A Phase III, Randomized, Double-blind Trial of Platinum Doublet Chemotherapy +/-Pembrolizumab (MK-3475) as Neoadjuvant/Adjuvant Therapy for Participants With Resectable Stage II, IIIA, and Resectable IIIB (T3-4N2) Non-small Cell Lung Cancer (NSCLC) (KEYNOTE-671)
Phase: PHASE3
Conditions: Non-small Cell Lung Cancer
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
A Phase III, Randomized, Double-blind Trial of Platinum 
Doublet Chemotherapy +/-Pembrolizumab (MK-3475) as
Neoadjuvant/Adjuvant Therapy for Participants with 
Resectable Stage II, IIIA, and Resectable IIIB (T3-4N2) 
Non-small Cell Lung Cancer
NCT03425643
29-November-2022

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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 Phase III, Randomized, Double-blind Trial of Platinum Doublet 
Chemotherapy +/- Pembrolizumab (MK-3475) as Neoadjuvant/Adjuvant Therapy for 
Participants with Resectable Stage II, IIIA, and Resectable IIIB (T3-4N2) Non-small Cell 
Lung Cancer (NSCLC) (KEYNOTE-671)
Protocol Number: 671-11
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: 2017-001832-21
Approval Date:  29 November 2022
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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 trial 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
Amendment 11
29-NOV-2022
The protocol was amended to add extended annual imaging to the Post-treatment 
Follow-up Phase and to specify assessments to be conducted during that time period.
Amendment 10
24-MAR-2022
To change the definition of EFS event to utilize investigator assessment as opposed 
to central review in this double-blind trial.
Amendment 09
23-JUN-2021
The protocol was amended to specify continuation of imaging assessments for 
participants starting new anticancer therapy who have not yet progressed, incorporate 
country-specific requirements, and update the dose modification and toxicity 
management guidelines for immune-related AEs.
Amendment 08
(China-specific)
16-OCT-2020
The protocol was amended to address recommendations from China’s regulatory 
authority regarding the sample size and duration of the Extension Portion of the study 
in China.
Amendment 07
(China-specific)
26-NOV-2019
The protocol was amended to add China extension and to clarify EGFR/ALK testing 
requirements.
Amendment 06
(Germany-specific)
19-JUL-2019
The protocol was amended to align with the global amendment (671-05).
Amendment 05
18-JUL-2019
The protocol was amended to include Stages IIA and resectable IIIB (N2), to update 
stratification to Stage II vs Stage III, and to provide additional clarifications 
throughout the document in order to increase the pool of eligible participants.
Amendment 04
(Germany-specific)
27-AUG-2018
The protocol was amended to align with the global amendment (671-03).
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Document
Date of Issue
Overall Rationale
Amendment 03
27-AUG-2018
The protocol was amended to increase the maximum dose of radiotherapy for 
participants with gross residual disease after surgery or for those participants who do 
not have surgery, to add a new baseline scan prior to the start of adjuvant 
pembrolizumab/placebo, to align the SAP with the program standard and to provide 
additional clarifications throughout the document.
Amendment 02
(Germany specific)
01-MAY-2018
The protocol was amended to align HIV, HBV, HCV, TB, Amylase, Lipase, and 
pregnancy testing with regulatory requirements at German sites.
Amendment 01
11-APR-2018
The protocol was amended based on the input from the regulatory agency and to 
align with the pembrolizumab program standard.
Original protocol
07-NOV-2017
N/A
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment 11
Overall Rationale for the Amendment:
The protocol was amended to add extended annual imaging to the Post-treatment Follow-up Phase and to specify assessments to be 
conducted during that time period.
Summary of Changes Table:
Section # and 
Name
Description of Change
Brief Rationale
2.4 Schedule of 
Activities – End 
of Treatment and 
Follow-up Visits 
(Arms A and B)
Added “Year 6 to End of 
Study” to the Post-treatment 
Follow-up Phase and specified 
imaging and safety assessments 
to be conducted during that time 
period.
Added imaging collection to 
Survival Follow-up Phase and 
removed statement that imaging 
was not captured in Survival 
Follow-up.
Changed statement that 
treatment-related late toxicity 
may be collected for >90 days 
instead of 5 years.
Added tissue collection. 
To provide guidance on continued imaging, safety data, and tissue collection 
for Year 6 to End of Study.
To allow for the collection of imaging which may be conducted in Survival 
Follow-up.
Shortened to more accurately reflect duration of treatment-related toxicity in 
alignment with Section 9.3.
Added as tissue may be collected at any point during the Post-treatment 
Phase and should be submitted to central vendor if obtained.
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Section # and 
Name
Description of Change
Brief Rationale
Corrected formatting of table by 
bringing up safety assessments 
to main table rather than 
previous format of separate 
table.
Correction.
9.2.1.3 End of 
Treatment and 
Follow-up Tumor 
Imaging
9.10.3.2 Follow-
up Visits
Added imaging schedule for 
Year 6 to End of Study.
To align with revisions to the Schedule of Activities (SoA).
9.1.10.1 Survival 
Follow-up
9.2.4 Survival 
Follow-up
9.10.3.3 Survival 
Follow-up
Added that if imaging is 
conducted in Survival Follow-
up, it is to be collected.
Added to ensure that although per-protocol imaging is not required, any 
imaging collected during Survival Follow-up is to be submitted.
5.4.1.3 Rationale 
for Patient-
reported 
Outcomes
9.2.2 Patient-
reported 
Outcomes
Added that ePRO collection 
continues through Year 5.
Added for clarity.
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Section # and 
Name
Description of Change
Brief Rationale
9.2.1.4 
Assessment of 
Disease
Added that biopsies collected 
during the Post-treatment Phase 
are to be submitted.
Added to ensure that if any biopsies are collected in the Post-treatment Phase 
they will be submitted.
Title Page
12.1 Appendix 1: 
Study 
Governance 
Considerations
MSD Code of 
Conduct for 
Clinical Trials
Throughout 
document
Sponsor entity name and 
address change.
Merck Sharp & Dohme Corp. underwent an entity name and address change 
to Merck Sharp & Dohme LLC, Rahway, NJ, USA. This conversion resulted 
only in an entity name change and update to the address.
5.3 Beginning 
and End of Study 
Definition
Removed example for lost to 
follow-up and added cross-
reference to Sec 8.3.
Added definition of study end.
Added the European Economic 
Area (EEA) definition of study 
start.
To ensure clarity and intent of the section.
Per REGULATION (EU) No 536/2014 OF THE EUROPEAN 
PARLIAMENT AND OF THE COUNCIL.
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Section # and 
Name
Description of Change
Brief Rationale
5.4.1.4 Planned 
Exploratory 
Biomarker 
Research
Removed specific reference to 
pembrolizumab and added 
broader wording regarding 
anticancer therapies.
To ensure exploratory biomarker section allows flexibility and current 
treatment options.
6.1 Inclusion 
Criteria
Corrected numbering for IC# 6-
9.
Correction to ensure numbering in section is accurate.
7.1 Treatments 
Administered
Added cross-reference to 
Appendix 7 for country-specific
information.
To ensure country-specific information is noted.
7.7.3 Prohibited 
Concomitant 
Medications
Added “replication-
incompetent” to list of 
acceptable COVID-19 vaccines.
Added to include Janssen vaccine.
8.3 Lost to 
Follow-up
Removed the note that a
participant is not considered 
lost to follow-up until the last 
scheduled visit.
To allow a participant to be considered “lost to follow-up” as appropriate for 
the study.
9.3 Adverse 
Events, Serious 
Adverse Events, 
and Other 
Reportable Safety 
Events
Added text that SAEs 
associated with medication 
errors, misuse, or abuse are to 
be documented.
Per REGULATION (EU) No 536/2014 OF THE EUROPEAN 
PARLIAMENT AND OF THE COUNCIL.
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Section # and 
Name
Description of Change
Brief Rationale
12.4 Appendix 4: 
Adverse Events: 
Definitions and 
Procedures for 
Recording, 
Evaluating, 
Follow-up, and 
Reporting
Added new section with 
definitions for medication 
errors, misuse, or abuse are to 
be documented. Renumbered 
subsequent sections 
accordingly.
Per REGULATION (EU) No 536/2014 OF THE EUROPEAN 
PARLIAMENT AND OF THE COUNCIL.
9.3.7 Events of 
Clinical Interest
Added that ALT/AST 
elevations are potential DILI 
events.
Clarity for the investigator/site to define what potential DILI is and to align 
with this acronym being used in the reporting table.
12.1 Appendix 1: 
Study 
Governance 
Considerations
MSD Code of 
Conduct for 
Clinical Trials
Throughout appendix, updated 
to Sponsor’s current Code of 
Conduct wording.
Updated to incorporate current Code of Conduct practices and requirements.
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Section # and 
Name
Description of Change
Brief Rationale
12.7 Appendix 7: 
Country-specific 
Requirements
China
Added biomarker collection and 
analysis requirements.
Added that enrollment may 
continue in China after global 
enrollment is complete.
Added that hospitalization is 
acceptable for treatment if SOC.
Added details on urinalysis.
Added at the request of China Health Authority.
12.7 Appendix 7: 
Country-specific 
Requirements 
Japan
Added whether study 
interventions are considered 
“test product(s)” in Japan.
Per recent PMDA Regulation changes.
12.7 Appendix 7: 
Country-specific 
Requirements 
United Kingdom
Added that participants 
assigned male sex at birth are to 
be advised to seek counselling 
on sperm storage before starting 
treatment with pemetrexed, 
etoposide, and/or platinum-
based therapy.
Health Authority standard requirements for United Kingdom.
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
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................5
1.
Synopsis.......................................................................................................................21
2.
Schedule of Activities (SoA)......................................................................................25
Trial Screening Procedures....................................................................................25
Preoperative (Neoadjuvant) Treatment................................................................29
Postoperative (Adjuvant Treatment) ....................................................................35
End of Treatment and Follow-up Visits (Arms A and B) ...................................40
3.
Introduction................................................................................................................43
Study Rationale .......................................................................................................43
Background..............................................................................................................44
Pharmaceutical and Therapeutic Background .....................................................44
Completed Clinical Studies..................................................................................46
Ongoing Clinical Studies .....................................................................................48
Information on Other Study-Related Therapy .....................................................49
Benefit/Risk Assessment.........................................................................................49
4.
Objectives/Hypotheses and Endpoints.....................................................................49
5.
Study Design...............................................................................................................52
Overall Design .........................................................................................................52
Data Monitoring Committee and Interim Analyses.............................................54
Study Diagram .....................................................................................................54
Number of Participants ..........................................................................................54
Beginning and End of Study Definition ................................................................55
Clinical Criteria for Early Study Termination .....................................................55
Scientific Rationale for Study Design....................................................................55
Rationale for Endpoints .......................................................................................57
Efficacy Endpoints........................................................................................57
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Rationale for Safety Endpoints.....................................................................57
Rationale for Patient-reported Outcomes (PROs) Endpoints .......................58
EORTC QLQ-C30 .................................................................................58
EORTC QLQ-LC13...............................................................................58
EQ-5D-5L ..............................................................................................59
Planned Exploratory Biomarker Research....................................................59
Planned Genetic Analysis .............................................................................60
Future Biomedical Research.........................................................................61
Rationale for the Use of Comparator/Placebo .....................................................61
Justification for Dose ..............................................................................................61
Starting Dose for This Trial .................................................................................61
Rationale for Dose Interval and Trial Design......................................................61
Documentation of Local Progression and Metastases .........................................62
Local Progression.................................................................................................62
Metastatic Disease ...............................................................................................62
6.
Study Population........................................................................................................62
Inclusion Criteria....................................................................................................62
Exclusion Criteria ...................................................................................................65
Lifestyle Restrictions...............................................................................................67
Meals and Dietary Restrictions............................................................................67
Caffeine, Alcohol, and Tobacco Restrictions ......................................................67
Activity ................................................................................................................68
Screen Failures ........................................................................................................68
Participant Replacement Strategy.........................................................................68
7.
Treatments..................................................................................................................68
Treatments Administered.......................................................................................68
Dose Modification (Escalation/Titration/Other)..................................................70
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).........................................................................................................71
Dose Modification and Toxicity Management of Infusion-Reactions 
Related to Pembrolizumab...................................................................................75
Other Allowed Dose Interruption for Pembrolizumab ........................................76
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Chemotherapy Dose Modifications .....................................................................76
Method of Treatment Assignment.........................................................................78
Stratification.........................................................................................................78
Blinding....................................................................................................................79
Preparation/Handling/Storage/Accountability ....................................................79
Dose Preparation..................................................................................................79
Handling, Storage and Accountability.................................................................79
Treatment Compliance...........................................................................................80
Administration and Compliance of IV Study Treatments 
(Pembrolizumab/Placebo and Chemotherapy).....................................................80
Concomitant Therapy.............................................................................................80
Rescue Medications and Supportive Care ...........................................................80
Systemic Corticosteroid Use.........................................................................80
Pemetrexed Premedication............................................................................81
Antiemetic Use..............................................................................................81
Acceptable Concomitant Medications .................................................................81
Prohibited Concomitant Medications...................................................................81
Treatment After the End of the Study ..................................................................82
Clinical Supplies Disclosure...................................................................................82
Standard Policies.....................................................................................................82
8.
Discontinuation/Withdrawal Criteria......................................................................83
Discontinuation of Study Treatment.....................................................................83
Withdrawal from the Study ...................................................................................84
Lost to Follow Up....................................................................................................85
9.
Study Assessments and Procedures..........................................................................85
Administrative and General Procedures ..............................................................86
Informed Consent.................................................................................................86
General Informed Consent............................................................................86
Consent and Collection of Specimens for Future Biomedical 
Research........................................................................................................86
Inclusion/Exclusion Criteria ................................................................................86
Participant Identification Card.............................................................................87
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Medical History ...................................................................................................87
Prior and Concomitant Medications Review .......................................................87
Prior Medications..........................................................................................87
Concomitant Medications.............................................................................87
Assignment of Screening Number.......................................................................87
Assignment of Treatment/Randomization Number.............................................88
Treatment Administration....................................................................................88
Timing of Dose Administration....................................................................88
Timing of Dose Administration of Pembrolizumab or Matching 
Placebo..........................................................................................................88
Timing of Dose Administration of Chemotherapy .......................................89
Cisplatin.................................................................................................89
Gemcitabine...........................................................................................89
Pemetrexed.............................................................................................89
Radiotherapy..........................................................................................90
Surgical Procedure Guidelines.............................................................................90
Preoperative Evaluation................................................................................90
Intraoperative Guidance................................................................................90
Perioperative Complications.........................................................................91
Evaluation and Reporting of Postoperative Complications..........................92
Postoperative Care ........................................................................................92
Pathology Specimen......................................................................................92
Withdrawal/Discontinuation................................................................................93
Survival Follow-up .......................................................................................93
Withdrawal From Future Biomedical Research ...........................................93
Participant Blinding/Unblinding..........................................................................94
Calibration of Critical Equipment........................................................................94
Tumor Tissue Collection for Biomarker Analysis...............................................95
Efficacy Assessments...............................................................................................95
Tumor Imaging and Assessment of Disease........................................................95
Initial Tumor Imaging...................................................................................95
Tumor Imaging During Trial ........................................................................96
End of Treatment and Follow-up Tumor Imaging........................................97
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Assessment of Disease..................................................................................97
Patient-reported Outcomes...................................................................................97
Medical Resource Utilization and Health Economics .........................................98
Survival Follow-up ..............................................................................................98
Adverse Events (AE), Serious Adverse Events (SAE) and Other 
Reportable Safety Events .......................................................................................98
Time Period and Frequency for Collecting AE, SAE and Other 
Reportable Safety Event Information ..................................................................99
Method of Detecting AE, SAE and Other Reportable Safety Events................101
Follow-up of AE, SAE and Other Reportable Safety Event Information..........101
Regulatory Reporting Requirements for SAE ...................................................102
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs................................................................................102
Pregnancy and Exposure During Breastfeeding ................................................102
Events of Clinical Interest (ECI)........................................................................103
Treatment of Overdose.........................................................................................103
Safety......................................................................................................................104
Physical Examinations.......................................................................................104
Full Physical Examination..........................................................................104
Directed Physical Examination...................................................................104
Vital Signs..........................................................................................................104
Electrocardiograms ............................................................................................104
Clinical Safety Laboratory Assessments............................................................104
Laboratory Safety Evaluations (Hematology, Chemistry, and 
Urinalysis)...................................................................................................105
Pregnancy Test............................................................................................105
Eastern Cooperative Oncology Group (ECOG) Performance Scale .................105
Pharmacokinetics..................................................................................................105
Pharmacodynamics...............................................................................................106
Biomarkers ............................................................................................................106
Planned Genetic Analysis Sample Collection....................................................106
Future Biomedical Research Sample Collection................................................106
Visit Requirements................................................................................................107
Screening............................................................................................................107
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Treatment Period................................................................................................107
Participants Discontinued From Study Intervention but Continuing to 
be Monitored in the Study..................................................................................108
Safety Follow-up Visit................................................................................108
Follow-up Visits..........................................................................................108
Survival Follow-up .....................................................................................108
Vital Status..................................................................................................109
10.
Statistical Analysis Plan ..........................................................................................109
Statistical Analysis Plan Summary......................................................................109
Responsibility for Analyses/In-House Blinding..................................................111
Hypotheses/Estimation .........................................................................................112
Analysis Endpoints................................................................................................112
Efficacy Endpoints.............................................................................................112
Safety Endpoints ................................................................................................113
Patient-reported Outcome (PRO) Endpoints......................................................113
Analysis Populations.............................................................................................113
Efficacy Analysis Population.............................................................................113
Safety Analysis Population................................................................................113
PRO Analysis Population ..................................................................................114
Statistical Methods................................................................................................114
Statistical Methods for Efficacy Analyses.........................................................114
Event-free Survival .....................................................................................114
Overall Survival..........................................................................................115
Major Pathological Response Rate.............................................................115
Pathological Complete Response Rate .......................................................115
Summary of Primary Analysis Approach for Key Efficacy 
Endpoints ....................................................................................................116
Statistical Methods for Safety Analyses ............................................................116
Statistical Methods for PRO Analyses: EORTC QLQ-C30 Global 
Health Status/QoL Score....................................................................................118
Summaries of Baseline Characteristics and Demographics...............................118
Interim Analyses ...................................................................................................118
Interim Safety Analyses.....................................................................................118
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Interim Efficacy Analyses..................................................................................119
Multiplicity ............................................................................................................120
Major Pathological Response Rate ....................................................................120
Pathological Complete Response Rate ..............................................................121
Event-free Survival ............................................................................................121
Overall Survival.................................................................................................122
Safety Analyses..................................................................................................124
Sample Size and Power Calculations ..................................................................124
Sample Size and Power for Efficacy Analyses..................................................124
Sample Size and Power for Safety Analyses .....................................................124
Subgroup Analyses................................................................................................125
Compliance (Medication Adherence)..................................................................125
Extent of Exposure................................................................................................126
11.
References.................................................................................................................126
12.
Appendices................................................................................................................133
Appendix 1: Study Governance Considerations ................................................133
MSD Code of Conduct for Clinical Trials.....................................................................133
Financial Disclosure.......................................................................................................135
Data Protection...............................................................................................................135
Confidentiality of Data ..................................................................................................135
Confidentiality of Participant Records...........................................................................136
Confidentiality of IRB/IEC Information........................................................................136
Committees Structure.....................................................................................................136
Trial Steering Committee...........................................................................................136
Executive Oversight Committee................................................................................136
Data Monitoring Committee......................................................................................136
Publication Policy ..........................................................................................................137
Compliance with Trial Registration and Results Posting Requirements.......................137
Compliance with Law, Audit and Debarment ...............................................................138
Data Quality Assurance .................................................................................................138
Source Documents .........................................................................................................139
Study and Site Closure...................................................................................................139
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Appendix 2: Collection and Management of Specimens for Future 
Biomedical Research.............................................................................................140
Appendix 3: Contraceptive Guidance.................................................................144
Definitions......................................................................................................................144
Contraception Requirements..........................................................................................145
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting............................................146
Definition of AE ............................................................................................................146
Definition of SAE ..........................................................................................................147
Additional Events Reported in the Same Manner As SAE............................................148
Recording AE and SAE .................................................................................................149
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor................152
Appendix 5: ECOG Performance Status............................................................154
Appendix 6: Clinical Laboratory Tests...............................................................155
Appendix 7: Country-specific Requirements .....................................................156
Germany-specific Requirements........................................................................156
China-specific Requirements.............................................................................156
Japan-specific Requirements..............................................................................157
Ireland ................................................................................................................158
United Kingdom.................................................................................................158
Appendix 8: List of Abbreviations ......................................................................159
Appendix 9: MASCC 2016 Guidelines................................................................163
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LIST OF TABLES
    
