
Statistical Methods
Statistical testing and inference for safety analyses are described in Section 9.6.2. Efficacy 
results that will be deemed to be statistically significant after consideration of the Type I 
error control strategy are described in Section 9.8, Multiplicity. Nominal p-values may be 
computed for other efficacy analyses, but should be interpreted with caution due to potential 
issues of multiplicity, sample size, etc.
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the supplemental 
SAP.
All statistical tests, unless otherwise specified, will be stratified for the stratification factors.
Progression-free Survival (PFS)
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. The treatment difference in PFS will be assessed by the stratified log-rank 
test (based on the stratification factors defined in Section 6.3.1.1). A stratified Cox 
proportional hazard model with Efron's method of tie handling will be used to assess the 
magnitude of the treatment difference (ie, HR) between the treatment arms. The HR and its 
95% confidence interval from the stratified Cox model with Efron's method of tie handling 
and with a single treatment covariate will be reported. The stratification factors used for 
randomization (See Section 6.3.1.1) 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. The true date of disease progression will be 
approximated by the date of the first assessment at which PD is objectively documented per 
RECIST 1.1 via BICR by the imaging vendor. Death is always considered as a confirmed PD 
event. Participants who do not experience a PFS event will be censored at the last disease 
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assessment. Sensitivity analyses will be performed for comparison of PFS based on 
investigator's assessment.
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 via BICR by the 
imaging vendor, one primary and 2 sensitivity analyses with a different set of censoring rules
will be performed. For the primary analysis, if the events (PD or death) are immediately after 
more than one missed disease assessment, the data are censored at the last disease assessment 
prior to missing visits. Also data after new anti-cancer therapy are censored at the last disease 
assessment prior to the initiation of new anti-cancer therapy. The first sensitivity analysis 
follows intention-to-treat principles. That is, PDs/deaths are counted as events regardless of 
missed study visits or initiation of new anti-cancer therapy. For the second sensitivity 
analysis, it considers discontinuation of treatment or initiation of an anti-cancer treatment 
subsequent to discontinuation of study-specified treatments, whichever occurs later, to be a 
PD event for participants without documented PD or death. If a participant meets multiple 
criteria for censoring, the censoring criterion that occurs earliest will be applied. The 
censoring rules for primary and sensitivity analyses are summarized in Table 10.
Table 10
Censoring Rules for Primary and Sensitivity Analyses of Progression-free 
Survival
Situation
Primary Analysis
Sensitivity Analysis 1
Sensitivity Analysis 2
Progressive disease 
(PD) or death 
documented after ≤ 1 
missed disease 
assessment; and before 
new anti-cancer 
therapy, if any
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or death
PD or death 
documented 
immediately after ≥2 
consecutive missed 
disease assessments or 
after new anti-cancer 
therapy, if any
Censored at last disease 
assessment prior to 
the earlier date of  ≥ 2 
consecutive missed 
disease assessment and 
new anti-cancer therapy, if 
any
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or death
No PD and no death; 
and new anti-cancer
treatment is not 
initiated
Censored at last disease 
assessment 
Censored at last disease 
assessment 
Progressed at treatment 
discontinuation due to 
reasons other than complete 
response; otherwise 
censored at last disease 
assessment if still on study 
or completed study 
treatment
No PD and no death; 
new anti-cancer
treatment is initiated
Censored at last disease 
assessment before new 
anti-cancer treatment
Censored at last disease 
assessment 
Progressed at date of new 
anti-cancer treatment
In case the proportional hazards assumption is not valid, supportive analyses using Restricted 
Mean Survival Time (RMST) method may be conducted for PFS to account for the possible 
non-proportional hazards effect.
Further details of sensitivity analyses will be described in sSAP as needed.
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Overall Survival (OS)
The non-parametric Kaplan-Meier method will be used to estimate the survival curves. The 
treatment difference in survival will be assessed by the stratified log-rank test (based on the 
stratification factor defined in Section 6.3.1.1). A stratified Cox proportional hazard model 
with Efron's method of tie handling will be used to assess the magnitude of the treatment 
difference (ie, the HR). The HR and its 95% confidence interval from the stratified Cox 
model with a single treatment covariate will be reported. The stratification factors used for 
randomization (See Section 6.3.1.1) will be applied to both the stratified log-rank test and the 
stratified Cox model. The Restricted Mean Survival Time (RMST) method may be 
conducted for OS to account for the possible non-proportional hazards effect and to estimate 
the absolute benefit of experimental treatment. A cure rate model may be applied to estimate 
the long-term effect.
Since participants in the control arm are allowed to switch to the pembrolizumab treatment 
after progressive disease, adjustment for the effect of crossover on OS may be performed 
based on recognized methods, eg, a two-stage method or the Rank Preserving Structural 
Failure Time (RPSFT) model, based on an examination of the appropriateness of the data to 
the assumptions required by the methods.
Further details of sensitivity analyses will be described in sSAP as needed.
Objective Response Rate (ORR) and Duration of Response (DOR)
The stratified Miettinen and Nurminen method will be used for the comparison of the ORR 
between the 2 treatment groups. The difference in ORR and its 95% confidence interval from 
the stratified Miettinen and Nurminen method with strata weighting by sample size will be 
reported. The stratification factors used for randomization (See Section 6.3.1.1) will be 
applied to the analysis.
If sample size permits, DOR will be summarized descriptively using Kaplan-Meier medians 
and quartiles. Only the subset of participants who show a confirmed complete response or 
partial response will be included in this analysis. Censoring rules for DOR are summarized in 
Table 11. 
For each DOR analysis, a corresponding summary of the reasons responding participants are 
censored will also be provided. Responding participants who are alive, have not progressed, 
have not initiated new anti-cancer treatment, have not been determined to be lost to 
follow-up, and have had a disease assessment within ~5 months of the data cutoff date are 
considered ongoing responders at the time of analysis. If a participant meets multiple criteria 
for censoring, the censoring criterion that occurs earliest will be applied.
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Table 11
Censoring Rules for DOR
Situation
Date of Progression or Censoring
Outcome
No progression nor death, no new anti-
cancer therapy initiated
Last adequate disease assessment
Censor
(non-event)
No progression nor death, new anti-cancer 
therapy initiated
Last adequate disease assessment before new anti-
cancer therapy initiated
Censor
(non-event)
Death or progression immediately after ≥2 
consecutive missed disease assessments or 
after new anti-cancer therapy, if any
Earlier date of last adequate disease assessment 
prior to ≥2 missed adequate disease assessments 
and new anti-cancer therapy, if any
Censor
(non-event)
Death or progression after ≤1 missed disease 
assessments and before new anti-cancer 
therapy, if any
PD or death
End of response
(event)
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for evaluation of 
response.  
Analysis Strategy for Key Efficacy Endpoints
The primary analysis approach for the primary and key secondary efficacy endpoints are 
summarized in Table 12. Sensitivity analysis methods are described above for each endpoint 
as applicable.
The strategy to address multiplicity issues with regard to multiple efficacy endpoints, and 
interim analyses is described in Section 9.7, Interim Analyses and in Section 9.8,
Multiplicity.
Table 12
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Statistical Method†
Analysis 
Population
Missing Data Approach
Dual Primary Endpoints
PFS per RECIST 1.1 by blinded 
independent central review 
(BICR) by the imaging vendor
Test: Stratified Log-rank test 
to assess the treatment 
difference
Estimation: Stratified Cox 
model with Efron’s tie 
handling method to assess the 
magnitude of treatment 
difference
ITT
Primary censoring rule
Sensitivity analysis 1
Sensitivity analysis 2
OS
Test: Stratified Log-rank test 
to assess the treatment 
difference
Estimation: Stratified Cox 
model with Efron’s tie 
handling method to assess the 
magnitude of treatment 
difference
ITT
Model based
(censored at the last date the 
participant was known to be 
alive)
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Endpoint/Variable
(Description, Time Point)
Statistical Method†
Analysis 
Population
Missing Data Approach
Key Secondary Endpoints
ORR per RECIST 1.1 by blinded 
independent central review 
(BICR) by the imaging vendor
Test and Estimation: Stratified 
M&N method with sample 
size weights††
ITT
Participants without 
assessments are considered 
non-responders and 
conservatively included in 
denominator
DOR per RECIST 1.1 by blinded 
independent central review 
(BICR) by the imaging vendor
Descriptive statistics for range 
and Kaplan-Meier estimate of 
median
Participants in ITT 
population with an 
objective response
  † Statistical models are described in further detail in the text. For stratified analyses, the stratification factors used for 
randomization (Section 6.3.1.1) will be applied to the analysis.
†† Miettinen and Nurminen method
Abbreviations: DOR=duration of response; ITT=intention-to-treat; ORR=objective response rate; OS=overall survival; 
PFS=progression-free survival; RECIST=Response Evaluation Criteria in Solid Tumors 1.1; 
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests and vital signs. In the primary safety comparison, participants who 
crossover to pembrolizumab monotherapy are censored at time of crossover (ie, AEs 
occurring during treatment with pembrolizumab are excluded for control-arm participants). 
Additional safety summary may be conducted for the crossover population including all 
safety events starting from the date of the first dose of pembrolizumab. Safety data from the 
Second Course Treatment Phase will be summarized separately and not be included in the 
primary safety comparison.
Adverse Events
Adverse events will be coded using the standard MedDRA and grouped system organ class. 
Adverse events will be graded by the investigator according to the Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.0.
Tiered Approach
The analysis of safety results will follow a tiered approach (Table 13). The tiers differ with 
respect to the analyses that will be performed. Adverse experiences (specific terms as well as 
system organ class terms) and events that meet predefined limits of change in laboratory and
vital signs parameters are either pre-specified as Tier-1 endpoints, or will be classified as 
belonging to "Tier 2" or "Tier 3", based on the number of events observed.  
Tier 1 Events
Safety parameters or adverse experiences of special interest that are identified a priori 
constitute “Tier 1” safety endpoints that will be participant to inferential testing for statistical 
significance with p values and 95% confidence intervals to be provided for between-
treatment comparisons. For this protocol, there are no Tier 1 events.  
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% confidence intervals 
provided for between-treatment differences in the proportion of participants with events.
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Membership in Tier 2 requires that at least 10% of participants in any treatment group exhibit 
the event. The threshold of at least 10% participants was chosen because patient population 
enrolled in this study are in critical conditions and usually experience various adverse events 
of similar types regardless of treatment, events reported less frequent than 10% of 
participants would obscure the assessment of overall safety profile and add little to the 
interpretation of potentially meaningful treatment 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 safety parameters that meet predefined limits of change.
In addition to individual events that occur in ≥10% or more participants in any treatment 
group, the broad AE categories consisting of the proportion of participants with Grade 3 to 5 
AEs (≥2% of participants in 1 of the treatment groups) and SAEs (≥2% of participants in 1 of 
the treatment groups) will be considered Tier 2 endpoints. The 95% confidence intervals will 
be provided for between-treatment differences in the percentage of participants with events; 
these analyses will be performed using the Miettinen and Nurminen method, an 
unconditional, asymptotic method.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment group are provided for Tier 3 safety parameters.
Continuous Safety Measures 
For continuous measures such as changes from baseline in laboratory and vital signs 
parameters, summary statistics for baseline, on-treatment, and change from baseline values 
will be provided by treatment group in table format.  
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Table 13
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive Statistics
Tier 2
Grade 3 to 5 AE (incidence ≥2% of participants in one of the 
treatment groups)
X
X
Serious AE (incidence ≥2% of participants in one of the 
treatment groups)
X
X
AEs (incidence ≥10% of participants in one of the treatment 
groups)
X
X
Tier 3
Any AE
X
Any Grade 3 to 5 AE
X
Any Serious AE 
X
Any Drug-related AE
X
Any Serious and Drug-related AE
X
Any Grade 3 to 5 and Drug-related AE
X
Discontinuation due to AE
X
Death
X
Specific AEs, SOCs (incidence <10% of participants in all 
of the treatment groups)
X
Change from baseline results (lab toxicity shift)
X
AE=adverse event; CI=confidence interval; SOC=system organ class.
Statistical Methods for PRO Analyses
To assess change from baseline in the EORTC QLQ-C30 global health status/QoL scale 
score (items 29 and 30), the constrained longitudinal data analysis (cLDA) model will be 
applied for treatment comparison of pembrolizumab + chemotherapy versus saline placebo + 
chemotherapy. The response variable consists of baseline values and the values observed at 
each pre specified post-baseline time point for primary analysis. The model will be adjusted 
for treatment by time interaction and stratification factors as covariates. Least square mean 
change from baseline will be summarized.
The Kaplan-Meier method will be used to estimate the TTD survival curve for the composite 
endpoint of cough (LC13 Q1), chest pain (LC13 Q10) or dyspnea (QC30 Q8) in each 
treatment group. The TTD is defined as the time to the first onset of 10 points or more 
deterioration in cough, chest pain, or dyspnea from baseline with confirmation by the 
subsequent visit of 10 points or more deterioration from baseline in any of these 3 symptoms. 
A stratified Cox PH model with Efron's method of tie handling will be used to assess the 
magnitude of the treatment difference for the pembrolizumab + chemotherapy and saline 
placebo + chemotherapy regimen. Stratification factors used for randomization will be used 
in the stratified Cox PH model.
Details of additional PRO analyses will be included in the sSAP.
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Summaries of Baseline Characteristics, Demographics, and Other Analyses
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and 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 participants 
screened, randomized, the primary reasons for screening failure, and the primary reason for 
discontinuation will be displayed. Demographic variables (eg, age, gender), baseline 
characteristics, and prior and concomitant therapies will be summarized by treatment either 
by descriptive statistics or categorical tables.
Interim Analyses
An external data monitoring committee (eDMC) will be convened to review the unblinded 
efficacy results and accumulating safety at the planned interim analyses. An external 
unblinded statistician and programmer will be responsible for conducting and presenting the 
interim analyses results to the eDMC. The eDMC responsibilities and review schedules will 