Table 1
Adequate Organ Function Laboratory Values......................................................65
Table 2
Study Interventions...............................................................................................69
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ....................................................................72
Table 4
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines.............................................................................................................75
Table 5
Dose Modifications...............................................................................................76
Table 6
Recommended Dose Modifications for Cisplatin/Pemetrexed for 
Hematological Toxicity ........................................................................................77
Table 7
Recommended Dose Modifications for Cisplatin/Gemcitabine for 
Hematological Toxicity ........................................................................................77
Table 8
Recommended Dose Modifications for Chemotherapy for Non-
Hematological Toxicity ........................................................................................78
Table 9
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events....................................................................................100
Table 10
Analysis Strategy for Key Efficacy Endpoints...................................................116
Table 11
Analysis Strategy for Safety Parameters ............................................................118
Table 12
Summary of Interim and Final Analyses Strategy..............................................119
Table 13
Possible α-levels and Approximate mPR Rate Difference Required to 
Demonstrate Efficacy for mPR rate....................................................................121
Table 14
Possible α-levels and Approximate pCR Rate Difference Required to 
Demonstrate Efficacy for pCR rate ....................................................................121
Table 15
Efficacy Boundaries and Properties for Planned Analyses of EFS....................122
Table 16
Efficacy Boundaries and Properties for Planned Analyses of OS......................123
Table 17
Two-sided 95% Confidence Intervals of Differences in Incidence of AE 
Rates Between the Two Treatment Groups for 393 Participants in Each 
Treatment Arm....................................................................................................125
Table 18
Protocol-Required Safety Laboratory Assessments ...........................................155
Table 19
Recommended Doses of Corticosteroids* (Dexamethasone).............................163
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LIST OF FIGURES
Figure 1
Study Design.........................................................................................................54
Figure 2
Multiplicity Graph for Type I Error Control ......................................................120
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1. Synopsis
Protocol Title:  
Phase III, Randomized, Double-blind Trial of Platinum Doublet Chemotherapy +/-
Pembrolizumab (MK-3475) as Neoadjuvant/Adjuvant Therapy for Participants with 
Resectable Stage II, IIIA, and Resectable IIIB (T3-4N2) Non-small Cell Lung Cancer 
(NSCLC) (KEYNOTE-671)
Short Title: 
Chemo +/- Pembrolizumab (MK-3475) as Perioperative Therapy for Stage II, IIIA-
Resectable IIIB (N2) NSCLC
Objectives/Hypotheses and Endpoints:
All objectives and hypotheses apply to male/female adult participants (≥18 years of age) with 
resectable Stages II or IIIA-B (N2) non-small cell lung cancer (NSCLC). Neoadjuvant 
chemotherapy (NAC) is a platinum doublet chemotherapy of 4 cycles of cisplatin with 
gemcitabine or pemetrexed.
Objective/Hypothesis
Endpoint
Primary

Objective: To evaluate event-free 
survival (EFS) by biopsy assessed by 
a local pathologist or by investigator-
assessed imaging using RECIST 1.1.
Hypothesis #1: NAC plus 
pembrolizumab followed by surgery 
and adjuvant pembrolizumab 
improves EFS by biopsy assessed by 
local pathologist or by investigator-
assessed imaging using RECIST 1.1 
compared to NAC plus placebo 
followed by surgery and adjuvant 
placebo.

EFS is defined as the time from 
randomization to the first of the following 
events: disease or local progression, 
inability to resect tumor, local or distant 
recurrence, or death (see Section 10.4 for 
details).

Objective: To evaluate the overall 
survival (OS).
Hypothesis #2: NAC plus 
pembrolizumab followed by surgery 
and adjuvant pembrolizumab 
improves OS compared to NAC plus 
placebo followed by surgery and 
adjuvant placebo.

OS is defined as the time from 
randomization to death due to any cause.
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The study will be considered positive if NAC plus pembrolizumab followed by surgery 
and adjuvant pembrolizumab demonstrates superior EFS or OS at an interim or final 
analysis compared to NAC plus placebo followed by surgery and adjuvant placebo.
Secondary

Objective: To evaluate the rate of 
major pathological response (mPR) 
assessed by blinded central laboratory 
pathologist following NAC +/-
pembrolizumab.
Hypothesis #3: NAC plus 
pembrolizumab improves mPR rate 
assessed by blinded central laboratory 
pathologist compared to NAC plus 
placebo.

mPR is defined as ≤10% viable tumor 
cells in the resected primary tumor and all 
resected lymph nodes.

Objective: To evaluate the rate of 
pathological complete response (pCR) 
in the resected primary tumor and 
lymph nodes assessed by blinded 
central laboratory pathologist 
following NAC +/- pembrolizumab.
Hypothesis #4: NAC plus 
pembrolizumab improves pCR rate 
assessed by blinded central laboratory 
pathologist compared to NAC plus 
placebo.

pCR is defined as the absence of residual 
invasive cancer on hematoxylin and eosin 
stained slides of the resected lung 
specimen and lymph nodes following 
completion of neoadjuvant therapy (ie,
ypT0/Tis ypN0).

Objective: To evaluate mean change 
from baseline in the neoadjuvant 
phase and in the adjuvant phase in 
global health status/quality of life 
(QoL) using the European 
Organization for Research and 
Treatment of Cancer (EORTC) QoL 
questionnaire (QLQ)-C30.

The QoL is based on the global health 
status/QoL scale (items 29 and 30) of the 
EORTC-QLQ-C30.

Objective: To evaluate the safety and 
tolerability of NAC plus 
pembrolizumab followed by surgery
and adjuvant pembrolizumab.

Participant experiencing adverse events 
(AEs).

Participant discontinuing study drug due 
to AEs. 

Participant experiencing perioperative 
complications.
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Overall Design:
Study Phase
Phase III
Clinical Indication
Neoadjuvant/Adjuvant treatment for participants with Resectable 
Stage II or IIIA-B (N2) NSCLC
Population
Participants with resectable Stage II or IIIA-B (T3-4N2) NSCLC
Study Type
Interventional
Type of Design
Randomized, multi-site
Type of Control
Placebo-controlled
Study Blinding
Double-blind
Estimated Duration of 
Trial
The Sponsor estimates that the trial will require approximately
8.5 years from the time the first participant (or their legally 
acceptable representative) provides documented informed 
consent until the last participant’s last study-related contact.
Number of Participants:
Approximately 786 participants will be enrolled.
Treatment Groups and Duration:
Treatment Groups
There are 2 treatment arms: 

Treatment Arm A: Neoadjuvant - pembrolizumab (4 cycles) 
plus chemotherapy (platinum doublet) followed by surgery.  
Adjuvant - pembrolizumab (13 cycles)
o
Pembrolizumab: 200 mg fixed dose, intravenously (IV) 
every 3 weeks (Q3W), in the neoadjuvant and adjuvant 
treatment periods.
o
Postoperative radiation therapy (RT) may be 
administered if microscopic residual disease or gross 
residual disease remains.