be outlined in the eDMC charter. The recommendation of the eDMC will be communicated 
to an executive oversight committee of the Sponsor. In the event of a recommendation to halt 
the trial early due to safety concerns, the Sponsor will communicate this to the appropriate 
regulatory agencies. If the eDMC recommends modifications to the design of the protocol or 
discontinuation of the study, this executive oversight committee may be unblinded to results 
at the treatment level in order to act on these recommendations.
A limited number of additional Sponsor personnel may be unblinded, if required, in order to 
act on the recommendations of the eDMC. The extent to which individuals are unblinded to 
the results will be documented. Additional logistical details, revisions to the above plan and 
data monitoring guidance will be provided in the eDMC Charter.
Efficacy Interim Analyses
Three IAs are planned in addition to the FA for this study. For the interim and final analyses, 
all randomized participants will be included. The primary purpose of the IAs is to 
demonstrate superior efficacy. Safety data will also be reviewed at each planned IA to assess 
the overall risk: benefit. Details on the boundaries for establishing statistical significance 
with regard to efficacy are discussed further in Section 9.8. The trial will continue until the 
number of deaths (see Section 9.9) is approximately equal to the targeted number for the FA, 
irrespective of the outcome from the IAs. 
The analyses planned, endpoints evaluated, and drivers of timing are summarized in 
Table 14.
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Table 14
Summary of Interim and Final Analyses Strategies
Analyses
Key 
Endpoints
Timing
Estimated Time after First 
Participant Randomized
Primary Purpose of 
Analysis
IA1
PFS
OS
~6 months after the 
last participant has
been randomized.
~30 months  
Demonstrate PFS 
superiority
Demonstrate OS  
superiority
IA2 (Final 
PFS 
Analysis)
PFS
OS
~16 months after the 
last participant has
been randomized 
AND approximately
414 PFS events have 
been observed.
~40 months 
Demonstrate PFS 
superiority
Demonstrate OS  
superiority
IA3
OS
~29 months after the 
last participant has
been randomized.
~53 months
Demonstrate OS  
superiority
FA
OS
~42 months after the 
last participant has
been randomized
AND approximately 
423 deaths have 
occurred for the final 
OS analysis.
~66 months
Demonstrate OS 
superiority
Note: For the final analysis, if the events accrue slower than expected such that the targeted number of events 
cannot be reached in the anticipated timeframe, the Sponsor may conduct the analysis with approximately 2 
additional months of follow-up, or when the specified number of events is observed, whichever occurs first. If 
the observed number of OS events at the time of IA3 is very close to the target number of events at final 
analysis (if more than ~98% information fraction, ie, ~415 OS events), then IA3 will become the final analysis
using the remaining alpha that has not been spent at the earlier analyses, and will be performed at ~29 months 
after the last participant has been randomized and approximately 423 deaths have occurred.
FA=final analysis; IA=interim analysis; ORR=objective response rate; OS=overall survival; PFS=progression-
free survival.
Safety Interim Analyses
Accumulating safety data will be reviewed approximately every 6 months after the first 
participant is randomized. Interim safety analyses will also be performed at each planned IA
described in Section 9.7.1 to assess the overall risk: benefit. Further details on the timing of 
safety monitoring will be specified in the eDMC charter.
Multiplicity
The trial uses an extension of the graphical method of Maurer and Bretz [Maurer, W. and 
Bretz, F. 2013] to provide strong multiplicity control for multiple hypotheses while making 
the interim and final analysis timing be more flexible [Anderson and Gause, manuscript 
submitted]. According to Maurer and Bretz approach, study hypotheses may be tested in a 
group sequential fashion, and when a particular null hypothesis is rejected, the alpha 
allocated to that hypothesis can be reallocated to other hypothesis tests. The extended 
graphical method spends alpha as a function of the minimum of the actual event information 
fraction and the expected event information fraction. This ensures that spending will be no 
more aggressive than the information fraction method, while at the same time ensuring not 
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all alpha is spent prior to final planned analysis calendar time. Figure 6 shows the initial one-
sided alpha allocation for each hypothesis in the ellipse representing the hypothesis. The 
weights for reallocation from each hypothesis to the others are represented in the boxes on 
the lines connecting hypotheses.
Note: If both PFS and OS null hypotheses are rejected, the reallocation strategy allows re-testing of ORR at alpha=0.025 based on the 
p-value at IA1
ORR=objective response rate; OS=overall survival; PFS=progression-free survival
Figure 6
Type I Error Reallocation Strategy
Objective Response Rate
The study does not allocate initial alpha to ORR. ORR will be formally tested only if the 
hypotheses for PFS and/or OS is significant. The testing of ORR will be based on all 
randomized subjects. If the null hypotheses for OS and PFS are rejected at IA1 or at a time 
later than IA1, the p-value of ORR from the IA1 analysis will be compared to the α level 
passed to ORR from PFS and/or OS. Power at the possible alpha-levels as well as the 
approximate treatment difference required to reach the bound (ORR difference) are shown in
Table 15 assuming underlying 34% and 54% response rates in the control and experimental 
groups, respectively. 
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Table 15
Possible Alpha-levels and Approximate Objective Response Rate (ORR)
Difference Required to Demonstrate Efficacy for ORR at Interim Analysis 1
Alpha
ORR difference
Power
0.0000125
~0.19
0.60
0.025
~0.09
0.99
Progression-Free Survival 
The PFS hypothesis may be tested at alpha=0.0125 (initially allocated alpha), or 
alpha=0.0249875 (if OS null hypothesis is rejected), or alpha=0.025 (if both OS and ORR 
null hypothesis are rejected). Table 16 shows the boundary properties for each of these alpha-
levels, which were derived using a Lan-DeMets O'Brien-Fleming spending function based on 
predicted number of events at the planned time of interim analysis. Note that the final row 
indicates the total power to reject the null hypothesis for PFS at each alpha-level. Also note 
that if the OS null hypothesis is rejected at an interim or final analysis, each PFS interim and 
final analysis test may be compared to its updated bounds considering the alpha reallocation 
from the OS hypothesis.
Table 16
Efficacy Boundaries and Properties for Progression-free Survival Analyses
Analysis
Value
=0.0125
=0.0249875
=0.025
IA1: 88%*
N: 492
Events: 367
Month: 30
Z
2.4121
2.1158
2.1155
p (1-sided) §
0.0079
0.0172
0.0172
HR at bound
0.7772
0.8017
0.8017
P(Cross) if HR=1†
0.0079
0.0172
0.0172
P(Cross) if HR=0.7#
0.8435
0.9038
0.9038
IA2: 100%*
N: 492
Events: 414
Month: 40
Z
2.3169
2.0491
2.0489
p (1-sided) §
0.0103
0.0202
0.0202
HR at bound
0.7963
0.8176
0.8176
P(Cross) if HR=1†
0.0125
0.0250
0.025
P(Cross) if HR=0.7#
0.9135
0.9492
0.9492
*Percentage of expected number of events at FA
§p (1-sided) is the nominal alpha for testing.
HR at bound is the approximate HR required to reach an efficacy bound
†P(Cross if HR=1) is the cumulative probability of crossing a bound under the null hypothesis
#P(Cross if HR=0.7) is the cumulative probability of crossing a bound under the alternative hypothesis
Abbreviations: FA=final analysis; HR=hazard ratio; IA=interim analysis.
The bounds provided in the table above are based on the assumption that the expected 
number of events at IA1 and IA2 are 367 and 414, respectively. At the time of an analysis, 
the observed number of events may differ substantially from the expected. To avoid 
overspending at an IA and leave reasonable alpha for the FA, the minimum alpha spending 
strategy will be adopted. At an IA, the information fraction used in Lan-DeMets spending 
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function to determine the alpha spending at the IA will be based on the minimum of the 
expected information fraction and the actual information fraction at each analysis. 
Specifically:

In the scenario that the events accrue slower than expected and the observed number of 
events is less than the expected number of events at a given analysis, the information 
fraction will be calculated as the observed number of events at the IA over the target 
number of events at FA. 

In the scenario that the events accrue faster than expected and the observed number of 
events exceeds the expected number of events at a given analysis, then the information
fraction will be calculated as the expected number of events at the IA over the target 
number of events at FA.
The FA will use the remaining Type I error that has not been spent at the earlier analyses. 
The event counts for all analyses will be used to compute correlations.
Of note, while the information fraction used for alpha spending calculation will be the 
minimum of the actual information fraction and the expected information fraction, the 
correlations required for deriving the bounds will still be computed using the actual 
information fraction based on the observed number of events at each analysis over the target 
number of events at FA.
The minimum spending approach assumes timing is not based on any observed Z-value and 
thus the Z test statistics used for testing conditioned on timing are multivariate normal. Given 
the probabilities derived with the proposed spending method, the correlations based on actual 
event counts are used to compute bounds that control the Type I error at the specified alpha 
level for a given hypothesis conditioned on the IA timing. Since this is true regardless of 
what is conditioned on, the overall Type I error for a given hypothesis is unconditionally 
controlled at the specified level. By using more conservative spending early in the study, 
power can be retained to detect situations where the treatment effect may be delayed.
Overall Survival
The OS hypothesis may be tested at alpha=0.0125 (initially allocated alpha), or 
alpha=0.0249875 (if the PFS null hypothesis is rejected) or alpha=0.025 (if both the PFS and 
ORR null hypothesis are rejected). Table 17 demonstrates the bounds and boundary 
properties for OS hypothesis testing derived using a Lan-DeMets O'Brien-Fleming spending 
function based on predicted number of events at the planned time of interim analysis. Note 
that if the PFS null hypothesis is rejected at an interim or final analysis, each OS interim and 
final analysis test may be compared to its updated bounds considering the alpha reallocation 
from the PFS hypothesis.
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Table 17
Efficacy Boundaries and Properties for Overall Survival Analyses
Analysis
Value
=0.0125
=0.0249875
=0.025
IA1: 57%*
N: 492
Events: 242
Month: 30
Z 
3.1029
2.7437
2.7434
p (1-sided) §
0.0010
0.0030
0.0030
HR at bound 
0.6710
0.7027
0.7027
P(Cross) if HR=1†
0.0010
0.0030
0.0030
P(Cross) if HR=0.72#
0.2938
0.4269
0.4270
IA2: 76%*
N: 492
Events: 321
Month: 40
Z 
2.6699
2.3635
2.3632
p (1-sided) §
0.0038
0.0091
0.0091
HR at bound 
0.7420
0.7678
0.7678
P(Cross) if HR=1†
0.0041
0.0100
0.0100
P(Cross) if HR=0.72#
0.6135
0.7254
0.7254
IA 3: 91%*
N: 492
Events: 385
Month: 53
Z 
2.4311
2.1545
2.1542
p (1-sided) §
0.0075
0.0156
0.0156
HR at bound 
0.7804
0.8028
0.8028
P(Cross) if HR=1†
0.0088
0.0187
0.0188
P(Cross) if HR=0.72#
0.7959
0.8666
0.8666
FA: 100%*
N: 492
Events: 423
Month: 66
Z 
2.3405
2.0788
2.0786
p (1-sided) §
0.0096
0.0188
0.0188
HR at bound 
0.7964
0.8170
0.8170
P(Cross) if HR=1†
0.0125
0.0250
0.0250
P(Cross) if HR=0.72#
0.8644
0.9147
0.9147
* Percentage of expected number of events at FA
§p (1-sided) is the nominal α for testing.
HR at bound is the approximate HR required to reach an efficacy bound
†P(Cross if HR=1) is the cumulative probability of crossing a bound under the null hypothesis
#P(Cross if HR=0.72) is the cumulative probability of crossing a bound under the alternative hypothesis
Abbreviations: FA=final analysis; HR=hazard ratio; IA=interim analysis.
The bounds provided in the table above are based on the assumption that the expected 
number of events at IA1, IA2, IA3, and FA are 242, 321, 385, and 423, respectively. At the 
time of an analysis, the observed number of events may differ substantially from the 
expected. To avoid overspending at an IA and leave reasonable alpha for the FA, the 
minimum alpha spending strategy will be implemented for OS in the same manner as PFS 
(Section 9.8.2).
Safety Analyses
The eDMC has responsibility for assessment of overall risk: benefit. At each planned interim 
analysis, eDMC will review the accumulating safety data in addition to the unblinded 
efficacy results. No separate safety interim analysis is planned; therefore, it will not require a 
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separate multiplicity adjustment as they are associated with the planned efficacy interim 
analysis.
Sample Size and Power Calculations
With 414 PFS events, the study has ~91% power for detecting a HR of 0.7 at initially 
assigned 0.0125 (one-sided) significance level, ~95% power for detecting a HR of 0.7 at 
0.025 (one-sided) significance level. 
With 423 deaths, the study has ~86% power for detecting a HR of 0.72 at 0.0125 (one-sided) 
significance level and ~91% power for detecting a HR of 0.72 at 0.025 (one-sided) 
significance level. The assumption of HR of 0.72 does not take into account the crossover
treatment in this study. The actual power could be lower than 91% if the HR for OS is larger 
than 0.72 due to crossover effect.  
With ~492 participants at IA1, the study has ~60% power for detecting a 20% difference in 
ORR (54% vs 34%) at 0.0000125 (one-sided) significance level if one of PFS or OS 
hypothesis is rejected. The study has ~99% power for detecting a 20% difference in ORR 
(54% versus 34%) at 0.025 (one-sided) significance level if both PFS and OS hypotheses are
rejected.
The planned sample size is approximately 492 participants assuming: (1) the enrollment 
period of approximately 24 months; (2) the duration of PFS and OS follow exponential 
distribution; (3) median PFS is 5.4 months in the control group and the true HR is 0.7; (4) 
median OS is 15 months in the control group and the true HR is 0.72, as estimated
approximately from Cortellini, IMPRESS, FLAURA, and AURA3 studies based on prior 
treatment history of osimertinib [Papadimitrakopoulou, V. A., et al 2020] [Cortellini, A., et al 
2020] [Ramalingam, S. S., et al 2020] [Soria, J. C., et al 2015] [Mok, T. S. K., et al 2017]; 
(5) the annual dropout rate is 15% for PFS (as estimated approximately from KEYNOTE-
189) and 1% for OS; (6) the number of events and alpha levels of IAs and FA are as 
specified in Section 9.7 and Section 9.8.
Subgroup Analyses
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 each subgroup. The following 
are examples of classification variables:

Age category (<65 vs ≥65 years)

Sex (female, male)

Race (white, non-white)

Geographic region (East Asia vs Non-East Asia)

Smoking history (never, current/former)

Treatment history (osimertinib, no osimertinib)

T790M mutation (positive, negative, unknown)
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
EGFR mutation (L858R, DEL19)

PD-L1 expression (TPS ≥50% vs TPS <50%; TPS ≥1% vs TPS <1%; TPS <1% vs 
1%≤TPS≤49% vs TPS ≥50%)

Platinum chemotherapy (cisplatin, carboplatin)
The consistency of the treatment effect will be assessed using descriptive statistics for each 
category of the subgroup variables listed above. If the number of participants in a category of 
a subgroup variable is <10% of the ITT population, the subgroup analysis will not be 
performed for this category of the subgroup variable, and this subgroup variable will not be 
displayed in the forest plot. 
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles. Summary 
statistics will be provided on extent of exposure for All Subjects As Treated (ASaT)
population.
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10. Supporting Documentation and Operational Considerations
Appendix 1: Regulatory, Ethical and Study Oversight Considerations
Code of Conduct for Interventional Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
I.
Introduction
A. Purpose
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD), through its subsidiaries, conducts clinical trials worldwide 
to evaluate the safety and effectiveness of our products. As such, we are committed to designing, planning, 
conducting, analyzing, and reporting these trials in compliance with the highest ethical and scientific standards. 
Protection of participants in clinical trials is the overriding concern in the design and conduct of clinical trials. In all 
cases, MSD clinical trials will be conducted in compliance with MSD’s global standards, local and/or national 
regulations (including all applicable data protection laws and regulations), and International Council for 
Harmonisation Good Clinical Practice (ICH GCP) E6 and ICH General Considerations for Clinical Studies E8, and 
in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (eg, contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or which 
are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the full control 
of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy, 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be adequate to address the specific purpose 
of the trial and shall respect the data protection rights of all participants, trial site staff and, where applicable, third 
parties. Input may be considered from a broad range of stakeholders, including patient advocacy groups/patients 
representing the trial population, caregivers, and healthcare providers to ensure operational feasibility. Trial design 
also includes proactive identification of critical to quality factors using a risk-based approach. Plans are then 
developed to assess and mitigate risks to those factors as appropriate during the trial. All trial protocols are and 
will be assessed for the need and capability to enroll underrepresented groups. Participants must meet protocol 
entry criteria to be enrolled in the trial.
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities and 
staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, sites are 
evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to successfully conduct 
the trial. Individuals involved in trial conduct receive training commensurate with their role prior to their 
becoming involved in the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts to 
raise awareness of clinical trial opportunities in various communities. MSD will seek to engage underrepresented 
groups and those disproportionately impacted by the disease under study. MSD will support clinical trial 
investigators to enroll underrepresented groups and expand access to those who will ultimately use the products 
under investigation. 
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3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus source 
documentation according to standard operating procedures. Per MSD policies and procedures, if potential fraud, 
scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related Significant Quality Issues are 
reported, such matters are investigated. When necessary, appropriate corrective and/or preventative actions are 
defined and regulatory authorities and/or ethics review committees are notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the extent 
scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important to 
patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis generating rather than 
hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be underpowered 
and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A.Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority acceptance/authorization 
prior to implementation of the trial or amendment, in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations and ICH Guidelines. Changes to the protocol that are required urgently to 
eliminate an immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee 
approval. MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance 
with local and/or national regulations. 
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a 
minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Trial designs include procedures and systems for the identification, monitoring, and reporting of safety 
concerns. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
During trial planning, the need for an independent Data Monitoring Committee (DMC) is assessed. DMC review of 
data accumulated during the conduct of the trial is integral to the well-being of trial participants.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all applicable 
data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on behalf of 
MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records that might 
identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
E. Trial Results
At the time of providing informed consent and in accordance with local laws and regulations, participants should be 
informed about the plans for availability of trial results.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to enroll 
participants in its trials. However, when enrollment is particularly challenging, additional payments may be made to 
compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent on 
medical record review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may wish 
to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As noted 
above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc) will be 
consistent with local guidelines and practices. 
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request. 
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
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The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
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 IRB, IEC, 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 study 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 Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents in 
order to verify worksheet/CRF data. By signing the consent form, the participant agrees to 
this process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant 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 participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. 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.
Committees Structure
Executive Oversight Committee
The Executive Oversight Committee (EOC) is comprised of members of Sponsor Senior 
Management. The EOC will receive and decide upon any recommendations made by the 
DMC regarding the study.
Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study. 
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The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (see Section 9.7) and 
recommend to the EOC whether the study should continue in accordance with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments. 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and site contact information. 
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
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for Human Use of Technical Requirements for Registration of Pharmaceuticals for Human 
Use Good Clinical Practice: Consolidated Guideline and other generally accepted standards 
of GCP); and all applicable federal, state and local laws, rules and regulations relating to the 
conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers or from government programs for procedures included as part of the study
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection, and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study 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 or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
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Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including participants' documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP. 
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
Refer to Section 10.12 for country-specific requirements.
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Appendix 2: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research3,4
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways drugs/vaccines may interact with
o
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3,4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
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signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons. 
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3,4
In order to optimize the research that can be conducted with future biomedical research
specimens, it is critical to link participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like gender, age, medical history and treatment outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical study site, unique codes will be placed on the future biomedical research
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube. 
5. Biorepository Specimen Usage3,4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3,4
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the principal investigator for the main study. If medical 
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records for the main study are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@MSD.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for future biomedical research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable. 
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed. 
7. Retention of Specimens3,4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3,4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3,4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
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If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3,4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3,4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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Appendix 3:  Contraceptive Guidance and Pregnancy Testing
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below) 
Women in the following categories are not considered WOCBP:
●
Premenarchal
●
Premenopausal female with 1 of the following:
○
Documented hysterectomy
○
Documented bilateral salpingectomy
○
Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
●
Postmenopausal female
○
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
▪
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with 2 FSH measurements in the 
postmenopausal range is required. 
○
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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Contraception Requirements
Male Participants
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to one of the following during the protocol defined time frame in Section 5.1: 
●
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent.
●
Use a male condom plus partner use of an additional contraceptive method when having 
penile-vaginal intercourse with a WOCBP who is not currently pregnant.
o
The following are not acceptable methods of contraception:
▪
Periodic abstinence (calendar, symptothermal, postovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea
method (LAM).
▪
Male and female condom cannot be used together.
○
A combination of male condom with either cap, diaphragm or sponge with 
spermicide are considered acceptable, but not highly effective, birth control methods.
○
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration.
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 18
during the protocol-defined time frame in Section 5.1. 
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Table 18
Highly Effective Contraception Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly.
●
Combined (estrogen- and progestogen- containing ) hormonal contraception b, c
○
Oral 
○
Intravaginal 
○
Transdermal 
○
Injectable
●
Progestogen-only hormonal contraception b, c
○
Oral 
○
Injectable 
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.
●
Progestogen-only contraceptive implant b, c 
●
Intrauterine hormone-releasing system (IUS) b
●
Non-hormonal intrauterine device (IUD)
●
Bilateral tubal occlusion
●
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used. 
●
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatment. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods 
for participants of clinical studies. 
a) Typical use failure rates are higher than perfect-use failure rates (ie, when used 
consistently and correctly). 
b) If hormonal contraception efficacy is potentially decreased due to interaction with study 
treatment, condoms must be used in addition to the hormonal contraception during the 
treatment period and for at least 120 days after the last dose of pembrolizumab and up to 
180 days after last dose of chemotherapeutic agents, corresponding to time needed to 
eliminate study treatment after the last dose of study treatment.
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) 
guidelines, acceptable hormonal contraceptives are limited to those which inhibit ovulation. 
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Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test within 72 hours of the first dose. If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test will be required. Monthly pregnancy testing should be 
conducted as per local regulations where applicable.
Following initiation of treatment, pregnancy testing will be performed whenever an expected 
menstrual cycle is missed or when pregnancy is otherwise suspected and as required locally.
Refer to Section 10.12 for country-specific requirements.
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Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definition of AE
AE definition
●
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study treatment, whether or not considered 
related to the study treatment.
●
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
●
NOTE: for purposes of AE definition, study treatment (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, device, 
diagnostic agent, medical device, combination product, or protocol specified 
procedure whether investigational (including placebo or active comparator product) 
or marketed, manufactured by, licensed by, provided by or distributed by the Sponsor 
for human use in this study.
Events meeting the AE definition
●
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator.
●
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
●
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
Note: Congenital disorders (eg, present from birth) not detected or diagnosed prior to 
study intervention administration do not qualify for reporting as AE.
●
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
●
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. 
●
For all reports of overdose (whether accidental or intentional) with an associated AE, 
the AE term should reflect the clinical symptoms or abnormal test result. An overdose 
of study treatment without any associated clinical symptoms or abnormal laboratory 
results is reported using the terminology “accidental or intentional overdose without 
adverse effect.”
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●
Any new cancer (that is not a condition of the study). 
Note: Progression of the cancer under study is not a reportable event. Refer to 
Section 8.4.5 for additional details.
Events NOT meeting the AE definition 
●
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.
●
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
●
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
●
Surgery planned prior to informed consent to treat a pre-existing condition that has 
not worsened.
●
Refer to Section 8.4.5 for protocol specific exceptions
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met 
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
●
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing 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 an SAE. A pre-existing condition is a clinical condition that is diagnosed 
prior to the use of an MSD product and is documented in the patient’s medical history.
d. Results in persistent or significant disability/incapacity
●
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
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●
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
●
in offspring of participant taking the product regardless of time to diagnosis
f.
Other important medical events:
●
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize 
the participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.
●
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency department or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse.
Additional Events Reported in the Same Manner as SAE
Additional events which require reporting in the same manner as SAE
●
In addition to the above criteria, AEs meeting either of the below criteria, although 
not serious per ICH definition, are reportable to the Sponsor in the same time frame 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.
Recording AE and SAE
AE and SAE recording
●
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.
●
The investigator will record all relevant AE/SAE information on the AE
CRFs/worksheets at each examination.
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●
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the Sponsor in lieu of completion of the AE CRF page.
●
There may be instances when copies of medical records for certain cases are 
requested by the Sponsor. In this case, all participant identifiers, with the exception of 
the participant number, will be blinded on the copies of the medical records before 
submission to the Sponsor.
●
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
●
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
●
The investigator will make an assessment of intensity for each AE and SAE (and 
other reportable safety event) according to the NCI Common Terminology Criteria 
for Adverse Events (CTCAE), version 4]. Any AE which changes CTCAE grade over 
the course of a given episode will have each change of grade recorded on the AE
CRFs/worksheets.
●
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.
●
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL).
●
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL.
●
Grade 4: Life threatening consequences; urgent intervention indicated.
●
Grade 5: Death related to AE.
Assessment of causality
●
Did the Sponsor's product cause the AE?
●
The determination of the likelihood that the Sponsor's product caused the AE 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 
product and the AE based upon the available information
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●
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 AE:
●
Exposure:  Is there evidence that the participant 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 studies 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
●
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; (3) the study is a single-dose drug study); or (4) 
Sponsor's product(s) is/are only used one time.)
●
Rechallenge:  Was the participant 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 study is a single-dose drug study); or (3) 
Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN AE WHICH WAS SERIOUS 
AND WHICH MAY HAVE BEEN CAUSED BY THE SPONSOR'S PRODUCT, OR IF 
RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL 
POTENTIAL SIGNIFICANT RISK TO THE PARTICIPANT THEN THE 
RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE 
PROTOCOL, AND IF REQUIRED, THE INIRB/IEC.
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●
Consistency with Study 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 CRFs/worksheets by an 
investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
●
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:
Participant did not receive the Sponsor's product OR temporal sequence of the AE 
onset relative to administration of the Sponsor's product is not reasonable OR the 
AE is more likely explained by another cause than the Sponsor’s product. (Also 
entered for a participant with overdose without an associated AE.)
●
The investigator must review and provide an assessment of causality for each 
AE/SAE and document this in the medical notes.
●
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the Sponsor. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the Sponsor.
●
The investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
●
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements
●
For studies in which multiple agents are administered as part of a combination 
regimen, the investigator may attribute each AE causality to the combination regimen 
or to a single agent of the combination. In general, causality attribution should be 
assigned to the combination regimen (ie, 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 AE to the single agent.
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Follow-up of AE and SAE
●
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.
●
New or updated information will be recorded in the CRF.
●
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
●
The primary mechanism for reporting to the Sponsor will be the electronic data 
collection (EDC) tool. 
●
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
●
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form. 
●
Reference Section 8.4.1 for reporting time requirements 
●
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
●
After the study is completed at a given site, the EDC tool will be taken off-line to 
prevent the entry of new data or changes to existing data.
●
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the EDC tool has been taken off-line, then the 
site can report this information on a paper SAE form or by telephone (see next 
section).
●
Contacts for SAE reporting can be found in the Investigator Trial File Binder (or 
equivalent).
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SAE reporting to the Sponsor via paper CRF
●
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
●
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
●
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
●
Contacts and instructions for SAE reporting and paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent).
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Appendix 5: Clinical Laboratory Tests 