Treatment Arm B: Neoadjuvant - placebo (4 cycles) plus 
chemotherapy (platinum doublet) followed by surgery.  
Adjuvant - placebo (13 cycles)  
o
Placebo:  intravenously (IV) every 3 weeks (Q3W), in 
the neoadjuvant and adjuvant treatment periods.
o
Postoperative radiation therapy (RT) may be 
administered if microscopic residual disease or gross 
residual disease remains.
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Duration of 
Participation
Each participant will be in the study from the time the participant 
provides documented informed consent through the final 
protocol-specified contact. 
After a screening phase of 28 days, eligible participants will be 
stratified and randomized to receive study treatment until one of 
the conditions for discontinuation of study intervention is met
(see Section 8.1). 
After the end of treatment, each participant will be followed for 
the occurrence of AEs and participant-reported pregnancy as 
described under Section 9.3.
Participants who discontinue treatment for reasons other than 
documented disease progression/recurrence will have per 
protocol post treatment follow-up and imaging for disease status 
until: disease progression/recurrence is documented by 
radiograph (utilizing RECIST 1.1) and/or by biopsy when 
clinically appropriate, consent is withdrawn, or participant is lost 
to follow-up.  All participants will be followed by telephone for 
overall survival until death, withdraw of consent, or the end of 
the study.
Study governance considerations are outlined in Appendix 1: Study Governance 
Considerations. A list of abbreviations used in this document can be found in Appendix 8: 
List of Abbreviations.
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2. Schedule of Activities (SoA)
Trial Screening Procedures
Trial Period
Screening
Notes:
Participants who discontinue study treatment for reasons other than disease progression 
will enter Posttreatment Study Follow-up.
Participants who discontinue study treatment due to disease progression will enter Safety 
and Survival Follow-up.  
Participants may be rescreened once.
Visit Number/Title
Treatment Cycle
Week
Scheduled Day (s)
Scheduling Window (Days, unless noted)
-28 to -1
Administrative Procedures
Informed Consent
X
Documented informed consent will be obtained before any protocol-related intervention.
Informed Consent for Future Biomedical 
Research (FBR; optional)
X
Participant Identification Card
X
Inclusion/Exclusion Criteria
X
Demographics, Disease Details and Complete 
Medical History (includes substance usage)
X
Substances: tobacco.
Prior/Concomitant Medication Review
X
Prior medications – Record all medications taken within 28 days of first dose as well as 
medications regularly administered at intervals greater than 28 days prior to first dose. 
Concomitant medications – Enter new medications started during the study through the 
posttreatment Safety Follow-up.
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Trial Screening Procedures
Trial Period
Screening
Notes:
Visit Number/Title
Treatment Cycle
Week
Scheduled Day (s)
Scheduling Window (Days, unless noted)
-28 to -1
Screening Procedures
Scans performed as part of routine clinical management are acceptable for use as the 
baseline scan if they are of diagnostic quality, include all required anatomy, and performed 
within 60 days prior to randomization with the exception of the chest/abdomen CT scan, 
which must be performed within 28 days prior to randomization. These scans will be 
considered the baseline assessments for the study.
CT Chest and Abdomen
X
If the participant underwent the required CT scans prior to providing documented informed 
consent and within 28 days prior to randomization, repeat CT scans are not required.
MRI Brain With Contrast
X
If the participant is unable to undergo an MRI, head CT with contrast should be performed. 
If the participant is unable to have CT contrast, a head CT without contrast is acceptable. If 
the participant underwent the required brain imaging prior to signing ICF and within 60
days prior to randomization, repeat brain imaging is not required. For each participant, the 
same modality should be used throughout the study for response evaluation.
FDG-PET or FDG-PET/CT
X
If the participant underwent the required FDG-PET or FDG-PET/CT imaging prior to 
signing ICF and within 60 days before randomization, repeat imaging is not required.
Safety Procedures
Full Physical Examination
X
To be performed by the investigator or qualified designee.  
ECOG Performance Status
X
ECOG performance status must be 0 or 1 within 10 days of randomization AND also on 
the first day of dosing.
Weight, Height and Vital Signs
X
Vital signs to be collected include: temperature, heart rate, respiratory rate, blood pressure.  
12-Lead ECG (Local)
X
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Trial Screening Procedures
Trial Period
Screening
Notes:
Visit Number/Title
Treatment Cycle
Week
Scheduled Day (s)
Scheduling Window (Days, unless noted)
-28 to -1
Urine or Serum β-Human Chorionic 
Gonadotropin (β-hCG) Pregnancy Test (women of 
child-bearing potential [WOCBP] only) – as per 
local standard operating procedure (SOP)
X
Pregnancy testing is required at Screening and 24 hours before administration of every
dose of study treatment.
HIV, Hepatitis B And C Screen (Per Site SOP)
X
Testing is not required unless mandated by local health authority.
Hematology
X
Required during Screening (within 10 days before the start of study treatment). After 
Cycle 1, lab samples can be collected up to 72 hours prior to the next scheduled visit.
Chemistry
X
Urinalysis
X
Required during Screening (within 10 days before the start of study treatment).  After 
Cycle 1, lab samples can be collected up to 72 hours prior to the next scheduled Cycle.
Coagulation Tests (PT/INR and aPTT/PTT)
X
Required during Screening (within 10 days before the start of study treatment). Any 
participant receiving anticoagulant therapy should have coagulation tests monitored closely 
throughout the study. If clinically indicated, PTT may be performed if the local lab is 
unable to perform aPTT.
Thyroid Function (TSH, T3/FT3, and T4/FT4)
X
Required during Screening (within 10 days prior to the start of study treatment). After 
Cycle 1, laboratory samples can be collected up to 72 hours before the next scheduled 
collection time point.
AE/SAE Review
X
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Trial Period
Screening
Notes:
Visit Number/Title
Treatment Cycle
Week
Scheduled Day (s)
Scheduling Window (Days, unless noted)
-28 to -1
Tumor Tissue Sample Collection
Biopsy (Histology) for diagnosis and biomarkers
X
Tumor tissue (from primary tumor or lymph node) from pretreatment biopsy for Tumor 
Proportion Score (TPS) and diagnosis testing. 
Tumor tissue sufficient for histologic determination of PD-L1 TPS must be obtained within 
90 days prior to randomization. Common procedures employed to obtain sufficient tissue
for histologic examination are: core biopsy of the primary tumor, mediastinoscopic biopsy 
of lymph nodes with a biopsy forceps, open incisional biopsy of the primary tumor or 
lymph nodes, and VATs biopsy of the primary tumor or lymph nodes utilizing a biopsy
forceps. Other methods that provide sufficient tumor for histology may also be acceptable, 
seek Sponsor guidance. See the Procedures Manual and Vendor lab manual for additional 
information.
Confirmation from central laboratory that there is an evaluable tissue for TPS is required 
prior to randomization. Results of PD-L1 testing for stratification will be blinded to study 
sites.
Tissue Collection for Biomarker Analysis (tested 
centrally) 
X
Tumor tissue from pretreatment biopsy, if available, after TPS testing is performed.
EGFR/ALK testing results
X
Locally performed EGFR/ALK results (if available), should be entered into EDC collector. 
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Preoperative (Neoadjuvant) Treatment
Trial Period
Preoperative (Neoadjuvant)
Week 13-20
Notes:
The maximum interval from the first dose 
of neoadjuvant therapy to surgery is 20 
weeks. If the participant receives fewer 
than 4 cycles of neoadjuvant therapy, 
she/he can remain in the study and should 
undergo surgery within 4-8 weeks 
following the last dose of protocol therapy 
and receive adjuvant therapy. Participants 
who discontinue study treatment for 
reasons other than disease progression will 
enter post-treatment study follow-up.
Participants who discontinue study 
treatment due to disease progression will 
enter Survival Follow-up.  
†Please see Section 9.1.8 for further details 
regarding visit windows for Cycles 2 
through 4. 
Visit Number/Title
Treatment Cycle
1
2
3
4
Week
1
2
3
4
5
6
7
8
9
10
11
12
Cycle Day(s)
1
8
15
1
8
15
1
8
15
1
8
15
Scheduling Window (Days, unless noted)
±3
±3†
±3†
±3†
Prior/Concomitant Medication Review
X
X
X
X
X
X
X
X
X
Treatment Allocation via IVRS
X
Site personnel will access the IVRS prior to 
dosing on Cycle 1, Day 1 to obtain the 
participant’s allocation/randomization 
number
Vital Status 
Upon Sponsor request, participants may be 
contacted for survival information at any 
time during the study.
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Preoperative (Neoadjuvant) Treatment  
Trial Period
Preoperative (Neoadjuvant)
Week 13-20
Visit Number/Title
Treatment Cycle
1
2
3
4
Week
1
2
3
4
5
6
7
8
9
10
11
12
Cycle Day(s)
1
8
15
1
8
15
1
8
15
1
8
15
Scheduling Window (Days, unless noted)
±3
±3†
±3†
±3†
Trial Treatment Administration
Treatment must begin within 3 days of 
randomization. All study treatments must 
be initiated on Day 1 of each cycle after all 
procedures/assessments have been 
completed.  If the participant is unable to 
receive all the scheduled therapies on Day 
1, the non-administered therapies must be 
initiated within 72 hours of scheduled 
Cycle Day 1.  Note: If chemotherapy is
interrupted, all 3 therapies (cisplatin, 
gemcitabine/pemetrexed, and 
pembrolizumab/placebo) should be 
withheld for the duration of the 
interruption. If pembrolizumab/placebo is 
interrupted, chemotherapy does not have to 
be withheld. See Section 7.2 for details.
Please see Section 9.10.2 for further details 
regarding visit windows for Cycles 2 
through 4.
Pembrolizumab or Placebo
X
X
X
X
Cisplatin
X
X
X
X
Pemetrexed
X
X
X
X
Pemetrexed to be used for nonsquamous 
NSCLC only.
Gemcitabine
X
X
X
X
X
X
X
X
Gemcitabine to be used for squamous 
NSCLC only.
Surgery
X
Performed as part of planned standard of 
care (SOC). 
Participants who do not undergo surgery as 
originally planned (excluding participants 
with local disease progression or metastatic 
disease) should proceed to adjuvant 
treatment and receive RT followed by 
planned protocol treatment.
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Preoperative (Neoadjuvant) Treatment  
Trial Period
Preoperative (Neoadjuvant)
Week 13-20
Visit Number/Title
Treatment Cycle
1
2
3
4
Week
1
2
3
4
5
6
7
8
9
10
11
12
Cycle Day(s)
1
8
15
1
8
15
1
8
15
1
8
15
Scheduling Window (Days, unless noted)
±3
±3†
±3†
±3†
Tumor Tissue Sample Collection
Tissue Collection
As Clinically Indicated
Biopsies will be obtained for participants 
with suspected metastatic disease. Samples 
are to be reviewed by a local pathologist. 
Samples must also be sent to the central lab 
for central pathological review. Treatment 
will be based on the interpretation of the 
local pathologist.
Efficacy Procedures
Histopathology (mPR and pCR assessment)
X
Assessment of surgical margins and the 
resected specimens will be performed by 
the local pathologist. Samples will be sent 
to a central lab for evaluation of mPR and 
pCR.
Preoperative Imaging
X
X
If the participant receives: 
4 cycles: Imaging 3 weeks after Cycle 2 
and 3 weeks after Cycle 4 
3 cycles: Imaging 3 weeks after Cycle 2 
and 4 weeks after Cycle 3
2 cycles: Imaging 3 weeks after Cycle 2 
1 cycle: Imaging 3 weeks after Cycle 1 
Note that the imaging window is ± 7 days.
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Preoperative (Neoadjuvant) Treatment  
Trial Period
Preoperative (Neoadjuvant)
Week 13-20
Visit Number/Title
Treatment Cycle
1
2
3
4
Week
1
2
3
4
5
6
7
8
9
10
11
12
Cycle Day(s)
1
8
15
1
8
15
1
8
15
1
8
15
Scheduling Window (Days, unless noted)
±3
±3†
±3†
±3†
Patient-reported Outcomes (PROs)
EQ-5D -5L
X
X
PROs should be administered prior to all 
procedures/assessments.
The PROs are to be completed in the 
following order: EQ-5D-5L, EORTC 
QLQ-C30, and EORTC QLQ-LC13.
If the participant does not complete the 
PROs for any reason, the reason must be
captured. If the participant completes 
fewer than 4 cycles of neoadjuvant 
therapy, the PROs should be completed at 
the last scheduled visit prior to surgery.
Collections of all ePROs at 2 different time 
points must be completed prior to surgery. 
If the participant does not have surgery 
(refusal, physician decision, medical 
illness, etc.), then the second collection of
ePROs must be completed within 2 weeks 
prior to beginning radiotherapy or entering 
the adjuvant phase. 
EORTC QLQ-C30
X
X
EORTC QLQ-LC13
X
X
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Preoperative (Neoadjuvant) Treatment  
Trial Period
Preoperative (Neoadjuvant)
Week 13-20
Visit Number/Title
Treatment Cycle
1
2
3
4
Week
1
2
3
4
5
6
7
8
9
10
11
12
Cycle Day(s)
1
8
15
1
8
15
1
8
15
1
8
15
Scheduling Window (Days, unless noted)
±3
±3†
±3†
±3†
Safety Procedures
Directed Physical Examination
X
X
X
X
X
X
X
X
To be performed by the investigator or 
qualified designee.  
ECOG Performance Status
X
X
X
X
X
X
X
X
ECOG performance status must be
completed before dosing at each cycle. 
Prior to Cycle 1, ECOG score must be 0 or 
1.
Weight and Vital Signs
X
X
X
X
X
X
X
X
Vital signs to be collected include:
temperature, heart rate, respiratory rate, 
blood pressure.  
Urine or Serum β-Human Chorionic 
Gonadotropin (β-hCG) Pregnancy Test (WOCBP 
only) – as per local SOP
X
X
X
X
Pregnancy testing is required at Screening 
and 24 hours prior to administration of 
every dose of study treatment.
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Preoperative (Neoadjuvant) Treatment  
Visit Number/Title
Treatment Cycle
1
2
3
4
Week
1
2
3
4
5
6
7
8
9
10
11
12
Scheduled Day (s)
1
8
15
1
8
15
1
8
15
1
8
15
Scheduling Window (Days, unless noted)
±3
±3†
±3†
±3†
Hematology
X
X
X
X
X
X
X
X
After Cycle 1, lab samples can be 
collected up to 72 hours prior to the next 
scheduled cycle. Tests do not need to be 
repeated at C1D1 if they have been
performed within 10 days of study 
treatment.
Chemistry
X
X
X
X
X
X
X
X
Urinalysis
X
After Cycle 1, lab samples can be 
collected up to 72 hours prior to the last 
scheduled visit prior to surgery.
Coagulation Tests (PT/INR and aPTT/PTT)
As Clinically Indicated
Any participant receiving anticoagulant 
therapy should have coagulation tests 
monitored closely throughout the study. If 
clinically indicated, PTT may be 
performed if the local lab is unable to 
perform aPTT. Tests do not need to be 
repeated at C1D1 if they have been
performed within 10 days of study 
treatment.
Thyroid Function (TSH, T3/FT3, and T4/FT4)
X
X
To be drawn at Week 5, Week 11, and 
Week 17 (if applicable). After Cycle 1, 
lab samples can be collected up to 72 
hours prior to the next scheduled cycle.
Participants may be dosed in subsequent 
cycles after Cycle 1, Day 1 while thyroid 
function tests are pending.
AE/SAE Review
Continuous Reporting
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Postoperative (Adjuvant Treatment)
Trial Period
Postoperative (adjuvant)
Notes
Participants will receive up to 13 cycles of adjuvant therapy.
Participants who do not have surgery should have radiotherapy 
followed by the adjuvant pembrolizumab/placebo treatment 
phase. 
Participants who do have surgery and do not receive radiotherapy 
must begin adjuvant pembrolizumab/placebo treatment within 4-
12 weeks following surgery.
Participants who have surgery and radiotherapy must begin 
radiotherapy within 4-8 weeks following surgery. Adjuvant 
pembrolizumab/placebo must begin within 2-4 weeks following 
completion of radiotherapy.
Participants who do not have surgery should begin radiotherapy 
within 8 weeks of Day 1 of last chemotherapy cycle. 
Participants who discontinue study treatment for reasons other 
than disease progression/recurrence will enter Post-Treatment 
Study Follow-up.
Participants who discontinue study treatment due to disease 
progression/recurrence will enter Survival Follow-up.
Upon completion of adjuvant therapy, participants move into 
Post-Treatment Study Follow-up.
Dose interruptions are permitted in the case of medical/surgical 
events or logistical reasons not related to protocol therapy (eg, 
elective surgery, unrelated medical events, participant vacation, 
and/or holidays). The reason for interruption should be 
documented in the participant’s record.
Treatment Cycle
1
2
3
4
5
6
7
8-13
Week
1
4
7
10
13
16
19
22-37
Scheduled Day(s)
1
1
1
1
1
1
1
1
Scheduling Window (Days, unless 
noted)
±3
±3
±3
±3
±3
±3
±3
±3
Administrative Procedures
Prior/Concomitant Medication 
Review 
X
X
X
X
X
X
X
X
Concomitant medications – Enter new medications started during 
the study through the post-treatment Safety Follow up.
Vital Status
Upon Sponsor request, participants may be contacted for survival 
information at any time during the study.
Trial Treatment Administration
Pembrolizumab or Placebo 
Administration 
X
X
X
X
X
X
X
X
To be administered after all procedures/assessments have been 
completed. Adjuvant therapy should be started within 4-12 
weeks following surgery. 
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Trial Period
Postoperative (adjuvant)
Notes
Participants will receive up to 13 cycles of adjuvant therapy.
Participants who do not have surgery should have radiotherapy 
followed by the adjuvant pembrolizumab/placebo treatment 
phase. 
Participants who do have surgery and do not receive radiotherapy 
must begin adjuvant pembrolizumab/placebo treatment within 4-
12 weeks following surgery.
Participants who have surgery and radiotherapy must begin 
radiotherapy within 4-8 weeks following surgery. Adjuvant 
pembrolizumab/placebo must begin within 2-4 weeks following 
completion of radiotherapy.
Participants who do not have surgery should begin radiotherapy 
within 8 weeks of Day 1 of last chemotherapy cycle. 
Participants who discontinue study treatment for reasons other 
than disease progression/recurrence will enter Post-Treatment 
Study Follow-up.
Participants who discontinue study treatment due to disease 
progression/recurrence will enter Survival Follow-up.
Upon completion of adjuvant therapy, participants move into 
Post-Treatment Study Follow-up.
Dose interruptions are permitted in the case of medical/surgical 
events or logistical reasons not related to protocol therapy (eg, 
elective surgery, unrelated medical events, participant vacation, 
and/or holidays). The reason for interruption should be 
documented in the participant’s record.
Treatment Cycle
1
2
3
4
5
6
7
8-13
Week
1
4
7
10
13
16
19
22-37
Scheduled Day(s)
1
1
1
1
1
1
1
1
Scheduling Window (Days, unless 
noted)
±3
±3
±3
±3
±3
±3
±3
±3
Radiotherapy
Participants who have microscopic positive margins or 
extracapsular nodal extension after surgery should receive 
radiation therapy to a maximum of 60 Gy. For participants who 
do not have surgery or who have gross residual disease after 
surgery, the maximum radiation therapy dose is 70 Gy. 
Radiotherapy is not allowed for participants with completely 
resected N2 disease in the absence of extracapsular spread. 
Radiotherapy must begin within 4-8 weeks after surgery and 
cannot be administered concomitantly with adjuvant therapy. 
Adjuvant therapy must be started within 2-4 weeks of completion 
of radiotherapy. Please see radiotherapy manual for details.
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Trial Period
Postoperative (adjuvant)
Notes
Participants will receive up to 13 cycles of adjuvant therapy.
Participants who do not have surgery should have radiotherapy 
followed by the adjuvant pembrolizumab/placebo treatment 
phase. 
Participants who do have surgery and do not receive radiotherapy 
must begin adjuvant pembrolizumab/placebo treatment within 4-
12 weeks following surgery.
Participants who have surgery and radiotherapy must begin 
radiotherapy within 4-8 weeks following surgery. Adjuvant 
pembrolizumab/placebo must begin within 2-4 weeks following 
completion of radiotherapy.
Participants who do not have surgery should begin radiotherapy 
within 8 weeks of Day 1 of last chemotherapy cycle. 
Participants who discontinue study treatment for reasons other 
than disease progression/recurrence will enter Post-Treatment 
Study Follow-up.
Participants who discontinue study treatment due to disease 
progression/recurrence will enter Survival Follow-up.
Upon completion of adjuvant therapy, participants move into 
Post-Treatment Study Follow-up.
Dose interruptions are permitted in the case of medical/surgical 
events or logistical reasons not related to protocol therapy (eg, 
elective surgery, unrelated medical events, participant vacation, 
and/or holidays). The reason for interruption should be 
documented in the participant’s record.
Treatment Cycle
1
2
3
4
5
6
7
8-13
Week
1
4
7
10
13
16
19
22-37
Scheduled Day(s)
1
1
1
1
1
1
1
1
Scheduling Window (Days, unless 
noted)
±3
±3
±3
±3
±3
±3
±3
±3
Efficacy Procedures
Postoperative Imaging
X*
Every 16 weeks from date of randomization
(+/- 14 days)**
Every 16 calendar weeks (±14 days) from date of randomization.  
*New baseline CT scans are required PRIOR to the start of 
adjuvant pembrolizumab/placebo. Please see Section 9.2.1.2 for 
more details. 
**May be performed sooner if clinically indicated.
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Postoperative (Adjuvant) Treatment 
Trial Period
Postoperative (adjuvant)
Notes
Treatment Cycle
1
2
3
4
5
6
7
8-13
Week
1
4
7
10
13
16
19
22-37
Scheduled Day(s)
1
1
1
1
1
1
1
1
Scheduling Window (Days, unless 
noted)
±3
±3
±3
±3
±3
±3
±3
±3
Patient-reported Outcomes
EQ-5D-5L
X
X
X
X
X
X*
ePROs are to be administered prior to all 
procedures/assessments. PROs are to be completed in the 
following order: EQ-5D-5L, EORTC QLQ-C30, and EORTC 
QLQ-LC13.
*To be administered at Cycle 10 and Cycle 13.
EORTC QLQ-C30
X
X
X
X
X
X*
EORTC QLQ-LC13
X
X
X
X
X
X*
Safety Procedures
Full Physical Examination
X
Directed Physical Examination
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
ECOG performance status must be completed before dosing at 
each cycle. 
Weight and Vital Signs 
X
X
X
X
X
X
X
X
Vital signs to be collected include: temperature, heart rate, 
respiratory rate, and blood pressure.  
Urine or Serum β-Human Chorionic 
Gonadotropin (β-hCG) Pregnancy 
Test (WCBP only) – as per local 
SOP
X
X
X
X
X
X
X
X
The protocol requires pregnancy testing within 24 hours prior to
every dose of adjuvant treatment.
Hematology 
X
X
X
X
X
X
X
X
Laboratory samples can be collected up to 72 hours prior to the 
next scheduled cycle.
Chemistry 
X
X
X
X
X
X
X
X
Urinalysis 
X
X
X
X
Collected within 72 hours prior to Cycles 1, 4, 7, 10 and 13, 
unless clinically indicated.
Coagulation Tests (PT/INR and 
aPTT/PTT)
As Clinically Indicated
Any participant receiving anticoagulant therapy that requires 
laboratory testing should have coagulation tests monitored 
closely throughout the study. PTT may be performed if the local 
lab is unable to perform aPTT.
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Postoperative (Adjuvant) Treatment 
Trial Period
Postoperative (adjuvant)
Notes
Cycle 13 and Discontinuation Visit can be combined
Treatment Cycle
1
2
3
4
5
6
7
8-13
Week
1
4
7
10
13
16
19
22-37
Scheduled Day(s)
1
1
1
1
1
1
1
1
Scheduling Window (Days, unless 
noted)
±3
±3
±3
±3
±3
±3
±3
±3
Thyroid Function (TSH, T3/FT3, 
and T4/FT4)
X
X
X
X
X
To be drawn every 6 weeks from Cycle 1. Samples can be 
collected up to 72 hours prior to the next scheduled cycle. 
AE/SAE review
Continuous Reporting
Tumor Tissue Sample Collection
Tissue Collection 
As Clinically Indicated
Biopsies will be obtained for participants with suspected local 
progression (ie, participants who have not had surgery), 
metastases, or local recurrence. Samples are to be reviewed by a 
local pathologist. Samples must also be sent to the central lab for 
central pathological review. Treatment will be based on the 
interpretation of the local pathologist. 
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End of Treatment and Follow-up Visits (Arms A and B)
Trial Period
End of 
Treatment
Post-Treatment Follow-up
Survival 
FU
Notes:
Cycle 13 and 
Discontinuation Visit can be 
combined.
Post-Treatment Follow-up 
Visit timing should start 
from the date of last visit, 
either Discontinuation or 
Safety Follow-up, whichever 
is later
*See Section 5.3
Treatment Cycle/Day
Discontinuation
Safety FU
Year 2
Year 3
Years 4-
5
Year 6
to End 
of 
Study*
Scheduling Window (Days,
unless noted)
At time of 
Treatment 
Discontinuation
30 days from 
last dose 
±3 days
Q16W 
±21 days
Q16W
±21 days
Q6M 
±28 days
Q12M
±28 days
Q12 
Weeks ± 7 
days
Administrative Procedures
Prior/Concomitant Medication 
Review 
X
X
As Clinically Indicated
Post-Study Anticancer Therapy 
Status
X
By telephone contact in 
Survival FU. Status may be
collected more frequently at 
certain timepoints (refer to 
Section 9.10.3.3 for details). 
In addition, upon Sponsor 
request, participants may be 
contacted for survival 
information at any time 
during the study.
Vital Status
X
Efficacy Procedures
CT Chest and Abdomen
X
X
X
X
X
X*
Imaging timing should follow 
calendar days (from 
randomization) and should not 
be recalculated based on date 
of previous scans. Imaging is
still required for participants 
who have started a new
anticancer treatment.
*Participants in Survival 
Follow-up who have 
experienced PD should submit 
SOC imaging to the central 
vendor. Participants in 
Survival Follow-up who have 
not experienced PD should be 
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Trial Period
End of 
Treatment
Post-Treatment Follow-up
Survival 
FU
Notes:
Cycle 13 and 
Discontinuation Visit can be 
combined.
Post-Treatment Follow-up 
Visit timing should start 
from the date of last visit, 
either Discontinuation or 
Safety Follow-up, whichever 
is later
*See Section 5.3
Treatment Cycle/Day
Discontinuation
Safety FU
Year 2
Year 3
Years 4-
5
Year 6
to End 
of 
Study*
Scheduling Window (Days,
unless noted)
At time of 
Treatment 
Discontinuation
30 days from 
last dose 
±3 days
Q16W 
±21 days
Q16W
±21 days
Q6M 
±28 days
Q12M
±28 days
Q12 
Weeks ± 7 
days
given the option of continuing 
with the protocol-imaging 
schedule (and if unwilling, 
SOC images should be 
submitted).
EQ-5D-5L
X
X
X
X
X
ePROs are to be administered 
prior to all 
procedures/assessments. 
PROs are to be completed in 
the following order: EQ-5D-
5L, EORTC QLQ-C30, 
EORTC QLQ-LC13.
EORTC QLQ-C30
X
X
X
X
X
EORTC QLQ-LC13
X
X
X
X
X
Safety Procedures
Full Physical Examination
X
Directed Physical Examination
X
X
X
X
ECOG Performance Status
X
X
X
X
X
Weight and Vital Signs 
X
X
X
X
X
Vital signs to be collected
include: temperature, heart 
rate, respiratory rate, and 
blood pressure.
Hematology, Chemistry, Urinalysis 
X
X
As Clinically Indicated
Coagulation Tests (PT/INR and 
aPTT/PTT) 
As Clinically Indicated
Thyroid Function (TSH, T3/FT3 
and T4)
X
X
As Clinically Indicated
AE/SAE review
Continuous reporting
All AEs occurring up until 30 
days following end of study 
treatment and SAEs occurring 
up until 90 days following end 
of treatment or 30 days if the 
participant initiates new 
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Trial Period
End of 
Treatment
Post-Treatment Follow-up
Survival 
FU
Notes:
Cycle 13 and 
Discontinuation Visit can be 
combined.
Post-Treatment Follow-up 
Visit timing should start 
from the date of last visit, 
either Discontinuation or 
Safety Follow-up, whichever 
is later
*See Section 5.3
Treatment Cycle/Day
Discontinuation
Safety FU
Year 2
Year 3
Years 4-
5
Year 6
to End 
of 
Study*
Scheduling Window (Days,
unless noted)
At time of 
Treatment 
Discontinuation
30 days from 
last dose 
±3 days
Q16W 
±21 days
Q16W
±21 days
Q6M 
±28 days
Q12M
±28 days
Q12 
Weeks ± 7 
days
anticancer therapy, whichever 
is earlier should be reported. 
Treatment-related late toxicity 
may be collected for >90 
days.
Tumor Tissue Sample Collection
Tissue Collection
Biopsies will be obtained for 
participants with suspected 
local progression (ie, 
participants who have not had 
surgery), metastases, or local 
recurrence. Samples are to be 
reviewed by a local 
pathologist. Samples must 
also be sent to the central lab 
for central pathological 
review. Treatment will be 
based on the interpretation of 
the local pathologist.
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3. Introduction
Pembrolizumab (MK-3475) is a potent and highly selective humanized mAb of the 
immunoglobulin G4 (IgG4)/kappa isotype designed to directly block the interaction between 
PD-1 and its ligands, programmed cell death-ligand 1 (PD-L1) and programmed cell death-
ligand 2 (PD-L2).
Study Rationale
Lung cancer is the most common global cancer and is responsible for the majority of cancer 
deaths [Torre, L. A., et al 2015]. In 2012, the last year for which the World Health 
Organization statistics are available, an estimated 1.8 million new cases of lung cancer 
occurred (comprising 13% of total new global cancer cases) and resulted in ~1.5 million 
deaths. Due to widespread continued cigarette smoking, lung cancer will remain a significant 
worldwide public health problem for the foreseeable future.
Non-small cell lung cancer (NSCLC) represents 80% of lung cancers. Utilizing the eighth 
edition of the UICC/IASLC lung cancer staging, at the time of diagnosis approximately 63% 
of patients have clinical Stage IV disease, 9% have Stage I disease, 4% have Stage II, and 
27% have Stage III [Chansky, K., et al 2017]. Patients with clinical Stage IIIA disease 
represent 12% of patients with NSCLC. Similarly, clinical Stage IIIB constitutes 12% of 
patients with NSCLC. Five-year survival for patients with pathologically determined Stages 
II, IIIA, and IIIB disease following resection of the tumor approximates 49%, 38%, and 24%, 
respectively.
Standard treatment for patients with Stage II disease is surgery followed by adjuvant 
platinum doublet chemotherapy. Numerous trials and meta-analyses have demonstrated a 
statistically significant 5% improvement in overall survival for patients who received 3-4 
cycles of adjuvant chemotherapy [Detterbeck, F. 2008]. Doublets combining platinum with 
pemetrexed, gemcitabine, vinorelbine or docetaxel have produced similar results [Wakelee, 
H. A., et al 2016]. Neoadjuvant therapy has also been investigated in patients with Stage II 
NSCLC. Preoperative chemotherapy is generally better tolerated and permits direct 
observation of the drug effectiveness. The postoperative morbidity and mortality is not 
increased. The overall survival benefit is similar to that seen with adjuvant therapy
[Hellmann, M. D., et al 2014].
The presence of tumor in the mediastinal (N2) lymph nodes is the stage defining factor for 
most patients in the Stage IIIA category. However, the time at which the N2 disease is 
documented (preoperatively vs postoperatively) and the extent of N2 disease determine 
prognosis and treatment strategies [Kassis, E. S. 2008]. Patients who have a preoperative 
chest CT and PET that did not suggest metastases to the mediastinal lymph nodes (“falsely 
negative”) and are found to have N2 disease at surgery, have a five-year overall survival of 
approximately 25% [Detterbeck, F. 2008]. Adjuvant platinum doublet chemotherapy (4 
cycles of cisplatin with docetaxel or pemetrexed) improves overall survival by 5% 
[Detterbeck, F. 2008]. Patients who are found to have N2 disease following biopsy of 
enlarged mediastinal lymph nodes seen on chest CT and/or biopsy of FDG avid mediastinal 
lymph nodes have an even worse prognosis. If these patients go directly to surgery, overall 
five-year survival is 15% [Detterbeck, F. 2008].  Neoadjuvant therapy (chemotherapy ± 
radiotherapy) has been investigated and recent trials have demonstrated a 25% overall five-
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year survival. Neoadjuvant therapy followed by surgery for patients with preoperatively 
identified N2 disease has become a common therapeutic approach [National Comprehensive 
Cancer Network 2017]. Patients with Stage IIIB disease are considered potentially operable 
if the metastases are limited to the N2 lymph nodes. In practice, fewer than 10% of patients 
with clinical Stage IIIB disease undergo surgery [Chansky, K., et al 2017]. The above 
discussion regarding treatment of Stage IIIA patients with N2 disease is equally applicable to 
Stage IIIB patients with N2 disease. Administration of both neoadjuvant and adjuvant 
chemotherapy has not been adopted, mainly due to the inability of patients to tolerate the 
toxicity of chemotherapy before and after a thoracic operation.
The current trial builds upon data produced from previous MSD trials and is aligned with the 
design of other Phase 3 MSD sponsored trials for cancers that incorporate surgery as part of 
the therapeutic regimen. Comparison of a pembrolizumab-containing arm to current standard 
of care is necessary in order to demonstrate that pembrolizumab affects the individual study 
endpoints. A 2-arm trial of neoadjuvant vs. adjuvant pembrolizumab makes the unproven 
assumption of drug effectiveness. If no difference were to be found between these 2 arms, 
interpretation of the results would be difficult as both study arms could have been either 
superior or inferior to standard therapy. Alternatively, a significant difference between the 
study arms could be explained by the arm with the poorer results performing inferior to the 
standard of care. A 3-arm trial consisting of neoadjuvant, adjuvant, and standard of care arms 
would not test the possibility that perioperative (both neoadjuvant and adjuvant) treatment 
with pembrolizumab is necessary to improve event-free survival and overall survival.
The toxicity profile of pembrolizumab permits prolonged drug administration and allows 
treatment in the perioperative (both neoadjuvant and adjuvant) setting. KN-522 (breast) and 
KN-585 (gastric) combine neoadjuvant and prolonged adjuvant pembrolizumab 
administration. KN-091(lung) incorporates 17 postoperative pembrolizumab cycles. In the 
metastatic NSCLC setting, the combination of chemotherapy + pembrolizumab produced a 
greater response rate than chemotherapy alone (KEYNOTE-021) [Langer, C. J., et al 2016]. 
KN-671 was designed to take advantage of the ability to administer perioperative 
pembrolizumab and the proven superior response rates produced by the combination 
pembrolizumab with doublet chemotherapy when compared to chemotherapy alone.
Background
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475.
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies [Dong, H., et al 2002] [Sharpe, A. H. and Freeman, G. J. 
2002] [Brown, J. A., et al 2003] [Francisco, L. M., et al 2010] [Thompson, R. H., et al 2007] 
[Hino, R., et al 2010] [Nomi, T., et al 2007] [Gao, Q., et al 2009] [Hamanishi, J., et al 2007] 
[Fourcade, J., et al 2009] [Cai, G., et al 2004] [Blank, C. and Mackensen, A. 2007] [Iwai, Y., 
et al 2002] [Tsushima, F., et al 2006] [Korman, A., et al 2007] [Oble, D. A., et al 2009] 
[Topalian, Suzanne L., et al 2012] [Patnaik, A., et al 2012] [Hodi, F. S., et al 2010] 
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[Chapman, P. B., et al 2011] [Robert, C., et al 2011] [Bellati, F., et al 2009] [Ruffell, B., et al 
2010] [Shirabe, K., et al 2010] [Al-Shibli, K., et al 2010] [Clark, C. E., et al 2009] 
[Diederichsen, A. C. P., et al 2003] [Gao, Q., et al 2007] [Hillen, F., et al 2008] [Laghi, L., et 
al 2009] [Li, J. F., et al 2008] [Nemolato, S., et al 2008] [Nobili, C., et al 2008] [Oshikiri, T., 
et al 2003] [Piersma, S. J., et al 2008] [Rao, U. N. M., et al 2010]. In particular, the presence
of CD8+ T-cells and the ratio of CD8+ effector T-cells/FoxP3+ regulatory T-cells seems to 
correlate with improved prognosis and long-term survival in solid malignancies such as 
ovarian, colorectal, pancreatic, hepatocellular, malignant melanoma, and renal cell 
carcinoma. Tumor-infiltrating lymphocytes can be expanded ex vivo and re-infused, inducing 
durable objective tumor responses in cancers such as melanoma [Sasaki, A., et al 2008] 
[Shen, Z., et al 2010].
The programmed cell death protein-1 (PD-1) receptor-ligand interaction is a major pathway 
used 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. Programmed cell death 
protein-1 (encoded by the gene Pdcd1) is an Ig superfamily member related to CD28 and 
CTLA-4 that has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or programmed death-ligand 1 [PD-L2]) [Talmadge, J. 
E., et al 2007] [Usubütün, A., et al 1998]. The mechanism by which PD-1 down modulates 
T-cell responses is similar to, but distinct from that of CTLA-4, as both molecules regulate 
an overlapping set of signaling proteins [Nobili, C., et al 2008] [Leffers, N., et al 2009]. 
Programmed cell death protein-1 was shown to be expressed on activated lymphocytes 
including peripheral CD4+ and CD8+ T-cells, B-cells, T-regs and natural killer cells 
[Nishimura, H., et al 2000] [Pölcher, M., et al 2010]. The ligands for PD-1 (PD-L1 and PD-
L2) are constitutively expressed or can be induced in a variety of cell types, including non-
hematopoietic tissues as well as in various tumors [Leffers, N., et al 2009] [Suzuki, H., et al 
2010] [Chew, V., et al 2010] [Liotta, F., et al 2011]. Both ligands are type I transmembrane 
receptors containing both IgV- and IgC-like domains in the extracellular region and contain 
short cytoplasmic regions with no known signaling motifs. Binding of either PD-1 ligand to 
PD-1 inhibits T-cell activation triggered through the T-cell receptor. Programmed death-
ligand 1 is expressed at low levels on various non-hematopoietic tissues, most notably on 
vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-
presenting cells found in lymphoid tissue or chronic inflammatory environments. 
Programmed death-ligand 2 is thought to control immune T-cell activation in lymphoid 
organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues 
[Suzuki, H., et al 2010]. Although healthy organs express little (if any) PD-L1, a variety of 
cancers were demonstrated to express abundant levels of this T-cell inhibitor. High 
expression of PD-L1 on tumor cells (and to a lesser extent of PD-L2) has been found to 
correlate with poor prognosis and survival in various cancer types, including renal cell 
carcinoma [Ropponen, K. M., et al 1997], pancreatic carcinoma [Dudley, M. E., et al 2005], 
hepatocellular carcinoma [Hunder, N. N., et al 2008], and ovarian carcinoma [Okazaki, T., et 
al 2001]. Furthermore, PD-1 has been suggested to regulate tumor-specific T-cell expansion 
in participants with melanoma [Greenwald, R. J., et al 2005].
Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated anti-tumor responses 
as a monotherapy in models of squamous cell carcinoma, pancreatic carcinoma, melanoma, 
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and colorectal carcinoma. Blockade of the PD-1 pathway effectively promoted CD8+ T-cell 
infiltration into the tumor and the presence of interferon-gamma, granzyme B and perforin, 
indicating that the mechanism of action involved local infiltration and activation of effector 
T-cell function in vivo [Dudley, M. E., et al 2005] [Hamid, Omid, et al 2013] [Peters, S., et al 
2012] [Sandler, A. B., et al 2000] [Zatloukal, Petr, et al 2003] [Scagliotti, G. V., et al 2008].
MSD experiments have confirmed the in vivo efficacy of PD-1 blockade as a monotherapy as 
well as in combination with chemotherapy in syngeneic mouse tumor models (see the IB).
Completed Clinical Studies
Three clinical studies have been conducted to evaluate the efficacy of pembrolizumab 
monotherapy in the treatment of NSCLC:  KEYNOTE-001, KEYNOTE-010, and 
KEYNOTE-024.
KEYNOTE-001:
An open-label Phase 1 trial (KEYNOTE-001) was conducted to evaluate the safety and 
clinical activity of single-agent pembrolizumab. The dose escalation portion of this trial 
evaluated 3 dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks 
(Q2W), in participants with advanced solid tumors. All 3 dose levels were well tolerated and 
no dose-limiting toxicities were observed. Based on pharmacokinetic (PK) data showing a 
half-life of 21 days, the protocol was amended to change the dosing frequency in the 
expansion cohort to every 3 weeks (Q3W). All cohorts have completed enrollment.
In KEYNOTE-001, a total of 550 NSCLC participants were treated in several dose expansion 
cohorts with at least 1 dose of pembrolizumab. The initial data from 495 NSCLC participants 
were published and reported. The ORR was 19.4% (18.0% in the 394 previously treated 
participants and 24.8% in the 101 previously untreated participants). The response rate (RR) 
was similar regardless of dose, schedule, and histologic analysis. Current or former smokers 
had a RR of 22.5%, as compared with 10.3% among participants who had never smoked 
cigarettes.
Participants were required to submit a newly obtained tumor biopsy prior to initiating therapy 
with pembrolizumab to evaluate the tumors for expression of PD-L1. After evaluation of 
several methods for pathological assessment, in a training set, membranous PD-L1 
expression in at least 50% of tumor cells (TPS ≥50%) was selected as the cutoff point 
defining PD-L1 high. In a validation set of 313 participants, the RR was 45.2% in the 73 
participants with a TPS ≥50%, including 43.9% in previously treated participants and 50% in 
previously untreated participants, values that numerically exceeded the RR in the training 
group [Garon, E. B., et al 2015].
Pembrolizumab has been generally well tolerated. The most common treatment-related AEs 
were fatigue (19.4%), pruritus (10.7%), and decreased appetite (10.5%). Adverse events of 
Grade 3 or higher were reported in 47 of 495 patients (9.5%). The only treatment-related AEs 
of an inflammatory or immune-mediated nature that occurred in more than 2% of patients 
were infusion-related reactions (in 15 patients [3.0%]), hypothyroidism (in 34 patients 
[6.9%]), and pneumonitis (in 18 patients [3.6%]). One infusion reaction led to treatment 
discontinuation. All the patients with hypothyroidism were successfully treated with medical 
therapy [Garon, E. B., et al 2015].
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KEYNOTE-010:
KEYNOTE-010 was a randomized, adaptively designed Phase 2/3 trial of pembrolizumab at 
2 dose levels versus docetaxel in participants with NSCLC with PD-L1 positive tumors who 
had experienced disease progression after platinum-containing systemic therapy.  Participants 
were randomized according to their TPS (extent of PD-L1 expression) defined as follows:  a 
TPS ≥50% was considered strongly positive and a TPS = 1% to 49% was considered weakly 
positive. Approximately 920 participants were planned to be enrolled in this trial to examine 
the efficacy of pembrolizumab compared to docetaxel in an enriched population.
Overall, the results from KEYNOTE-001 and KEYNOTE-010 demonstrated that 
pembrolizumab provided substantial, clinically meaningful benefits in OS, PFS, and ORR in 
participants with NSCLC who progressed after platinum-containing chemotherapy and 
whose tumor cells expressed PD-L1.  The PD-L1 selection employed in KEYNOTE-010 
identified patients more likely to benefit from pembrolizumab and resulted in favorable 
hazard ratios (HR) in OS compared to docetaxel.
In previously treated participants with NSCLC with PD-L1, TPS ≥1%, and disease 
progression following platinum-containing chemotherapy, pembrolizumab provides a 
statistically significant and clinically meaningful OS benefit compared to standard docetaxel 
chemotherapy.
In KEYNOTE-010, pembrolizumab was superior to docetaxel in the strongly positive TPS 
≥50% stratum with regard to OS, with an HR of 0.54 (p=0.00024) and 0.50 (p=0.00002) for 
pembrolizumab 2 mg/kg Q3W versus docetaxel and 10 mg/kg Q3W versus docetaxel, 
respectively. Pembrolizumab was superior to docetaxel in the overall positive TPS ≥1% 
population with regard to OS, with an HR of 0.71 (p=0.00076) and 0.61 (p<0.00001) for 
pembrolizumab 2 mg/kg Q3W and 10 mg/kg Q3W, respectively. Pembrolizumab was 
superior to docetaxel in the strongly positive TPS ≥50% stratum with regard to PFS by 
independent review committee based on RECIST 1.1, with an HR of 0.58 (p=0.00009) and 
0.59 (p=0.00007) for pembrolizumab 2 mg/kg Q3W and 10 mg/kg Q3W, respectively, 
compared to docetaxel. Pembrolizumab provided numerically superior benefit in PFS by 
independent review committee based on RECIST 1.1 compared to docetaxel in the overall 
positive TPS ≥1% population, with an HR of 0.88 and 0.79 for pembrolizumab 2 mg/kg 
Q3W and 10 mg/kg Q3W, respectively; however, the differences were not statistically 
significant at the 0.001 level required per protocol.
KEYNOTE-024:
KEYNOTE-024 was a multicenter, international, randomized, open-label, controlled trial of 
intravenous (IV) pembrolizumab monotherapy versus the choice of multiple standard of care 
(SOC) platinum-based chemotherapies in participants previously untreated for their Stage IV 
NSCLC and whose tumors expressed PD-L1 at ≥50%.
First-line treatment with pembrolizumab significantly prolonged PFS (HR 0.50; 95% CI:  
0.37, 0.68; p<0.001) and OS (HR 0.60; 95% CI:  0.41, 0.89; p=0.005) compared with SOC 
chemotherapy, inclusive of pemetrexed maintenance for participants with nonsquamous 
tumors.
In addition, pembrolizumab was associated with a higher ORR, including a higher CR rate, 
as well as a longer DOR as compared to SOC.
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Pembrolizumab was better tolerated than chemotherapy and AEs were easily managed. The 
observed safety profile of the pembrolizumab arm was consistent with the safety profile for 
pembrolizumab established to date.  Based on the mechanism of action of pembrolizumab, 
immune-mediated AEs, including pneumonitis occurred at a greater frequency with 
pembrolizumab compared to chemotherapy.  Most immune-mediated events were of Grade 1 
or 2 severity, and none led to death.
These data underscore the substantial benefit of pembrolizumab as initial therapy for 
participants with previously untreated, advanced NSCLC whose tumors express high levels 
of PD-L1 (TPS ≥50%).
Ongoing Clinical Studies
KEYNOTE-021:
Pembrolizumab has been studied in combination with other agents in NSCLC patients in 
KEYNOTE-021. This Phase 1/2 trial assessed the safety and efficacy of pembrolizumab in 
combination with multiple therapeutic agents including chemotherapy (carboplatin and 
pemetrexed; and carboplatin, paclitaxel, and bevacizumab); EGFR inhibitors including 
erlotinib and gefitinib; and the CTLA-4 inhibitor, ipilimumab. Cohort G of the study
evaluated the efficacy and safety of pembrolizumab plus carboplatin and pemetrexed (CP) 
vs. CP alone as first-line therapy for advanced nonsquamous NSCLC.
KEYNOTE-021 Cohort G contained 123 participants of whom 60 were accrued to the 
pembrolizumab plus CP arm and 63 to the CP arm. Demographics were generally balanced 
between treatment arms. As of 08-AUG-2016, median follow-up was 10.6 months (range, 
0.8-19.3); median exposure was 8.0 months for pembrolizumab plus CP and 4.9 months for 
CP. In the CP arm, 43 participants discontinued therapy; 32 received subsequent anti-PD-1 
therapy as part of crossover (n=20) or off study (n=12). Pembrolizumab plus CP significantly 
improved ORR (55% vs. 29%; p=0.0016) and PFS (HR 0.53, 95% CI 0.31-0.91, p=0.0102; 
median 13.0 vs. 8.9 months). Overall survival was similar; 6-month survival rates were 92% 
in each arm. Without adjusting for exposure, for pembrolizumab plus CP vs. CP, treatment-
related AEs led to discontinuation in 10% vs. 13%, were of Grade ≥3 severity in 39% vs.
26%, and led to death in 2% (sepsis, n=1) vs. 3% (sepsis and pancytopenia, n=1 each). The 
most common any-grade treatment-related AEs were fatigue (64% vs. 40%), nausea (58% vs.
44%), and anemia (32% vs. 53%).
KEYNOTE-042:
This is a multicenter, international, randomized, open-label, controlled trial of IV 
pembrolizumab versus SOC platinum-based chemotherapy in participants previously 
untreated for their advanced or metastatic NSCLC and whose tumors express PD-L1 ≥1%.  
Approximately 1240 participants will be enrolled.
KEYNOTE-189:
This is a worldwide, randomized, active-controlled, parallel group, multi-site, double-blind 
trial of intravenous (IV) pembrolizumab combined with platinum-pemetrexed chemotherapy
versus saline placebo combined with platinum-pemetrexed chemotherapy in participants with 
advanced or metastatic nonsquamous NSCLC who had not previously received systemic 
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therapy for advanced disease and in whom EGFR- or ALK-directed therapy was not 
indicated. The total planned enrollment is 570 participants.
KEYNOTE-407:
This is a Phase 3 study of carboplatin and paclitaxel or nano particle albumin-bound
paclitaxel (nab-paclitaxel) with or without pembrolizumab in first-line metastatic squamous 
NSCLC.  The total planned enrollment is 560 participants.
Information on Other Study-Related Therapy
Platinum doublet chemotherapy (4 cycles of cisplatin with gemcitabine or pemetrexed) will 
be administered along with either pembrolizumab or placebo. For information on cisplatin,
gemcitabine, or pemetrexed, please refer to their respective product inserts. The BSA in m2
for cisplatin, gemcitabine, or pemetrexed should be calculated per local guidance. Please note 
that the strengths of the locally sourced study treatments may vary based on local country 
operation.
Benefit/Risk Assessment
The purpose of this study is to evaluate the safety and efficacy of pembrolizumab in the 
perioperative setting. As the administration of pembrolizumab with chemotherapy was 
proven safe and efficacious in KN-021 Cohort G, the Sponsor has chosen to administer 
pembrolizumab/placebo with each of the preoperative chemotherapy cycles. The current trial 
has been designed with a total of 17 cycles of pre- and postoperative 
pembrolizumab/placebo, aligning with the design of other MSD perioperative trials. 
It cannot be guaranteed that participants in clinical trials will directly benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
From the reference safety data in the accompanying Investigator’s Brochure (IB)—which 
includes all participants who received at least one dose of MK-3475 in KN-001 Part B1, B2,
B3, D, C, F1, F2, F3; KN-002 (original phase), KN-006, and KN-010—pembrolizumab has a 
positive benefit-risk profile and is well tolerated in the approved indications. This is 
evidenced by a low rate of toxicity Grade 3 to 5 drug-related AEs (13.8%), discontinuations 
due to AEs (11.9%), and deaths due to drug-related AEs (0.4%).
Additional details regarding specific benefits and risks for participants in this clinical trial 
may be found in the accompanying Investigator’s Brochure (IB) and Informed Consent 
documents.
4. Objectives/Hypotheses and Endpoints
All objectives and hypotheses apply to male/female adult participants (≥18 years of age) with 
resectable Stages II or IIIA-B (N2) non-small cell lung cancer (NSCLC). Neoadjuvant 
chemotherapy (NAC) is a platinum doublet chemotherapy of 4 cycles of cisplatin with 
gemcitabine or pemetrexed.
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Objective/Hypothesis
Endpoint
Primary