The tests detailed in Table 19 will be performed by the local laboratory per the SoA 
(Section 1.3). 

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. Refer to Section 10.12 
for country-specific requirements. 
Table 19
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Absolute 
Neutrophil Count
Absolute 
Lymphocyte 
Count
Chemistry
Blood Urea 
Nitrogen (BUN)
or urea (one or 
the other should 
be collected per 
institutional 
standard; both 
tests are not
required)
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT)
Total bilirubin 
(and direct 
bilirubin, if total 
bilirubin is 
elevated above 
the upper limit of 
normal)
Albumin
A measure of 
carbon dioxide 
(CO2 or 
Bicarbonate)a
Chloride
Phosphorous
Creatinineb
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Proteina
Glucose 
[Indicate if 
fasting or 
nonfasting]
Calcium
Alkaline 
phosphatase
Lactate 
Dehydrogenase
Coagulation
PT/INR
aPTT/PTTc
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Laboratory 
Assessments
Parameters
Routine 
Urinalysis

Specific gravity

Glucose, protein, blood, ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other Screening 
Testsd

Thyroid panele: T3/FT3, FT4, TSH

Follicle-stimulating hormone (FSH) (as needed in women of non-
childbearing potential only)

Highly sensitive serum or urine human chorionic gonadotropin (hCG) 
pregnancy test (as needed for WOCBP)

Hepatitis Serology -hepatitis B surface antigen [HBsAg], hepatitis B virus 
(HBV)-DNA, hepatitis C virus (HCV)-RNA, HCV antibody (if HCV-RNA is 
not the local standard of care), if required per local regulations.