Objective: To evaluate event-free 
survival (EFS) by biopsy assessed by a
local pathologist or by investigator-
assessed imaging using RECIST 1.1.
Hypothesis #1: NAC plus 
pembrolizumab followed by surgery and 
adjuvant pembrolizumab improves EFS 
by biopsy assessed by local pathologist or 
by investigator-assessed imaging using 
RECIST 1.1 compared to NAC plus 
placebo followed by surgery and 
adjuvant placebo.

EFS is defined as the time from 
randomization to the first of the 
following events: disease or local 
progression, inability to resect tumor, 
local or distant recurrence, or death (see 
Section 10.4 for details).

Objective: To evaluate the overall 
survival (OS).
Hypothesis #2: NAC plus 
pembrolizumab followed by surgery and 
adjuvant pembrolizumab improves OS 
compared to NAC plus placebo followed 
by surgery and adjuvant placebo.

OS is defined as the time from 
randomization to death due to any cause.
The study will be considered positive if NAC plus pembrolizumab followed by surgery and 
adjuvant pembrolizumab demonstrates superior EFS or OS at an interim or final analysis 
compared to NAC plus placebo followed by surgery and adjuvant placebo.
Secondary

Objective: To evaluate the rate of major 
pathological response (mPR) assessed by 
blinded central laboratory pathologist 
following NAC +/- pembrolizumab.

Hypothesis #3: NAC plus 
pembrolizumab improves mPR rate 
assessed by blinded central laboratory 
pathologist compared to NAC plus 
placebo.

mPR is defined as ≤10% viable tumor 
cells in the resected primary tumor and 
all resected lymph nodes.
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Objective/Hypothesis
Endpoint

Objective: To evaluate the rate of 
pathological complete response (pCR) in 
the resected primary tumor and lymph 
nodes assessed by blinded central 
laboratory pathologist following NAC +/-
pembrolizumab.
Hypothesis #4: NAC plus 
pembrolizumab improves pCR rate 
assessed by blinded central laboratory 
pathologist compared to NAC plus 
placebo.

pCR is defined as the absence of residual 
invasive cancer on hematoxylin and eosin 
stained slides of the resected lung 
specimen and lymph nodes following 
completion of neoadjuvant therapy (ie, 
ypT0/Tis ypN0).

Objective: To evaluate mean change from 
baseline in the neoadjuvant phase and in 
the adjuvant phase in global health 
status/quality of life (QoL) using the 
European Organization for Research and 
Treatment of Cancer (EORTC) QoL 
questionnaire (QLQ)-C30. 

The QoL is based on the global health 
status/QoL scale (Items 29 and 30) of the 
EORTC QLQ-C30.

Objective: To evaluate the safety and 
tolerability of NAC plus pembrolizumab
followed by surgery and adjuvant 
pembrolizumab.

Participant experiencing AEs.

Participant discontinuing study drug due 
to AEs.

Participant experiencing perioperative 
complications.
Tertiary/Exploratory

Objective: To evaluate changes in health-
related QoL assessment from baseline in 
the neoadjuvant phase and in the adjuvant 
phase.

Change from baseline in health-related 
QoL evaluated using the multi-item and 
single-item scales of EORTC QLQ-C30
and EORTC QLQ-LC13 scores:
o
Physical functioning (EORTC 
QLQC30 items 1-5)
o
Role functioning (EORTC QLQ 
C30, items 6-7)
o
Dyspnea (EORTC QLQC30 item 
8)
o
Cough (EORTC QLQ-LC13 item 
31) and
o
Chest pain (EORTC QLQ-LC13 
item 40)
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Objective/Hypothesis
Endpoint

Objective: To characterize health utilities 
in neoadjuvant and adjuvant phases using 
EQ-5D-5L.

Health utilities assessed using 
EQ-5D-5L.

Objective: To identify molecular 
(genomic, metabolic and/or proteomic) 
biomarkers that may be indicative of 
clinical response/resistance, safety, 
pharmacodynamic activity, and/or the 
mechanism of action of pembrolizumab 
plus chemotherapy used as neoadjuvant 
and in combination with pembrolizumab 
as adjuvant.

The relationship between molecular 
biomarkers and clinical activity that may 
be indicative of clinical 
response/resistance, safety, 
pharmacodynamic activity, and/or the 
mechanism of action of the study 
treatments.
5. Study Design
Overall Design
This is a randomized, placebo-controlled, double-blind Phase 3 trial of concomitant 
neoadjuvant platinum doublet chemotherapy plus pembrolizumab (4 cycles) followed by 
surgery and adjuvant pembrolizumab (13 cycles) vs. concomitant neoadjuvant platinum 
doublet chemotherapy plus placebo (4 cycles) followed by surgery and adjuvant placebo (13 
cycles) for participants with resectable Stage II or IIIA, or IIIB (N2) non-small cell lung 
cancer (NSCLC). The study will be conducted in conformance with Good Clinical Practices 
(GCP).
Approximately 786 participants will be randomized in a 1:1 ratio between 2 treatment arms: 
(1) Treatment Arm A: Neoadjuvant pembrolizumab plus platinum doublet chemotherapy
(4 cycles of cisplatin with gemcitabine or pemetrexed) followed by surgery and adjuvant 
pembrolizumab (13 cycles). 
(2) Treatment Arm B: Neoadjuvant placebo plus platinum doublet chemotherapy (4 cycles of 
cisplatin with gemcitabine or pemetrexed) followed by surgery and adjuvant placebo (13 
cycles). 
Stratification factors are as follows:
1) Stage (II, III) 
2) TPS (<50%, ≥50%)
3) Histology (Squamous, Nonsquamous)
4) Geographic Region (East Asia, non-East Asia)
Eligibility at Screening will be based on investigator assessment in accordance with the 
inclusion/exclusion criteria described in Section 6.1 – Inclusion Criteria and 6.2 – Exclusion 
Criteria.  
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Preoperative neoadjuvant treatment should begin within 3 days of randomization.  
In the preoperative treatment period for Arm A, pembrolizumab IV 200 mg fixed dose Q3W
in combination with platinum doublet (cisplatin with gemcitabine or pemetrexed) will be 
administered for 4 cycles; treatment will begin on Day 1 of each 3-week dosing cycle.  For 
Arm B, a comparative placebo in combination with platinum doublet (cisplatin with 
gemcitabine or pemetrexed) will be administered during the preoperative treatment period for 
4 cycles. During the postoperative treatment period, pembrolizumab IV 200 mg fixed dose 
Q3W or placebo will be administered for 13 cycles. Participants in either arm will undergo
radiation therapy if microscopic residual disease or gross residual disease is present.
Radiotherapy is not allowed for participants with completely resected N2 disease in the 
absence of extracapsular spread. If the participant did not have surgery due to refusal, 
physician decision, medical illness, or any reason other than local progression or metastatic 
disease, the participant should receive radiation therapy then continue to the adjuvant phase. 
Participants whose tumors are found to be unresectable during surgery due to growth into the 
mediastinum, invasion into major vascular structures, or any other circumstance in which the 
surgeon is unable to remove the tumor will no longer receive study therapy and will enter 
Safety and Survival Follow-up. Participants who develop metastatic disease will no longer 
receive study therapy and will enter Safety and Survival Follow-up.
All participants will have an imaging assessment prior to surgery after Cycle 2 at Week 7
(± 7 days) and after Cycle 4 at Week 13 (± 7 days). All imaging assessments will be 
evaluated by the investigator and submitted for BICR. Participants will undergo a potentially 
curative surgical resection performed as part of the local standard of care. Pathological 
staging will be per AJCC/UICC/IASLC lung cancer staging (8th edition). Assessment of 
surgical margins will be performed by the local pathologist on all specimen removed during 
surgery.  Samples of tumor tissue collected during the study from participants will be 
submitted to the designated central laboratories for blinded pathological response assessment 
and translational research as described in Section 9 –Study Assessments and Procedures.
Adverse events (AE) will be monitored throughout the study 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. 
Safety follow-up will be performed for participants who receive study treatment and for 
those with Early Discontinuations.  All participants will be followed for overall survival until 
death, withdrawal of consent, or the end of the study.
There is no crossover treatment phase planned as part of the study design.
The results of the PD-L1 testing will not be communicated to investigators or participants.
The unblinded study treatment arm will not be communicated to investigators or participants 
until the participant discontinues from the trial due to local progression (participants who 
have not had surgery), metastases, local recurrence, or study completion.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial SoA - Section 2. Details of each procedure 
are provided in Section 9 – Study Assessments and Procedures.
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Data Monitoring Committee and Interim Analyses
This study will use an external Data Monitoring Committee (DMC) to monitor safety and 
efficacy. Details of the composition and procedures for the DMC may be found in Appendix 
1: Study Governance Considerations and the DMC Charter. The role of the DMC in 
reviewing interim analysis data is outlined in Section 10.7. 
There will be 4 planned interim analyses and 1 final analysis. The first interim analysis will 
be conducted when approximately 326 EFS events have been observed. The second interim 
analysis will be conducted when approximately 416 EFS events have been observed. The 
third and fourth interim analysis will be conducted when approximately 285 and 340 deaths, 
respectively, have been observed and the final analysis will be conducted when 
approximately 386 deaths have been observed.
Study Diagram
The study design is depicted in Figure 1.
Figure 1
Study Design
1.
Primary tumor - positive margin at bronchus, pulmonary vessels, or structures abutting primary tumor 
lymph node - extracapsular extension.
Abbreviations: ECOG = Eastern Cooperative Oncology Group; EFS = event-free survival; NSCLC = non-small 
cell lung cancer; PS = performance scale; Q3W = every 3 weeks; mPR = major pathological response; OS = 
overall survival; pCR = pathological complete response; PRO = participant-reported outcomes; TPS = tumor 
proportion score
Number of Participants
Approximately 786 participants will be allocated/randomized as described in Section 10.1.
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Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent.  The overall study ends when the last participant 
completes the last study-related contact, withdraws from the study or is lost to follow-up 
(Section 8.3).
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory test result or at the time of final contact with the last participant, whichever 
comes last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EAA is defined as First Site Ready (FSR) in any Member State.
Clinical Criteria for Early Study Termination
Early study termination will be the result of the criteria specified below:
1. The study may be stopped early for safety at the recommendation of the DMC.
2. The trial may be stopped early for efficacy at the recommendation of the DMC if 
Arm A demonstrates superiority to Arm B in EFS or OS prior to the final analysis
(see Section 10 for details).
3. Quality or quantity of data recording is inaccurate or incomplete as assessed by the 
Sponsor.
4. Poor adherence to protocol and regulatory requirements.
5. Incidence or severity of adverse drug reaction in this or other studies indicates a 
potential health hazard to participants.
Scientific Rationale for Study Design 
Neoadjuvant therapy is the standard of care for patients with resectable Stage IIIA (N2) 
NSCLC identified during initial evaluation in whom surgery is planned [National 
Comprehensive Cancer Network 2017]. Surgery as initial treatment is standard of care for 
patient with clinical Stages I-II and some Stage IIIA (not N2) NSCLC. Adjuvant therapy is 
recommended for those patients whose tumors proved to be pathologic Stage IB (>4cm), II, 
or IIIA NSCLC [National Comprehensive Cancer Network 2017]). Numerous trials and 
meta-analyses have demonstrated a statistically significant 5% improvement in overall 
survival (OS) for patients who received 3-4 cycles of adjuvant chemotherapy [Pignon, J. P., 
et al 2008]. Doublets combining platinum with pemetrexed, gemcitabine, vinorelbine or 
docetaxel have produced similar results [Wakelee, H. A., et al 2016]. 
Though adjuvant therapy has been the standard of care for patients found to have Stages IB 
(T>4cm), II and IIIA following surgery, administration of neoadjuvant rather than adjuvant 
therapy has been investigated. Practical and theoretic justification for administration of 
neoadjuvant therapy to patients with operable NSCLC include: better ability to tolerate 
therapy and therefore more likely to receive greater amounts of the prescribed treatment, the 
ability to monitor the effect of therapy on the tumor, shrinkage of the tumor may reduce the 
extent of surgery, and finally, induction of the abscopal effect to destroy micrometastases. 
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Neoadjuvant therapy trials have commonly been designed with 2 or 3 cycles of preoperative 
chemotherapy and no adjuvant therapy. A choice of chemotherapy combinations has 
generally not been offered and the majority of regimens were platinum based. The modest 
survival benefits of neoadjuvant therapy in earlier stage disease are similar to those seen 
when similar treatment is given to the same group of patients in the adjuvant setting 
[Hellmann, M. D., et al 2014]. Therefore, design of a trial that involves administration of 
chemotherapy in the neoadjuvant setting may be supported from both a scientific and ethical 
perspective.
Following the publication of the results of a Phase 3 trial by Scagliotti in 2008, patients with 
no actionable tumor mutations and Stage IV nonsquamous tumors have commonly been 
treated with a pemetrexed containing regimen, while those patients with squamous tumors 
have preferentially been treated with a gemcitabine combination [Scagliotti, G. V., et al 
2008]. The use of pemetrexed or gemcitabine based upon histology has been applied to 
earlier stage disease in both the adjuvant and neoadjuvant settings [Wakelee, H. A., et al 
2016]. Gemcitabine and platinum has been safely and efficaciously utilized in a number of 
neoadjuvant trials [Spaggiari, L., et al 2016] [van Meerbeeck, J. P., et al 2007] [Scagliotti, G. 
V., et al 2012] [Van Zandwijk, N., et al 2000] as has pemetrexed and platinum [Chaft, J. E., 
et al 2016] [Scagliotti, G. V., et al 2008]. Cisplatin doublet chemotherapy utilizing 
pemetrexed and gemcitabine are appropriate to form the backbone chemotherapy for patients 
with nonsquamous and squamous cell tumors, respectively.
The effect of neoadjuvant therapy on the primary tumor correlates with survival. 
Retrospective analyses of neoadjuvant therapy studies in NSCLC have consistently 
demonstrated that those patients who had major pathological responses (mPR) or 
pathological complete responses (pCR) had the best overall survival (OS) [Hellmann, M. D., 
et al 2014]. mPR is defined as ≤ 10% viable tumor cells in the primary tumor and all resected 
lymph nodes. Chemotherapy produces a pCR in approximately 4% of patients and an mPR in 
approximately 20% [Mouillet, G., et al 2012] [Chaft, J. E., et al 2017] [Junker, K., et al 2001] 
[Hellmann, M. D., et al 2014]. A recently presented Phase 2 trial of single-agent neoadjuvant 
nivolumab in patients with resectable Stages I-IIIA NSCLC demonstrated a 43% mPR 
[Chaft, J. E., et al 2017]. Correlation with radiographic response or survival was not reported.
Keynote-021 Cohort G was a randomized Phase 2 open-label trial of carboplatin and 
pemetrexed with or without pembrolizumab in patients with advanced, nonsquamous 
NSCLC. The objective response radiographic rate (ORR) was 55% in patients treated with
the 3 drug combination, while ORR was only 29% in the group that received the 
chemotherapy doublet. The addition of a checkpoint inhibitor to platinum chemotherapy 
increases the tumor response when compared to chemotherapy alone. OS was not different 
between the 2 groups, but was not reported separately for those patients who had responded 
to therapy.
Keynote-024 was an open-label, Phase 3 trial, for patients with previously untreated 
advanced NSCLC with PD-L1 TPS ≥50% comparing pembrolizumab alone to platinum 
doublet chemotherapy. Pembrolizumab was administered every 3 weeks for 35 cycles. The 
ORR was 44.8% in the pembrolizumab group and 27.8% in the chemotherapy arm. Median 
DFS was 10.3 months in the pembrolizumab treated patients and 6.0 months in the 
chemotherapy group. Correlation of ORR with survival was not reported. In this select group 
of patients, pembrolizumab outperformed standard doublet chemotherapy.
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Additional support for the efficacy of the combination of pembrolizumab and chemotherapy 
is provided by the recently presented I-SPY 2 trial breast cancer trial. This was a Phase 2
randomized, controlled, multicenter trial for women with newly diagnosed, locally advanced 
breast cancer (Stage II/III). Patients were treated with weekly standard chemotherapy 
(paclitaxel) for 12 weeks, with or without pembrolizumab, followed by doxorubicin and 
cyclophosphamide every 3 weeks for 4 cycles. Forty-six of the 69 patients randomized to 
receive pembrolizumab underwent surgery. 
In the 21 patients with triple-negative breast cancer, an absolute increase in the estimated 
pCR of 40% was observed in the pembrolizumab arm (based on the estimated pathological
complete response rate of 60% with pembrolizumab plus standard therapy compared to 20% 
with standard therapy alone) [Nanda, R., et al 2017].
The majority of patients with resected Stage II and IIIA NSCLC are destined to suffer tumor 
recurrence despite the administration of standard adjuvant or neoadjuvant therapy. Survival 
following neoadjuvant therapy appears to correlate with the extent of the pathological
response.  The checkpoint inhibitor nivolumab alone produced a 43% mPR and in 
combination with doublet chemotherapy (in more advanced tumors), a 55% radiographic 
response. Long-term administration of pembrolizumab in patients with Stage IV disease has 
proven both feasible and efficacious. These observations support the investigation of 
pembrolizumab in combination with standard chemotherapy in the neoadjuvant setting and 
the continued administration of pembrolizumab as adjuvant therapy [Chaft, J. E., et al 2017].
Rationale for Endpoints
Efficacy Endpoints
This trial will use overall survival (OS) and event-free survival (EFS) as primary endpoints. 
Major pathological response (mPR) rate and pathological complete response (pCR) rate will 
be evaluated as secondary endpoints. 
OS is a standard assessment of clinical benefit in participants with NSCLC.
EFS is a common surrogate endpoint for OS that is used to evaluate the efficacy of 
neoadjuvant and adjuvant cancer therapy and is sometimes used as primary endpoint.  See 
Section 10.4 for the primary and secondary endpoint definitions.
Although no neoadjuvant therapy for NSCLC has been approved on the basis of mPR or 
pCR, there is support among physicians for using these endpoints [Hellmann, M. D. 2014], 
defined as follows:
mPR for this trial is defined as ≤10% viable tumor cells in primary resected tumor and all 
resected lymph nodes [Hellmann, M. D. 2014].
pCR for this trial is defined as the absence of residual invasive cancer on hematoxylin and 
eosin evaluation of the resected lung specimen and all sampled regional lymph nodes 
following completion of neoadjuvant systemic therapy (ie, ypT0/Tis ypN0).
Rationale for Safety Endpoints
Safety parameters commonly used for evaluating investigational systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence, 
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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. 
Rationale for Patient-reported Outcomes (PROs) Endpoints
Symptomatic improvement is considered a clinical benefit and accepted by health authorities
as additional evidence of the risk-benefit profile of any new study intervention. In this study, 
HRQoL and disease-related symptoms will be investigated via the following tools: EORTC 
QLQ-C30 and EORTC QLQ-LC13 questionnaires. Health utilities will be evaluated using 
the EQ-5D-5L PRO instrument. These measures are not pure efficacy or safety endpoints 
because they are affected by both disease progression and treatment tolerability.
The EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-5L PROs are to be completed by 
participants at various time points, beginning with baseline assessment, pre- and post-
surgery, and continuing every 4 months for Year 2, then biannually in Year 3 followed by 
annual follow-up through Year 5.
EORTC QLQ-C30
EORTC QLQ-C30 is a psychometrically and clinically validated instrument appropriate for 
assessing HRQoL in oncology studies [Aaronson, N. K., et al 1993]. The EORTC QLQ-C30 
is the most widely used cancer-specific HRQoL 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 quality of life (QoL) scale [Aaronson, N. K., et al 1993].
For the global health status or QoL and function scales, a higher value indicates a better level 
of function; for symptom scales and items, a higher value indicates increased severity of 
symptoms. Mean change from baseline in global health status/QoL scale of the EORTC 
QLQ-C30 will be evaluated as a secondary objective.
EORTC QLQ-LC13
The EORTC QLQ-LC13 is a disease-specific questionnaire developed and validated to 
address measurements specific to lung cancer. It is a modular supplement to the EORTC 
Core Quality of Life Questionnaire (QLQ-C30) covering 13 typical symptoms of lung cancer 
patients. The EORTC QLQ C30 and EORTC QLQ LC13 are used together to assess the 
quality of life of cancer patients in clinical trials: (1) the EORTC QLQ-C30 is a core quality 
of life questionnaire that covers general aspects of health-related quality of life, and (2) the 
EORTC QLQ-LC13 asks additional disease- or treatment-specific questions. Together, the 
lung cancer questionnaire module comprises both multi-item and single-item measures of 
lung cancer-associated symptoms (ie, coughing, hemoptysis, dyspnea, and pain) and side-
effects from conventional chemo- and radiotherapy (ie, hair loss, neuropathy, sore mouth and 
dysphagia).
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EQ-5D-5L
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome and will 
provide data to develop health utilities for use in health economic analyses [Rabin, R. and de 
Charro, F. 2001]. The 5 health state dimensions in the EQ-5D-5L: 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 their 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
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Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens consented for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes, 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 trial) 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 this Future Biomedical Research are presented in Appendix 2: Collection and 
Management of Specimens for Future Biomedical Research.
Rationale for the Use of Comparator/Placebo
Normal saline infusion Q3W will be used as placebo for pembrolizumab.  The use of saline 
placebo in combination with chemotherapy will ensure the objectivity of the investigator.  
The use of a placebo will test the hypotheses that (1) pembrolizumab and chemotherapy is 
superior to the combination of placebo and chemotherapy in participants with NSCLC, as 
measured by the rate of mPR and rate of pCR based on histologic examination of the resected 
specimen; and that (2) perioperative (neoadjuvant and adjuvant) pembrolizumab and
neoadjuvant chemotherapy is superior to the combination of perioperative placebo and 
neoadjuvant chemotherapy in participants with NSCLC, as measured by EFS and OS.
Justification for Dose
Starting Dose for This Trial
The dose of pembrolizumab planned to be studied in this trial is 200 mg fixed dose Q3W. 
Rationale for Dose Interval and Trial Design
Pembrolizumab is currently approved in the United States at a fixed dose of 200 mg Q3W. In 
the European Union (EU), pembrolizumab is currently approved for melanoma and 
previously treated NSCLC at 2 mg/kg Q3W and at 200 mg Q3W for all other indications. 
The use of a fixed dose is based on PK findings summarized below.
The PK profile of pembrolizumab is consistent with that of other humanized mAbs, which 
typically have a low clearance and a limited volume of distribution.  A population PK model, 
which characterized the influence of body weight and other participant covariates on 
exposure, using available data from 1139 participant (from KEYNOTE-001 and KEYNOTE-
002) has been performed.  The majority of these participants (1077; 94.6%) had advanced 
melanoma.  The distribution of exposures from the 200 mg fixed dose were predicted to 
considerably overlap those obtained with the 2 mg/kg dose, and importantly, maintained 
individual patient exposures within the exposure range established in melanoma as associated 
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with maximal clinical response.  This comparison also demonstrated that the 200 mg Q3W 
regimen provided no substantive differences in PK variability (range of the distribution of 
individual exposures) as seen with weight-based dosing.
In translating to other tumor indications, similar flat exposure-response relationships for 
efficacy and safety as observed in participants with melanoma can be expected, as the anti-
tumor effect of pembrolizumab is driven through immune system activation rather than 
through a direct interaction with tumor cells, rendering it independent of the specific tumor 
type.  In addition, available PK results in participants with melanoma, NSCLC, and other 
tumor types support a lack of meaningful difference in pharmacokinetic exposures obtained 
at tested doses among tumor types. 
A fixed-dose regimen is expected to simplify the dosing regimen (potentially reducing dosing 
errors), as well as be more convenient for physicians.  A fixed dosing scheme will also 
reduce complexity in the logistical chain at treatment facilities, as well as reducing waste.
The optimal duration of pembrolizumab has not been tested.  At this time, the recommended 
duration for treatment for patients with metastatic disease is 24 months. The Sponsor believes 
that the 17 cycles are important for participants with resected NSCLC and for participants 
whose tumors will be resected. Therefore, the Sponsor has elected to administer 4 cycles of 
pembrolizumab concomitantly with the neoadjuvant chemotherapy and the remaining 13 
cycles as adjuvant therapy. 
Documentation of Local Progression and Metastases
Local Progression
During the neoadjuvant phase, progression will be documented radiologically. A biopsy is 
not required. During the adjuvant and EOT Follow-up Phase, local progression will be 
confirmed via biopsy if not medically contraindicated. In the event that biopsy is not 
diagnostic or does not reveal malignancy, the investigator should reassess the corresponding 
radiographic progression.
Metastatic Disease
During all phases of the trial, metastatic disease should be confirmed via biopsy unless 
medically contraindicated. Note that fine needle aspiration is acceptable for the assessment of 
metastatic disease. In the event that biopsy is not diagnostic or does not reveal malignancy, 
the investigator should reassess the corresponding radiographic progression/recurrence.
6. Study Population
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. Male/female participants who are at least 18 years of age on the day of informed 
consent with previously untreated and pathologically confirmed resectable Stage II, 
IIIA, or IIIB (N2) NSCLC. (AJCC Version 8).  Lymph node disease requires 
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pathologic confirmation, while T3 (rib destruction) disease requires only radiographic 
documentation. A PET scan may be utilized as a surrogate for pathologic staging of 
N1 lymph nodes for participants with T2b and T4 tumors (the presence or absence of 
tumor in the N1 lymph nodes will not change the actual stage by which the 
participant is stratified).  Similarly, biopsy confirmation of N2 disease is not required 
for pathologically confirmed T3N1 tumors and T4N0-1 tumors, as knowledge of the 
N2 status will not change the stage.
2. Be able to undergo protocol therapy, including necessary surgery. 
Male participants:
3. If male, agrees to the following during the intervention period and for at least the time 
needed to eliminate each study intervention after the last dose of study intervention. 
The length of time required to continue contraception for each study intervention is as 
follows:
-
Chemotherapy: 95 days
•
Refrains from donating sperm
PLUS either:
•
Abstains from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long-term and persistent basis) and agrees to remain abstinent
OR
•
Uses contraception unless confirmed to be azoospermic (vasectomized or secondary 
to medical cause, documented from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview) as detailed 
below:

Uses a male condom plus partner use of an additional contraceptive method when 
having penile-vaginal intercourse with a WOCBP who is not currently pregnant. 
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-vaginal penetration.

Contraceptive use by men should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. If the 
contraception requirements in the local label for any of the study interventions is 
more stringent than the requirements above, the local label requirements are to be 
followed.
4. Removed.
Female participants:
5. A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies:

Not a WOCBP
OR
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
A WOCBP and:

Uses a contraceptive method that is highly effective (with a failure rate of 
<1% per year), with low user dependency, or be abstinent from 
heterosexual intercourse as their preferred and usual lifestyle (abstinent on 
a long-term and persistent basis), as described in Appendix 3 during the 
intervention period and for at least the time needed to eliminate each study 
intervention after the last dose of study intervention and agrees not to 
donate eggs (ova, oocytes) to others or freeze/store for her own use for the 
purpose of reproduction during this period. The length of time required to 
continue contraception for each study intervention is as follows:

Chemotherapy: 180 days

MK-3475: 120 days
The investigator should evaluate the potential for contraceptive method 
failure (ie, noncompliance, recently initiated) in relationship to the first 
dose of study intervention. Contraceptive use by women should be 
consistent with local regulations regarding the methods of contraception 
for those participating in clinical studies. If the contraception requirements 
in the local label for any of the study interventions is more stringent than 
the requirements above, the local label requirements are to be followed.

Has a negative highly sensitive pregnancy test (urine or serum as required 
by local regulations) within 24 hours for urine or within 72 hours for 
serum before the first dose of study intervention. If a urine test cannot be 
confirmed as negative (eg, an ambiguous result), a serum pregnancy test is 
required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive. Additional
requirements for pregnancy testing during and after study intervention are 
in Section 9.5.4.2.

Medical history, menstrual history, and recent sexual activity has been 
reviewed by the investigator to decrease the risk for inclusion of a woman 
with an early undetected pregnancy.
Informed Consent
6. The participant (or legally acceptable representative) has provided documented
informed consent/assent for the trial.  The participant may also provide consent for 
Future Biomedical Research. However, the participant may participate in the study 
without participating in Future Biomedical Research.
Disease-state Specific Criteria
7. Have available formalin-fixed paraffin-embedded (FFPE) tumor tissue sample blocks 
for submission. If blocks are not available, have unstained slides for submission for 
central PD-L1 testing. See Vendor Lab Manual for further details.
8. Have an ECOG performance status of 0 to 1 within 10 days of randomization.
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9. 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.
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/La
Renal
Measured or calculatedb creatinine 
clearance OR GFR
≥60 mL/min for participant with creatinine levels 
>1.5 × institutional ULN OR GFR criterion, eg, 
60 mL/min/1.73 m2
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin within normal limits for 
participants with total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN 
Endocrine
Thyroid stimulating hormones (TSH)
Within normal limits. Note:  If TSH is not within normal 
limits at baseline, the participant may still be eligible if 
T3 (or free T3) and free T4 are within the normal limits
Coagulation
International normalized ratio (INR) OR 
prothrombin time (PT)
Activated partial thromboplastin time 
(aPTT)
≤1.5 × ULN unless 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.
a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.
b Creatinine clearance (CrCl) should be calculated per institutional standard OR GFR criterion. Note 
that creatinine levels must be ≤1.5 × ULN.
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:
1. Removed in Amendment 10 for duplication of requirement with IC #5.
2. Has one of the following tumor locations/types: 

NSCLC involving the superior sulcus

Large cell neuro-endocrine cancer (LCNEC)

Sarcomatoid tumor
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3. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease that requires steroids.
4. Has an active infection requiring systemic therapy.
5. Has had an allogenic tissue/solid organ transplant. 
6. Has a known severe hypersensitivity (≥Grade 3) to pembrolizumab, its active 
substance and/or any of its excipients. (Refer to the respective Investigator’s
Brochure for a list of excipients.)
7. Has a known severe hypersensitivity (≥Grade 3) to any of the study chemotherapy 
agents and/or to any of their excipients.
8. 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.
9. Has a known history of human immunodeficiency virus (HIV) infection. No HIV 
testing is required unless mandated by local health authority.
10. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] 
reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is 
detected) infection. 
Note: No testing for hepatitis B and hepatitis C is required unless mandated by local 
health authority.
11. Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the participant’s
participation for the full duration of the trial, or is not in the best interest of the 
participant to participate, in the opinion of the treating investigator.
13. Has known psychiatric or substance abuse disorders that would interfere with 
cooperating with the requirements of the trial.
Prior/Concomitant Therapy
14. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or 
with an agent directed to another coinhibitory T-cell receptor (eg, CTLA-4, OX-40, 
CD137).
15. Has received prior systemic anticancer therapy including investigational agents for 
the current malignancy prior to randomization/allocation.
Note: Must have recovered from all AEs due to previous therapies for other 
medical conditions to ≤Grade 1 or baseline.  Residual ≤Grade 2 neuropathy is 
acceptable.
Note: Must have recovered adequately from any previous surgical procedure 
prior to starting trial treatment
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16. Has received prior radiotherapy within 2 weeks of start of trial treatment.  Participants 
must have recovered from all radiation-related toxicities, not require corticosteroids, 
and not have had radiation pneumonitis.
17. Has received a live or live attenuated vaccine within 30 days prior to the first dose of 
trial drug.  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.
Refer to Section 7.7.3 for information on COVID-19 vaccines.
Prior/Concurrent Clinical Study Experience
18. Is currently participating in or has participated in a trial of an investigational agent or 
has used an investigational device within 4 weeks prior to the first dose of trial 
treatment.
Note:  Participants who have entered the Follow-up Phase of an investigational trial 
may participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
Diagnostic Assessments
19. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (dose
exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of trial drug.
20. Has a known additional malignancy that is progressing or requires active treatment 
within the past (5 years).  
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of 
the skin, noninvasive bladder carcinoma, or any carcinoma in situ (eg, in situ cervical 
cancer or breast carcinoma) that have undergone potentially curative therapy are not 
excluded.
Other Exclusions
21. Removed in Amendment 10 for duplication of requirement with IC #5.
Lifestyle Restrictions
No lifestyle restrictions are required for this study.
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
Caffeine, Alcohol, and Tobacco Restrictions
No caffeine, alcohol or tobacco restrictions are required.
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Activity
No activity restrictions are required.
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 adverse events or serious adverse events (SAE) meeting reporting 
requirements as outlined in the data entry guidelines.
Participant Replacement Strategy
A participant who discontinues from trial treatment or withdraws from the trial will not be 
replaced.
7. 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 study treatment(s) to be used in this trial are outlined below in Table 2. Country-specific 
differences are noted in Appendix 7.
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Table 2
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment Period/
Vaccination Regimen
Use
IMP/ 
NIMP
Sourcing
Arm A
Experimental
Pembrolizumab
Biological/
Vaccine
Solution for 
Infusion
25 mg/mL
200 mg
IV Infusion
Day 1 of each 21-day 
cycle for 4 cycles 
followed by surgery 
and 13 cycles
Test Product
IMP
Central
Arm A
Experimental
Cisplatin
Drug
Solution for 
Infusion
1 mg/mL
75 mg/m2
IV Infusion
Day 1 of each 21-day 
cycle for 4 cycles
Background 
Treatment
NIMP
Local or 
Central
Arm A
Experimental
Gemcitabine
(squamous 
tumors)
Drug
Solution for 
Infusion
1000 mg/vial
1000 mg/m2
IV Infusion
Day 1 and Day 8 of 
each 21-day cycle for 
4 cycles
Background 
Treatment
NIMP
Local or 
Central
Arm A
Experimental
Pemetrexed
(nonsquamous 
tumors)
Drug
Solution for 
Infusion
500 mg/vial
500 mg/m2
IV Infusion
Day 1 of each 21-day 
cycle for 4 cycles
Background 
Treatment
NIMP
Local or 
Central
Arm B
Placebo 
Comparator
Normal saline
Drug
Solution for 
Infusion
N/A
N/A
IV Infusion
Day 1 of each 21-day 
cycle for 4 cycles 
followed by surgery 
and 13 cycles
Placebo
IMP
Local
Arm B
Placebo 
Comparator
Cisplatin
Drug
Solution for 
Infusion
1 mg/mL
75 mg/m2
IV Infusion
Day 1 of each 21-day 
cycle for 4 cycles
Background 
Treatment
NIMP
Local or 
Central
Arm B
Placebo 
Comparator
Gemcitabine
(squamous 
tumors)
Drug
Solution for 
Infusion
1000 mg/vial
1000 mg/m2
IV Infusion
Day 1 and Day 8 of 
each 21-day cycle for 
4 cycles
Background 
Treatment
NIMP
Local or 
Central
Arm B
Placebo 
Comparator
Pemetrexed
(nonsquamous 
tumors)
Drug
Solution for 
Infusion
500 mg/vial
500 mg/m2
IV Infusion
Day 1 of each 21-day 
cycle for 4 cycles
Background 
Treatment
NIMP
Local or 
Central
EEA =European Economic Area; IMP=investigational medicinal product; N/A=not applicable; NIMP=noninvestigational medicinal product; Q3W=every 3 weeks.
The classification of IMP and NIMP 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/NIMP may exist. In these circumstances, local legislation is followed.
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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. The trial site is responsible for recording the lot 
number, manufacturer, and expiry date for any locally purchased product as per local 
guidelines unless otherwise instructed by the Sponsor.
Refer to section 9.1.8 for details regarding administration of the study treatment.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Modification (Escalation/Titration/Other)
If appropriate, the investigator may attribute each toxicity event to cisplatin, pemetrexed, 
gemcitabine, or pembrolizumab (either to the agent alone or to the combination of these 
agents) and use a stepwise dose reduction. Dose modifications must be based on the 
maximum toxicity experienced during a cycle. Treatment-related toxicity must resolve to 
Grade ≤1 or baseline before resuming the subsequent cycle, with the exception of alopecia, 
Grade 2 fatigue, and endocrine-related AEs requiring treatment or hormone replacement, 
which may be Grade ≤2. Dose modifications and toxicity management guidelines for 
immune-related AEs associated with pembrolizumab are outlined in Section 7.2.1 and Table 
3 below.
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 third dose modification to any 
particular component will have that agent discontinued. Pembrolizumab dose reductions are 
not permitted.  Pembrolizumab treatment may be interrupted or discontinued due to toxicity. 
Reduction of one chemotherapy agent and not the other agent is appropriate if, in the opinion 
of the Investigator, the toxicity is clearly related to that chemotherapy agent. 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 in the 
approved product labels. Please refer to approved local product labels for dose modifications 
regarding the chemotherapy regimen for cisplatin/pemetrexed and cisplatin/gemcitabine. 
The following dose levels and dose modification are recommended if a dose modification is 
needed (Table 6, Table 7, and Table 8). 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 during the first 4 cycles if appropriate.
Please note that if one or more of the chemotherapy agents are interrupted, all 3 therapies 
(cisplatin, gemcitabine/pemetrexed, and pembrolizumab/placebo) should be withheld for the 
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duration of the interruption. If only pembrolizumab/placebo is interrupted, chemotherapy 
may continue during the pembrolizumab/placebo interruption. However, if the complication 
leading to the pembrolizumab interruption would be made worse by continued chemotherapy 
(i.e. hepatitis), the chemotherapy should either be interrupted or reduced.
Immune-Related Events and Dose Modification (Withhold, Treat, Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation. Based on the severity of irAEs, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids.
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 3.
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Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin 
if the irAEs are not controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 
after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants for signs and symptoms of 
pneumonitis
Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate corticosteroid
treatment
Add prophylactic antibiotics for opportunistic 
infections
Recurrent Grade 2 
or Grade 3 or 4 
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) and of bowel 
perforation (ie, peritoneal signs and ileus)
Participants with ≥Grade 2 diarrhea suspecting colitis 
should consider GI consultation and performing 
endoscopy to rule out colitis
Participants with diarrhea/colitis should be advised to 
drink liberal quantities of clear fluids. If sufficient 
oral fluid intake is not feasible, fluid and electrolytes 
should be substituted via IV infusion.
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST / ALT 
Elevation or 
Increased 
Bilirubin
Grade 2
Withhold
Administer corticosteroids 
(initial dose of 0.5-1 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor with liver function tests (consider weekly or 
more frequently until liver enzyme value returned to 
baseline or is stable)
Grade 3 or 4 
Permanently 
discontinue
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure
Withhold a
Initiate insulin replacement 
therapy for participants with 
T1DM
Administer anti-
hyperglycemic in participants 
with hyperglycemia
Monitor participants for hyperglycemia or other signs 
and symptoms of diabetes
Hypophysitis
Grade 2
Withhold
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue a
Hyperthyroidism 
Grade 2
Continue
Treat with non-selective 
beta-blockers (eg, 
propranolol) or thionamides 
as appropriate
Monitor for signs and symptoms of thyroid disorders
Grade 3 or 4
Withhold or 
Permanently 
discontinue a
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidism
Grade 2-4
Continue
Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care
· Monitor for signs and symptoms of thyroid disorders
Nephritis and 
renal dysfunction
Grade 2
Withhold
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper
Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1 
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
All Other irAEs
Persistent Grade 2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold or 
discontinue b
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 
diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating
physician. If control achieved or ≤ Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
b
Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically important irAEs (eg, 
vasculitis and sclerosing cholangitis).
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Dose Modification and Toxicity Management of Infusion-Reactions Related to 
Pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 4.
Table 4
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs as medically 
indicated until the 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 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the 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 (e.g., 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 
treatment with pembrolizumab
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 (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (e.g., renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor 
or ventilatory support 
indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the 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 treatment with pembrolizumab.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the 
period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov.
Other Allowed Dose Interruption for Pembrolizumab
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. The reason for 
interruption should be documented in the participant's study record.
Chemotherapy Dose Modifications
Please refer to approved local product labels for dose modifications regarding the 
chemotherapy regimen for cisplatin/pemetrexed and cisplatin/gemcitabine. The following 
dose levels and dose modification are recommended if a dose modification is needed.
Table 5
Dose Modifications
Dose level 0
Dose level -1
Dose level -2
Dose level -3
Cisplatin
75 mg/m2
56 mg/m2
38 mg/m2
Discontinue
Pemetrexed
500 mg/m2
375 mg/m2
250 mg/m2
Discontinue
Gemcitabine
1000 mg/m2
750 mg/m2
500 mg/m2
Discontinue
The BSA in m2 should be calculated per local guidance.
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Table 6
Recommended Dose Modifications for Cisplatin/Pemetrexed for Hematological 
Toxicity
Pemetrexed
Cisplatin
Platelets (106/L)
ANC (106/L)
Dose level (DL) from Table 5
≥50,000  
AND
≥ 500
DL 0
DL 0
≥50,000 
AND
< 500
DL -1
DL -1
<50,000
without bleeding 
AND
ANY
DL -1
DL -1
<50,000
with Grade ≥ 2 bleeding 
AND
ANY
DL -2
DL -2
ANY  
AND
< 1,000 + fever ≥ 38.5°C 
(101°F)
DL -1
DL -1
Table 7
Recommended Dose Modifications for Cisplatin/Gemcitabine for Hematological 
Toxicity
Gemcitabine
Cisplatin
Platelets 
(106/L)
ANC (106/L)
DL level from Please 
refer to approved 
local product labels 
for dose 
modifications 
regarding the 
chemotherapy 
regimen for 
cisplatin/pemetrexed 
and 
cisplatin/gemcitabine. 
The following dose 
levels and dose 
modification are 
recommended if a 
dose modification is 
needed. Table 5
DL level from Please 
refer to approved 
local product labels 
for dose 
modifications 
regarding the 
chemotherapy 
regimen for 
cisplatin/pemetrexed 
and 
cisplatin/gemcitabine. 
The following dose 
levels and dose 
modification are 
recommended if a 
dose modification is 
needed. Table 5
≥100,000 
AND
≥1000
DL0
DL 0
50,000-99,999 
OR
500-999
DL-1
DL-1
<50,000
OR
<500
Hold 
Hold 
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Table 8
Recommended Dose Modifications for Chemotherapy for Non-Hematological 
Toxicity
Pemetrexed
Cisplatin
Gemcitabine
Event
CTC Grade
Dose level (DL) from Please refer to approved local product 
labels for dose modifications regarding the chemotherapy 
regimen for cisplatin/pemetrexed and cisplatin/gemcitabine. 
The following dose levels and dose modification are 
recommended if a dose modification is needed. Table 5
Nausea or 
vomiting
Grade 3 or 4
DL 0
DL 0
DL 0
Diarrhea
Grade 3 or 4
DL -1
DL -1
Hold
Mucositis
Grade 3 or 4
DL -2
DL 0
Hold
Neurotoxicity
Grade 2
DL 0
DL -2
DL 0
Grade 3 or 4
DL -1
Discontinue
Hold
Transaminase 
elevation
Grade 3
DL -1
DL -1
Discontinue
Grade 4
Discontinue
Discontinue
Discontinue
Other non-
hematological 
toxicity
Grade 3 or 4
DL -1
DL -1
Hold
**NOTE: Permanently discontinue gemcitabine for any of the following non-hematologic 
adverse reactions: 