HIV-RNA (if required by local regulations)
NOTES :
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. 
The carbon dioxide may be either a measurement of CO2 or bicarbonate as an electrolyte.
b. Creatinine: GFR (measured or calculated) or creatinine clearance can be used in place of creatinine. Creatinine 
Clearance should be calculated using the Cockcroft-Gault Method: Refer to Section 10.8 for the appropriate 
calculation.
c. Coagulation factors (PT/INR and aPTT/PTT) should be tested as part of the screening procedures for all 
participants. Any participant receiving anticoagulant therapy should have coagulation factors monitored closely 
throughout the trial.
d. May use central lab only if local lab is not capable.
e. T3 is preferred. If not available, Free T3 (FT3) may be tested.
All protocol-required safety laboratory assessments will be performed by a local laboratory.
The investigator (or medically qualified designee) must document their review of each laboratory safety report.
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Appendix 6: Eastern Cooperative Oncology Group (ECOG) Performance Status
GRADE
ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work
2
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
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to bed or 
chair
5
Dead
As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, 
T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair.
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Appendix 7:  MASCC 2016 Guidelines
Rolia F, Molassiotis A, Herrstedt J, et al. 2016 MASCC and ESMO guideline update for the 
prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea and 
vomiting in advanced cancer patients. Ann Oncol (2016) 27 (suppl_5): v119-v133, 2016.
http://www.mascc.org/antiemetic-guidelines
Investigators may use local equivalent or more current guidelines, if available.
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Appendix 8: Calculated Creatinine Clearance
Original, Weight-Based Cockcroft and Gault Formula for Calculated Creatinine
Clearance for Men
For serum creatinine concentration in mg/dL:
CrCl =
(mL/min)
(140 – agea) (wtb) 1.0
72 serum creatinine (mg/dL)
For serum creatinine concentration in mol/L:
CrCl =
(mL/min)
(140 – agea) (wtb) 1.0
0.81 serum creatinine (mol/L)
a
Age in years.
b
Weight (wt) in kilograms.
Source: Cockcroft and Gault 1976.
Original, Weight-Based Cockcroft and Gault Formula for Calculated Creatinine
Clearance for Women
For serum creatinine concentration in mg/dL:
CrCl =
(mL/min)
(140 – agea) (wtb) 0.85
72 serum creatinine (mg/dL)
For serum creatinine concentration in mol/L:
CrCl =
(mL/min)
(140 – agea) (wtb) 0.85
0.81 serum creatinine (mol/L)
a
Age in years.
b
Weight (wt) in kilograms.
Source: Cockcroft and Gault 1976.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41
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Appendix 9: Abbreviations
Abbreviation
Expanded Term
1L
first-line (therapy)
AE
adverse event
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
APaT
All Participants as Treated
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under curve
BCG
Bacillus Calmette-Guérin vaccine
BICR
blinded independent central review
C1D1
Cycle 1 Day 1
CD28
cluster of differentiation 28
CI
confidence interval
CNS
central nervous system
COPD
chronic obstructive pulmonary disease
COVID-19
coronavirus disease caused by severe acute respiratory syndrome 
coronavirus 2
CR
complete response
CrCl
creatinine clearance
CRF
case report form
CRP
C-reactive protein
CSR
Clinical Study Report
CT
computed tomography
ctDNA
circulating tumor deoxyribonucleic acid
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
CTR
Clinical Trials Regulation
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid
DOR
duration of response
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Abbreviation
Expanded Term
ECG 
electrocardiogram
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eDMC
external Data Monitoring Committee
EDC
electronic data collection
EGFR
epidermal growth factor receptor
EMA
European Medicines Agency
EOC
Executive Oversight Committee
EORTC
European Organisation for Research and Treatment of Cancer
EOT
end of treatment
EQ-5D-5L
EuroQol 5-dimension, 5-level Questionnaire
EU
European Union
FA
final analysis
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
GCP
Good Clinical Practice
HBV
hepatitis B virus
HCV
hepatitis C virus
HER2
human epidermal growth factor receptor 2
HIV
human immunodeficiency virus
HR
hazard ratio
HRQoL
health related quality of life
HRT
hormone replacement therapy
IA
interim analysis
IB
Investigator’s Brochure
ICF
informed consent form
iCPD
iRECIST confirmed progressive disease
iCR
iRECIST complete response
IEC
independent ethics committee
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Abbreviation
Expanded Term
Ig
immunoglobulin
IgG4
immunoglobulin G4 monoclonal antibody
IHC
immunohistochemistry
ILD
interstitial lung disease
IMP
Investigational Medical Product
INR
international normalized ratio
IPASS
Iressa Pan-Asia Study
iPR
iRECIST partial response
irAE
immune-related adverse event
IRB
institutional review board
iRECIST
modified RECIST for immune-based therapeutics
iSD
iRECIST stable disease
ITT
intent-to-treat
iUPD
iRECIST unconfirmed progressive disease
IV
intravenous
IVRS/IWRS
interactive voice response system/ integrated web response system
KL-6
Krebs von den Lungen 6; biomarker for ILD
mAb
monoclonal antibody
MASCC
Multinational Association of Supportive Care in Cancer
MRI
magnetic resonance imaging
mTOR
mammalian target of rapamycin
NCI CTCAE
National Cancer Institute Common Terminology Criteria for 
Adverse Events
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
PBPK
physiological based pharmacokinetics
PD
progressive disease
PD-1
programmed cell death 1 protein
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
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Abbreviation
Expanded Term
PFS
progression-free survival
PK
pharmacokinetic
PR
partial response
PRO
patient reported outcome
Q2W
every 2 weeks
Q3W
every 3 weeks
QLQ-C30
Quality of Life Questionnaire Core 30
QLQ-LC13
Quality of Life Questionnaire and Lung Cancer Module 13
QLQ-LC30
Quality of Life Questionnaire and Lung Cancer Module 30
QoL
quality of life
RECIST
Response Evaluation Criteria in Solid Tumors 1.1
RNA
ribonucleic acid
SAE
serious adverse event
SCLC
Small cell lung cancer
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SP-D
surfactant protein D
SpO2
blood oxygen saturation level
SoA
Schedule of Activities
SOC
standard of care
sSAP
supplemental Statistical Analysis Plan
TEA
Treatment Eligibility Assessment
TK
tyrosine kinase
TKI
tyrosine kinase inhibitor
TPS
tumor proportion score
T-reg
regulatory T cell
TTD
time to true deterioration
WOCBP
woman of childbearing potential
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Appendix 10: Description of the iRECIST Process for Assessment of Disease
Progression
Assessment at Screening and Prior to RECIST 1.1 Progression
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment.
Assessment and Decision at RECIST 1.1 Progression
For participants who show evidence of radiological PD by RECIST 1.1 as determined by the 
Investigator, the Investigator will decide whether to continue a participant on study treatment 
until repeat imaging is obtained using iRECIST for participant management (see Table 8 and 
Figure 3). This decision by the Investigator should be based on the participant’s overall 
clinical condition.
Clinical stability is defined in Section 7.1.
Any participant deemed clinically unstable should be discontinued from study treatment at
central verification of site-assessed first radiologic evidence of PD, and is not required to 
have repeat tumor imaging for confirmation of PD by iRECIST.
If the Investigator decides to continue treatment, the participant may continue to receive 
study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per Investigator assessment. Images should continue to be sent into the 
central imaging vendor for potential retrospective BICR.
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:

Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir
o
Note: the iRECIST publication uses the terminology “sum of measurements”, but 
“sum of diameters” will be used in this protocol, consistent with the original 
RECIST 1.1 terminology.

Unequivocal progression of non-target lesion(s) identified at baseline

Development of new lesion(s)
iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, 
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression.
At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or non-measurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target. 
The sum of diameters of these lesions will be calculated, and kept distinct from the sum of 
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diameters for target lesions at baseline. All other new lesions will be followed qualitatively 
as New Lesions – Non-target.
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the participant will be classified as progression confirmed 
(with an overall response of iCPD), or as showing persistent unconfirmed progression (with 
an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:

Any of the factors that were the basis for the initial iUPD show worsening
o
For target lesions, worsening is a further increase in the sum of diameters of 
≥5 mm, compared to any prior iUPD time point
o
For non-target lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the 
“unequivocal” standard of RECIST 1.1
o
For new lesions, worsening is any of these:

An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD 
time point 

Visible growth of new non-target lesions 

The appearance of additional new lesions

Any new factor appears that would have triggered PD by RECIST 1.1
Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:

None of the progression-confirming factors identified above occurs AND

The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation imaging proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
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Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:

None of the progression-confirming factors identified above occurs, AND

The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold. 
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset”. This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit or if RECIST 1.1 PD has not been 
verified centrally, an exception to continue study treatment may be considered following 
consultation with the Sponsor. In this case, if study treatment is continued, tumor imaging 
should continue to be performed following the intervals as outlined in Section 8.2 and 
submitted to the central imaging vendor.
Detection of Progression at Visits After Pseudo-progression Resolves
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events:

Target lesions
o
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from 
nadir) either for the first time, or after resolution of previous pseudo-progression. 
The nadir is always the smallest sum of diameters seen during the entire trial, 
either before or after an instance of pseudo-progression.

Non-target lesions
o
If non-target lesions have never shown unequivocal progression, their doing so for 
the first time results in iUPD.
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o
If non-target lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
non-target lesions, taken as a whole.

New lesions
o
New lesions appear for the first time
o
Additional new lesions appear
o
Previously identified new target lesions show an increase of ≥5 mm in the new 
lesion sum of diameters, from the nadir value of that sum
o
Previously identified non-target lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception:  if new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve 
to iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication [Seymour, L., et 
al 2017].
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Appendix 11: 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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Appendix 12: Country-specific Requirements
Sweden-specific Information
1. Section 4.2.1.2 Safety Endpoints
Safety parameters commonly used for evaluating investigational systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence 
of, causality, and outcome of adverse events (AEs)/serious adverse events (SAEs); 
and changes in vital signs and laboratory values. Adverse events will be assessed as 
defined by CTCAE, Version 4.0. 
2. Section 10.1 Appendix 1 Regulatory, Ethical and Study Oversight Considerations 

Code of Conduct for Clinical Trials
o
III. Participant Protection
–
A. Ethics Committee Review (Institutional Review Board 
[IRB]/Independent Ethics Committee [IEC]) and Health Authorities
The protocol, protocol amendments, ICF, Investigator Brochure, and 
other relevant documents must be submitted to and approved by the 
applicable Competent Authority and IRB/IEC before the study is 
initiated in accordance with EU Directive 2001/20/EC, Article 10 (a) 
and/or local requirements. Any amendments to the protocol will 
require IRB/IEC and Competent Authority approval before 
implementation of changes made to the study design, except for 
changes necessary to eliminate an immediate hazard to study 
participants [2001/20/EC, Article 10 (c)].

Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the 
study for medical, safety, regulatory, administrative, or other reasons consistent 
with applicable laws, regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the 
Sponsor will promptly notify that study site’s IRB/IEC.
In the EU [CT-1 (2010/C 82/01)], the sponsor must send immediate end-of-study 
notification to the national competent authority and the Ethics Committee of the 
Member State concerned. The end-of-study notification must be sent within 15 
days after the study is halted to clearly describe the reasons and follow-up 
measures, if any, taken for safety reasons. The 15-day notification applies only for 
early termination of the study. Otherwise the time window to send end-of-study 
notification is 90 days in the EU.
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Germany-specific Information
1. Section 1.3.1 Schedule of Activities for Initial Treatment Phase

HIV testing is required at screening.

Hepatitis B and Hepatitis C testing is required at screening.
2. Section 5.2 Exclusion Criteria

Exclusion Criterion 17: HIV testing is required for participants who are residents 
of Germany.

Exclusion Criterion 18: Hepatitis B and C testing is required for participants who 
are residents of Germany.

Exclusion Criterion 19: TB testing is required for participants who are residents of 
Germany.
3. Section 1.3.2 Schedule of Activities for Crossover Treatment Phase
Monthly urine pregnancy testing is required during treatment as well as at the end of 
study treatment.
4. Section 1.3.3 Schedule of Activities for Second Course Retreatment Phase
Monthly urine pregnancy testing is required during treatment as well as at the end of 
study treatment.
5. Section 10.3 Appendix 3: Contraceptive Guidance and Pregnancy Testing
Monthly urine pregnancy testing after randomization is required during treatment as 
well as at the end of study treatment.
6. Section 10.5 Appendix 5: Clinical Laboratory Tests
TB added to Other Tests
Japan-specific Information
Section 1.3 Schedule of Activities – footnotes
1. For the assistance to early diagnosis of pneumonitis/ILD in study participants, the 
following items such as pulse oximetry monitoring (SpO2), C-reactive protein (CRP), 
Krebs von den Lungen 6 (KL-6), and surfactant protein D (SP-D) will be measured in 
this study. These items should be measured in the following timing:
o
SpO2: at the timing of vital sign assessment.
o
CRP, KL-6 and SP-D: at Screening*, pre-dose on Day 1 of every cycle, end of 
treatment and safety follow-up visit (30 days after last dose).
* should be measured at the timing of clinical laboratory tests (such as 
hematology/ chemistry).
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2. In the case that pneumonitis/ILD occurs, regardless of causality with study 
medication, an independent ILD evaluation committee will conduct adjudication of 
cases of the pneumonitis/ILD. For this purpose, relevant data such as chest imaging 
(from the baseline to the recovery of pneumonitis/ILD) will be submitted to MSD 
K.K.
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11. References
[Aaronson, N. K., et al 
1993]
Aaronson NK, Ahmedzai S, Bergman B, 
Bullinger M, Cull A, Duez NJ, et al. The 
European Organization for Research and 
Treatment of Cancer QLQ-C30: a quality-of-life 
instrument for use in international clinical trials in 
oncology. J Natl Cancer Inst 1993;85(5):365-76.
[03Q3QL]
[Bergman, B., et al 
1994]
Bergman B, Aaronson NK, Ahmedzai S, Kaasa S, 
Sullivan M. The EORTC QLQ-LC13: a modular 
supplement to the EORTC core quality of life 
questionnaire (QLQ-C30) for use in lung cancer 
clinical trials. Eur J Cancer 1994;30A(5):635-42.
[00VTZB]
[Chemnitz, J. M., et al 
2004]
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