Unexplained dyspnea or other evidence of severe pulmonary toxicity

Severe hepatic toxicity

Hemolytic-uremic syndrome

Capillary leak syndrome

Posterior reversible encephalopathy syndrome
Method of Treatment Assignment
Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS).  There are 2 study treatment arms.  
Participants will be assigned randomly in a 1:1 ratio to pembrolizumab + chemotherapy or 
placebo + chemotherapy, respectively.
Stratification
Treatment allocation/randomization will be stratified according to the following factors:
1. Stage (II, III)
2. TPS (<50%, ≥50%)
3. Histology (Squamous, Non-squamous)
4. Region (East-Asia, non-East-Asia)
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Blinding
A double-blinding technique with in-house blinding will be used.  Pembrolizumab and 
placebo will appear identical so that the blind is maintained.  The participant, the investigator 
and Sponsor personnel or delegate(s) who are involved in the study treatment administration 
or clinical evaluation of the participants are unaware of the group assignments.
See Section 9.1.11 for a description of the method of unblinding a participant during the trial, 
should such action be warranted.
Preparation/Handling/Storage/Accountability
Dose Preparation
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual.  Dosing and preparation of pembrolizumab will be performed by an unblinded 
pharmacist. Concomitant chemotherapeutic/immunotherapeutic agents will be prepared and 
administered as per the approved product label(s).
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 trial sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate.  Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The trial site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of study 
treatments in accordance with the protocol and any applicable laws and regulations.
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Treatment Compliance
An interval from first dose of neoadjuvant therapy to surgery of >20 weeks without an 
approved Sponsor Consultation Form will result in discontinuation from the study.  
Interruption >12 weeks between 2 consecutive cycles in the adjuvant treatment phase will 
result in discontinuation from study treatment. 
Administration and Compliance of IV Study Treatments 
(Pembrolizumab/Placebo and Chemotherapy)
Administration of study medication(s) will be witnessed 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.
In the adjuvant phase, participants will receive 13 cycles of adjuvant treatment.
Instructions for preparing and administering pembrolizumab are provided in the Pharmacy 
Manual. Chemotherapy should be prepared and administered per the approved product 
labels. 
Concomitant Therapy
Record all medications taken within 28 days of first dose as well as medications regularly 
administered at intervals greater than 28 days prior to first dose and up to 30 days after the 
last dose of study treatment. All concomitant medications administered during SAEs and 
ECIs are to be recorded as defined in Section 9.3.
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 7.2.
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. 
Systemic Corticosteroid Use
Systemic corticosteroids are permitted in the following situations:

To mediate potential immune-related AEs as guided in Table 3.

As pre/post-medication to prevent AEs associated with chemotherapy or IV contrast.

Brief, limited use of systemic corticosteroids (≤7 days) are permitted where such use 
is considered standard of care (e.g., for COPD exacerbation).
o
Replacement doses of steroids (for example, prednisone 5 to 7.5 mg daily) are 
permitted while on study, as is the use of local steroids.
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Pemetrexed Premedication
All participants receiving pemetrexed should be premedicated with steroids as per approved 
label and local standard practices. In addition, all participants assigned to pemetrexed must 
take a folic acid preparation or multivitamin with folic acid containing between 350 to 1000 
mcg daily. At least 5 daily doses of folic acid must be taken during the 7-day period 
preceding the first dose of pemetrexed and dosing should continue during the full course of 
therapy and for 21 days after the last dose of pemetrexed.
Participants must also receive one intramuscular injection of vitamin B12 1000 mcg during 
the week preceding the first dose of pemetrexed and during Cycle 3. 
Antiemetic Use
For participants receiving chemotherapy, antiemetic therapy should follow Multinational 
Association of Supportive Care in Cancer (MASCC) or appropriate local guidelines 
(Appendix 8: MASCC 2016 Guidelines; Appendix 9, Table 19) and should, for all cycles, 
include a 5-HT3 receptor antagonist, dexamethasone (or equivalent), and aprepitant (or 
equivalent NK-1 receptor antagonist) as per the guideline followed.
Acceptable Concomitant Medications
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 case report form (eCRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date may also be included on the eCRF. Denosumab or zoledronic acid 
administered for treatment of osteoporosis is permissible.  
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 during the study, discontinuation from study therapy may be required. 
The investigator should discuss any questions regarding this with the MSD 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, MSD, and the participant.
Listed below are prohibited concomitant therapies or vaccinations during screening and the 
course of the study:
1. Antineoplastic systemic chemotherapy or biological therapy.
2. Immunotherapy not specified in this protocol.
3. Chemotherapy not specified in this protocol.
4. Radiation therapy not specified in this protocol.
5. Investigational agents other than pembrolizumab.
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6. Live or live attenuated vaccines within 30 days prior to the first dose of trial treatment 
and while receiving study treatment. Examples of live vaccines include, but are not 
limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, 
BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally 
killed virus vaccines and are allowed. However, intranasal influenza vaccines (e.g., 
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 it is an mRNA vaccine, replication-incompetent 
adenoviral vaccine, or inactivated vaccine. These vaccines will be treated just as any 
other concomitant therapy.
Investigational vaccines (i.e., those not licensed or approved for Emergency Use) are not 
allowed.
7. Systemic corticosteroids except for AE management as described in Section 7.7.1.1.
8. For participants receiving radiotherapy, prophylactic growth factor support such as 
erythropoietin or granulocyte-colony stimulating factor is not permitted while receiving 
radiotherapy.  
Participants who, in the assessment of the investigator, require the use of any of the 
aforementioned treatments for clinical management should be discontinued from treatment.
Treatment After the End of the Study
There is no study-specified treatment following the end of the study.
Clinical Supplies Disclosure
This trial is blinded but supplies are provided open label; therefore, an unblinded pharmacist 
or qualified trial 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 
trial to unblind participants and to unmask study treatment identity. In the event that the 
emergency unblinding call center is not available for a given site in this trial, the central 
electronic treatment allocation/randomization system (IVRS/IWRS) should be used in order 
to unblind participants and to unmask study treatment identity.  The Sponsor will not provide 
random code/disclosure envelopes or lists with the clinical supplies.
See Section 9.1.11, Participant Blinding/Unblinding, for a description of the method of 
unblinding a participant during the trial, should such action be warranted.
Standard Policies
MK-3475 will be provided by the trial site as the innovator product pembrolizumab as 
needed.  No generic substitution is permitted.
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For trials using Controlled Substances, all Federal, State, Province, Country, etc. regulations 
must be adhered to in regard to the shipping, storage, handling and dispensing of controlled 
substances. Additionally, the investigator should have the appropriate controlled drug 
license(s) as mandated by Federal, State, Province, Country, etc. laws in which the trial is 
being conducted.
At the close of the trial after unblinding, a letter is to be sent by the investigator to those 
participants who received placebos in the image of the Sponsor’s product to provide the 
following advice:
“You have participated in a trial conducted by the Sponsor. This is to advise you that you 
were among those who received a look-alike infusion created to resemble the drug Keytruda 
(pembrolizumab) as much as possible. You did not receive the active drug Keytruda 
(pembrolizumab) as manufactured by MSD.”
8. Discontinuation/Withdrawal Criteria
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 2 - Schedule of Activities 
and Section 9.10.3 – Discontinued Participants Continuing to be Monitored in the Study.
Participants may discontinue study treatment at any time for any reason or be dropped 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 trial 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 9.1.10 – Withdrawal/Discontinuation.
Participants who wish to discontinue from treatment and/or imaging may retain consent 
specifically for the noninvasive Survival Follow-up portion of the study. All participants are 
encouraged to be followed for vital status until death or the closure of the study, if they 
consent to do so.
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

Local progression that precludes surgery during the neoadjuvant phase (does not 
require biopsy)

Biopsy-proven metastases during the neoadjuvant phase, unresectable disease (as 
determined during surgery) and biopsy-proven recurrent disease during the adjuvant 
phase as outlined in in Section 5.6
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
Local progression or biopsy-proven metastatic disease for those participants who 
have not undergone surgery, have received radiation, and have entered the adjuvant 
phase

Unacceptable adverse experiences

Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment

Intercurrent illness other than another malignancy as noted above that prevents 
further administration of treatment

Any study intervention-related toxicity specified as a reason for permanent 
discontinuation as defined in the guidelines for dose modification due to AEs in 
Section 7.2

Participant who does not have surgery and does not have radiotherapy

A confirmed positive serum pregnancy test

Noncompliance with trial treatment or procedure requirements

Investigator’s decision to discontinue the participant

Administrative reasons
For participants who are discontinued from study treatment but continue to be monitored in 
the trial, see Section 2 – Schedule of Activities (SoA), and Section 9.10.3 – Discontinued 
Participants Continuing to be Monitored in the Study for those procedures to be completed at 
each specified visit.
Discontinuation from study treatment is permanent. Once a participant is discontinued, 
he/she shall not be allowed to restart study treatment.
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 withdraws from the study, they will no longer receive study treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from Future Biomedical Research, are 
outlined in Section 9.1.10 – Withdrawal/Discontinuation. 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 8.3 – Lost to Follow Up.
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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, phone 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.
9. 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 assuring that procedures are conducted by 
appropriately qualified or trained staff.  Delegation of trial site personnel 
responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).

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 procedures meet 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 maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, can be found in the Procedures 
Manual.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
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Administrative and General Procedures
Informed Consent
The investigator or qualified designee must obtain documented informed consent from each 
potential participant or their legally acceptable representative prior to participating in this 
clinical trial or Future Biomedical Research. If there are changes to the participant’s status 
during the trial (eg, health or age of majority requirements), the investigator or 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 their legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
Specifics about the study and the study population are to be included in the study informed 
consent form.
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 
their questions, and obtain documented informed consent before performing any procedure-
related to the 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 or qualified designee 
to ensure that the participant qualifies for the study.
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Participant Identification Card
All participants will be given a Participant Identification Card identifying them as 
participants in a research study. The card will contain trial site contact information (including 
direct telephone numbers) to be utilized in the event of an emergency. The investigator or 
qualified designee will provide the 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 prior to first dose as well as medications regularly administered at intervals 
greater than 28 days prior to first dose.
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the trial through the Safety Follow-up visit.
All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 9.3.
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 or treatment 
allocation.  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 9.10.1.  
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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.
Treatment Administration
Administration of trial medication will be monitored by the investigator and/or trial staff.
Study Treatment should begin within 3 days of randomization for Cycle 1, Day 1.  After 
Cycle 1 in the neoadjuvant phase, cycle visits can occur from 21 days up to 12 weeks after 
the prior cycle, so that the neoadjuvant cycle visit is at least a minimum of 21 days from the 
prior cycle to avoid the dose overlap. The total duration of the neoadjuvant phase should not 
exceed 20 weeks. During the adjuvant treatment phase, the treatment cycle visit window is ±
3 days. The specific time of pembrolizumab infusion (e.g., time of the week for first 
administration; time of the day for each administration) should be taken into consideration 
for study visit procedures. All trial treatments will be administered on an outpatient basis. All 
study treatments must be initiated on Day 1 of each cycle after all procedures/assessments 
have been completed.  If the participant is unable to receive all the scheduled therapies on 
Day 1, the non-administered therapies must be given within 72 hours of scheduled Cycle Day 
1.
Timing of Dose Administration
Depending on the treatment arm and chemotherapy, study treatments will generally be 
administered in the following order:  pembrolizumab or matching placebo, gemcitabine or 
pemetrexed, and cisplatin. Details of administering the individual components are discussed 
below.
Cycle 1 must begin given within 3 days of randomization. All study treatments must be 
initiated on Day 1 of each cycle. Study treatment is to be administered on Day 1 of each 
cycle after all procedures/assessments have been completed. If the participant is unable to 
receive all the scheduled therapies on Day 1, the non-administered therapies must be initiated 
within 72 hours of scheduled Cycle Day 1.  
Timing of Dose Administration of Pembrolizumab or Matching Placebo
Study treatment with pembrolizumab/placebo should be administered on Day 1 of each cycle 
after all procedures/assessments have been completed as detailed in the SoA (Section 2). All 
study treatments should be administered on an outpatient basis. Study treatment of 
pembrolizumab/placebo in the neoadjuvant phase has a +3 day visit window from 
randomization to C1D1. Study treatment of pembrolizumab/placebo may be administered up 
to 3 days before or after the scheduled Day 1 of each cycle in the adjuvant phase due to 
administrative reasons.
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Pembrolizumab will be administered as a dose of 200 mg using a 30-minute IV infusion. 
Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window of -5 
minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for pembrolizumab reconstitution, 
preparation of the infusion fluid, and administration of infusion solution. Pembrolizumab will 
be prepared by the unblinded pharmacist and will be dispensed by the blinded pharmacist and 
administered by blinded and qualified trial site personnel.
The placebo will be a normal saline solution prepared by the unblinded pharmacist. The 
placebo will be dispensed by the blinded pharmacist and administered by blinded and 
qualified trial site personnel in the same manner as the investigational product 
(pembrolizumab). 
Timing of Dose Administration of Chemotherapy
Cisplatin
Cisplatin 75 mg/m2 will be administered as an IV infusion over 60 minutes (-5 min/+10 
minutes) OR as outlined in local standard practices on Day 1 of every 3-week neoadjuvant 
cycle following pemetrexed or gemcitabine. All participants should be premedicated with 
steroids and anti-emetics as per the approved label and local standard practices.
Gemcitabine
Gemcitabine 1000 mg/m2 will be administered as an IV infusion over 30 minutes (-5 
min/+10 minutes) on Day 1 and Day 8 of every 3-week neoadjuvant cycle. All participants 
should be pre-medicated as per the approved label and local standard practices.
Pemetrexed
Pemetrexed 500 mg/m2 will be administered as an IV infusion over 10 minutes (-2 min/+5 
minutes) on Day 1 of every 3-week neoadjuvant cycle. Although participant receives 
pemetrexed on Day 1 of every 3-week cycle, they are to report to study site for completion of 
safety labs on Day 8, as stated in Section 2.2 of Schedule of Activities. All participants 
should be premedicated with steroids as per the approved label and local standard practices. 
In addition, all participants assigned to pemetrexed must take a folic acid preparation or 
multivitamin with folic acid containing between 350 to 1000 mcg daily. At least 5 daily 
doses of folic acid must be taken during the 7-day period preceding the first dose of 
pemetrexed and dosing should continue during the full course of therapy and for 21 days 
after the last dose of pemetrexed.
Participants must also receive one intramuscular injection of vitamin B12 1000 mcg during 
the week preceding the first dose of pemetrexed and during Cycle 3.
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.
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Radiotherapy
Participants who have microscopic positive margins or extracapsular nodal extension should
receive radiation therapy to a maximum of 60 Gy. For participants who do not have surgery
or who have gross residual disease after surgery, the maximum radiation therapy dose is 70
Gy. Radiotherapy is not allowed for participants with completely resected N2 disease in the 
absence of extracapsular spread. Radiotherapy must begin within 4-8 weeks after surgery, 
and cannot be administered concomitantly with adjuvant therapy. Radiotherapy local testing 
requirements should be followed. In addition, radiotherapy records must be submitted to the 
central radiologist according to the guidelines in the Radiotherapy Manual. Adjuvant therapy
must begin within 2-4 weeks of completing radiation therapy.
Surgical Procedure Guidelines
Preoperative Evaluation
Physiologic Evaluation
A Cardiology consultation is recommended if the participant is taking any cardiac 
medications, has a suspected cardiac disease, is unable to climb 2 flights of stairs, or has a 
Thoracic Cardiac Risk Index (ThRCRI) >1.5 [Brunelli, A., et al 2013].
As reference, the following criteria outline the scoring for Thoracic Cardiac Risk Index 
Points:

Pneumonectomy: 1.5 points

Previous ischemic heart disease: 1.5 points

Previous stroke or transient ischemic attack: 1.5 points

Creatinine >2 mg/dL: 1 point.
Pulmonary Evaluation
If the predicted post-operative (PPO) forced vital capacity (FEV1) and percent predicted 
postoperative diffusing capacity for carbon monoxide (PPO DLCO) >60%, no further 
preoperative pulmonary tests are recommended.
If either PPO FEV1 <30% or PPO DLCO <30%, a formal cardiopulmonary exercise test
(CPET) with measurement of maximal oxygen consumption (VO2 max) is recommended. A 
VO2 max <10 mL/kg/min or <35% predicted indicates a high risk for perioperative death and
cardiopulmonary complications with major anatomic lung resection through thoracotomy.
Evaluation by a Pulmonologist and Cardiologist should occur prior to surgery. Non-operative
treatment of the lung cancer should be considered.
Intraoperative Guidance
Routine general anesthesia according to institutional guidelines should be 
performed. Perioperative antibiotics and steroids are administered per institutional 
guidelines. Surgeons are encouraged to avoid the use of steroids where possible. Prohibited 
medications are detailed in Section 7.7 – Concomitant Therapy. Any permitted perioperative 
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steroids should be administered after all study-related tissue and blood samples have been 
collected.
Primary Tumor
Surgery must be a lobectomy, bilobectomy, pneumonectomy, sleeve lobectomy, sleeve 
pneumonectomy, or chest wall resection with any of the previously listed resections. Please 
note that wedge resection or segmentectomy is NOT permitted. The surgeon should describe 
in the operative report the extent of macroscopic disease with particular comparison to extent 
at initial presentation.
Lymph Node
Preferred mediastinal lymph node (N2) dissection consists of complete removal of all 
accessible ipsilateral mediastinal lymph node levels. N1 lymph nodes are generally removed 
as part of the resected lobe or lung. N1 lymph nodes removed separately from the specimen 
should be accurately labeled and submitted to the pathologist as separate specimens.  The 
operative report should contain a detailed description of the lymph node dissection including 
the nodal levels and, if possible, the number of lymph nodes removed. 
Acceptable lymph node dissection involves removal of at least 2 N2 levels (one of which is 
Level 7).
Additional lymph node requirements include: 

Lymph node level specimens should be labeled with the appropriate 
number/description prior to leaving the operating room

If a lymph node level is explored and no lymph nodes are present, the exploration and 
negative findings should be documented in the operative note

All lymph nodes which contained documented metastatic disease prior to neoadjuvant 
therapy should be removed during surgery

Lymph nodes levels will be defined according to the criteria of the joint AJCC/UICC 
classification shown in the IASLC Staging Manual (2nd Edition)
Perioperative Complications
Morbidity associated with pulmonary surgery includes both intraoperative and postoperative 
complications, which may contribute to increased length of inpatient hospital stay and delay 
time to initiation of adjuvant therapy. Management is at the discretion of the treating 
physician as per local SOC.
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Evaluation and Reporting of Postoperative Complications
Potential postoperative complications include but are not limited to:

Bronchopleural fistula

Bacterial pneumonia

Acute respiratory failure

Postoperative hemorrhage

Atelectasis

Aspiration pneumonia

Acute pulmonary edema

Wound infection

Pneumothorax

Bronchospasm

Pulmonary embolism

Acute Respiratory Distress Syndrome

Bronchitis

Pleural effusion

Purulent pleuritis

Deep Vein Thrombosis
All postoperative complications will be reported and graded, if applicable, in the same way 
as other AEs (see Appendix 4) and will be identified by the investigator and/or surgeon as 
post-surgical complications.
Postoperative Care
Postoperative care should proceed per institutional guidelines
Pathology Specimen
The primary resection specimen submitted to a local pathologist should include the entire 
surgically resected lesion and all resected lymph nodes. On pathological examination, 
margins are defined as negative (R0) if: 

No invasive cancer at bronchial margin or soft tissue surrounding bronchus

No invasive cancer at pulmonary artery or pulmonary vein margins or surrounding 
soft tissue

No invasive cancer at medial, lateral, superior and inferior margins of chest wall 
resection

No minimal margin distance

Bronchial dysplasia is considered a negative margin
Margins are defined as positive if: 

Microscopic invasive cancer at bronchial, pulmonary vein or pulmonary arterial 
margins or surrounding soft tissue (R1)

Carcinoma in situ at bronchial margin (R1)

Gross residual disease (R2)
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Specimens should be processed per institutional guidelines but should include separation of 
lymph node specimens into distinct levels prior to pathology submission.
Communication from surgeon to local pathologist should follow local practice and 
institutional guidelines. Sample transport, storage, and shipment instructions for pathology 
specimens obtained during surgery will be provided in the Laboratory (or equivalent) 
Manual. 
Representative specimens (slides or blocks) of tumor tissue collected during surgery from all 
participants will be submitted to the designated central laboratories (see Laboratory Manual 
or equivalent) for blinded pathological response assessment of the pCR and mPR endpoints.
Withdrawal/Discontinuation
Participants who discontinue study treatment prior to completion of the treatment period 
should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the trial, all applicable activities 
scheduled for the discontinuation visit should be performed at the time of withdrawal.  Any 
adverse events which are present at the time of withdrawal should be followed in accordance 
with the safety requirements outlined in Section 9.3 - Adverse Events.
Survival Follow-up
Participants who withdraw consent for treatment and/or imaging are encouraged to remain on 
the noninvasive Survival Follow-up portion of the study. The only procedures associated 
with this phase are telephone contacts to assess vital status and the current state of the 
participant’s NSCLC. The noninvasive nature and societal benefit of Survival Follow-up 
(every 12 weeks ± 7 days) should be explained to the participant by the site staff, particularly 
when discontinuing treatment or imaging. Although per-protocol scheduled imaging ends 
when participants enter Survival Follow-up, all imaging that is conducted thereafter should 
be submitted. Participants may withdraw their consent at any time from any or all portions of 
the study.
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 trial.  If 
medical records for the main trial 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 trial data and 
results.  No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
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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 THE PARTICIPANT UNLESS 
NECESSARY.
When the investigator or delegate needs to identify the drug used by a participant and the 
dosage administered in case of emergency eg, the occurrence of serious adverse events, 
he/she will contact the emergency unblinding call center by telephone and make a request for 
emergency unblinding.  As requested by the investigator or delegate 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 or delegate must enter the 
intensity/toxicity grade of the adverse events observed, the relation to study drug, the reason 
thereof, etc., in the medical chart etc.
For studies that require unblinding as part of the study design (e.g., disease recurrence, 
progression, or completion of study treatment) to support treatment decisions, the Site must 
first contact the Sponsor for approval of non-emergent unblinding at the time of local 
laboratory confirmation of disease recurrence, disease progression, or completion of study 
treatment. Once authorization is granted by the Sponsor for non-emergent unblinding, the 
site will contact IVRS/IVXS to receive the participant’s unblinded treatment arm. The 
emergency unblinding center should not be used for non-emergent unblinding.
Participants whose treatment assignment has been unblinded by the investigator/delegate 
and/or non-study treating physician must be discontinued from study drug, but should 
continue to be monitored in the trial.
Additionally, the investigator must go into the IVRS system and perform the unblind in the 
IVRS system to update drug disposition.  In the event that the emergency unblinding call 
center is not available for a given site in this trial, IVRS/IWRS should be used for emergency 
unblinding in the event that this is required for 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 are unblinded 
so that the appropriate follow-up medical care can be provided to the participant.
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device 
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
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information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:

Laboratory equipment-as required for inclusion labs and safety assessments

Imaging equipment-as required for efficacy assessments

Drug administration equipment-as required for storage, preparation and 
administration (infusion) of protocol treatment 
See protocol-specified guidance in the Administrative Binder, Procedures Manual, and 
Pharmacy Manual. 
Tumor Tissue Collection for Biomarker Analysis
PD-L1 expression will be tested by a central laboratory as part of screening. A biopsy that 
produces tissue suitable for histologic determination of PD-L1 TPS is required and may be 
obtained from either the primary tumor or lymph node containing metastatic disease (not 
previously irradiated). Methods that produce suitable specimens include, but are not limited 
to: percutaneous core needles and cup forceps/incisional biopsies via mediastinoscopy, 
thoracoscopy, thoracotomy, and mediastinotomy. The specimen must be provided to the 
central laboratory during screening and must have been obtained within 90 days prior to
randomization. FFPE tissue blocks are preferred to slides. Detailed instructions for tissue 
collection, processing, and shipment are provided in the Vendor Lab Manual.
The tissue analysis will include PD-L1 TPS used for stratification.
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. Tumor imaging is strongly preferred to be acquired by 
computed tomography (CT). Magnetic resonance imaging (MRI) should be used only when 
CT is contraindicated or for imaging of the brain. Brain imaging is required for all 
participants at screening. MRI is preferred; however, CT imaging will be acceptable if MRI 
is medically contraindicated. The same imaging technique regarding modality and the use of 
contrast should be used in a participant throughout the trial to optimize the visualization of 
existing and new tumor burden. 
All images from the sites will be sent to a central imaging vendor. 
Note: The exact same image acquisition and processing parameters should be used 
throughout the study per the Site Imaging Manual. 
Initial Tumor Imaging
Scans performed as part of routine clinical management are acceptable for use as the baseline 
scan if they are of diagnostic quality, include all required anatomy, and performed within 60 
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days prior to randomization with the exception of the chest CT scan, which must be 
performed within 28 days prior to randomization. These scans will be considered the baseline 
assessments for the study.
Tumor Imaging During Trial
For participants receiving all 4 cycles of neoadjuvant therapy, the first on-trial imaging 
assessment will be performed 3 weeks after completion of 2 cycles of preoperative therapy, 
at approximately 7 weeks (42 days ±7 days) after the first dose of trial treatment (or earlier if 
clinically indicated). The second imaging assessment will take place 3 weeks after 4 cycles 
of preoperative therapy, at approximately 13 weeks (84 days ±7 days) after the first dose of 
trial treatment, before surgery (or earlier if clinically indicated).
If the participant receives fewer than 4 cycles, the following schedule should be followed: 

If the participant receives 3 cycles: Imaging performed 3 weeks after Cycle 2 and 4
weeks after Cycle 3  

If the participant receives 2 cycles: Imaging performed 3 weeks after Cycle 2 

If the participant receives 1 cycle: Imaging performed 3 weeks after Cycle 1 
Note: If the participant receives only 1 or 2 cycles, then s/he will have just one set of CT 
scans in the neoadjuvant phase.
Following resection of their lung cancer, participants must have new baseline imaging within 
4 weeks prior to the start of adjuvant pembrolizumab/placebo treatment. Participants who 
receive post-operative radiotherapy must have new baseline imaging after completion of the 
radiotherapy, but within 4 weeks prior to the start of adjuvant pembrolizumab/placebo 
treatment. 
Imaging in the adjuvant phase will be performed every 16 weeks (±14 days), or more 
frequently if clinically indicated, starting from the date of randomization. If the first 
scheduled image in the adjuvant phase falls within ±4 weeks of the new baseline scan, the 
first scheduled image in the adjuvant phase is not required. 
All participants who discontinue study treatment for reasons other than progressive disease or 
recurrence enter the post treatment Follow-up Phase. Imaging will be based upon the date of 
randomization.
Participants who do not undergo surgery and do not undergo radiotherapy are not required to 
have new baseline imaging. Participants will be followed in the Follow-up Phase to perform 
imaging every 16 weeks (± 21 days) from date of randomization. Imaging will be performed 
for assessment of local progression and/or metastatic disease.
Imaging timing should follow calendar days and should not be adjusted for delays in cycle 
starts. Imaging should continue to be performed until local disease progression or metastatic 
disease, withdrawal of consent, or death, whichever occurs first. All supplemental imaging 
must be submitted to the central imaging vendor. All imaging acquired within the protocol-
specified window of time around a scheduled imaging visit can be classified as pertaining to 
that visit.
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Per RECIST 1.1, PR and CR should be confirmed by a repeat tumor imaging assessment 
obtained 4 weeks or longer from the date the response was first documented, unless the 
participant is scheduled for surgery. The tumor imaging performed to confirm a response 
may be performed, at the earliest, 4 weeks after the first indication of a response, or at the 
next scheduled scan.
End of Treatment and Follow-up Tumor Imaging
All participants who discontinue study treatment for any reason, including completion of 13 
cycles of adjuvant treatment, should have tumor imaging performed at the time of treatment 
discontinuation (±4 week window). If imaging was obtained within 4 weeks before the date 
of discontinuation, then imaging at treatment discontinuation is not mandatory. 
For participants who discontinue study treatment for reasons other than progressive disease 
or recurrence, every effort should be made to continue monitoring their disease status by 
tumor imaging using the post treatment Follow-up Phase imaging schedule of every 16 
weeks (± 21 days) through the end of year 3, then every 6 months (± 28 days) for years 4 and 
5, and then every 12 months (± 28 days) thereafter. Imaging will be based upon the date of 
randomization to monitor disease status until local disease progression or metastatic disease, 
withdrawal of consent from imaging, or death, whichever occurs first.
NOTE: For participants who have started a new anticancer therapy for reasons other than 
disease progression, imaging assessments will continue as indicated in Section 2.4. Where 
allowed, participants who have not progressed but have declined study-specific imaging 
should be encouraged to submit imaging performed as standard of care (even 
retrospectively).
For participants who discontinue protocol-specified imaging for progressive disease or 
recurrence based on investigator assessment, where allowed, all efforts should be made to 
send in subsequent standard of care imaging (even retrospectively) to the central imaging 
vendor for potential review.
Assessment of Disease
During the neoadjuvant phase and for those participants who have not had or will not have 
surgery, RECIST 1.1 will be used as the primary measure for assessment of tumor response, 
date of disease progression, and as a basis for all protocol guidelines related to disease status 
(e.g., discontinuation of trial therapy). In the postoperative adjuvant phase, chest and 
abdominal CT scans will be performed at regular intervals for assessment of disease 
recurrence. Other radiologic tests may be performed as clinically indicated. Biopsy 
confirmation of metastatic disease that occurs during the neoadjuvant phase or recurrent 
disease that occurs during the adjuvant phase or Post-treatment Follow-up Phase is required 
unless medically contraindicated.
Patient-reported Outcomes
The EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ-LC13 questionnaires will be 
administered by trained study site personnel and completed electronically by the participants 
in the following order: EQ-5D-5L first, then EORTC eQLQ-C30, and lastly the EORTC 
eQLQ-LC13. The questionnaires should be administered prior to dosing at Cycle 1 and Cycle 
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4 Week 11 during the neoadjuvant treatment phase and then at Cycles 1, 2, 3, 4, 7, 10, and 13
during the adjuvant treatment. They also need to be completed at the EOT, 30 day Safety 
Follow-up, and the post-treatment follow-up visits through Year 5.
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 reason must be captured.
Medical Resource Utilization and Health Economics
All-cause hospitalizations and emergency room 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 
anticancer therapy, whichever is earlier.
Survival Follow-up
Once a participant experiences a progression/recurrence, the participant moves into the 
Survival Follow-up Phase and will be contacted by telephone approximately every 12 weeks 
± 7 days to assess vital status until death, withdrawal of consent, or the end of the study, 
whichever occurs first. Post-study treatments and the participant’s response to them will also 
be collected. Participants in Survival Follow -up who have experienced PD should submit 
SOC imaging to the central vendor. Participants in Survival Follow-up who have not 
experienced PD should be given the option of continuing with the protocol-imaging schedule 
(and if unwilling, SOC images should be submitted). 
If a participant withdraws consent for treatment and/or imaging, the participant is still 
encouraged to remain in the Survival Follow-up Phase and sites should ensure the participant 
understands the noninvasive nature of this phase.
MSD will request vital status data more frequently than every 12 weeks at specific time 
points during the study. For example, vital status may be requested prior to an external DMC 
safety review, efficacy interim analyses, and final analysis. All participants who are in the 
Follow-up and Survival Follow-up Phases and not known to have died prior to the request for 
these additional vital status time points will be contacted at that time.
Adverse Events (AE), Serious Adverse Events (SAE) and Other Reportable Safety 
Events
The definitions of an adverse event (AE) or serious adverse event (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 Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting.
Progression of the cancer under study is not considered an adverse event as described in 
Section 9.3.5 – Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs, and Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.
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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, who is a qualified physician, and any designees are responsible for 
detecting, assessing, documenting, and reporting events that meet the definition of an AE or 
SAE as well as other reportable safety events. Investigators need to document if an SAE was 
associated with a medication error, misuse, or abuse. Investigators remain responsible for 
following up AE, SAEs and other reportable safety events for outcome according to Section 
9.3.3.
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 pre-screening 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.
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 trial, 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 180 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.

All-cause hospitalizations and all-cause emergency room (ER) visits (except as related to 
scheduled surgery and the use of a hospital specialty unit [HSU] according to the 
institution guidelines) from the time of treatment allocation/randomization through 90
days following cessation of study treatment, or 30 days following cessation of study 
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treatment, if the participant initiates new anticancer therapy, whichever is earlier, must be 
reported by the investigator using HOSP form for hospitalization and HSU form for ER 
visits.
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 timeframes as indicated in Table 9.
Table 9
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-Specified 
Follow-up Period
Reporting Time 
Period:
After the 
Protocol-
specified Follow-
up Period
Timeframe 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
Nonserious 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
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Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-Specified 
Follow-up Period
Reporting Time 
Period:
After the 
Protocol-
specified Follow-
up Period
Timeframe 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
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) 
Exception: A 
positive pregnancy 
test at the time of 
initial screening is 
not a reportable 
event unless the 
participant has 
received study 
intervention.
Report all
Previously 
reported – Follow 
to 
completion/termin
ation; 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 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
Method of Detecting AE, SAE 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 non-leading 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, ECI, 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 8.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
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outcome.  Further information on follow-up procedures is given in Appendix 4: Adverse 
Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting.
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 towards 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 Adverse Events will be reported to regulatory authorities, IRB/IECs 
and investigators in accordance with all applicable global laws and regulations, ie, per 
ICH Topic E6 (R1) Guidelines for Good Clinical Practice.

Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) 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 Investigator’s Brochure 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 9.3.1.  
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the trial.  Any suspected endpoint which upon review 
is not progression of the cancer under study will be forwarded to Global Safety as an SAE 
within 24 hours of determination that the event is not progression of the cancer under study.
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered adverse 
events, any pregnancy or infant exposure during breastfeeding in a participant (spontaneously 
reported to the investigator or their designee), including the pregnancy of a male participant's 
female partner, that occurs during the trial are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as 
serious events (Important Medical Events).  If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
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Events of Clinical Interest (ECI)
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
Events of clinical interest for this trial include: 
1. an overdose of Sponsor's product, as defined in Section 9.4 – Treatment of Overdose, that 
is not associated with clinical symptoms or abnormal laboratory results.
2. Potential DILI events defined as an elevated AST or ALT lab value that is greater than or 
equal to 3X the upper limit of normal and an elevated total bilirubin lab value that is 
greater than or equal to 2X the upper limit of normal and, at the same time, an alkaline 
phosphatase lab value that is less than 2X the upper limit of normal, as determined by 
way of protocol-specified laboratory testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
3. Surgical complications which will be considered as SAEs include broncho-pleural
fistulas, re-operation, supraventricular arrhythmia, pneumonia, and respiratory failure
[Scagliotti, G. V., et al 2012]. This list is not exhaustive and other serious surgical 
complications, such as deep vein thrombosis and pulmonary embolism, should be 
reported within 24 hours of learning of event. SAEs will be assessed as defined by 
CTCAE, Version 4.0.
ECIs that occur after the consent form is signed but before treatment randomization must be 
reported by the investigator to MSD if the event caused the participant to be excluded from 
the study or is the result of a protocol-specified intervention.
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 MSD within 24 hours of 
the learning of the event.
Treatment of Overdose
For this trial, an overdose of pembrolizumab is 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 pembrolizumab, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria 
are met.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
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Safety
Details regarding specific safety procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant can be found in the Procedures 
Manual.
Planned time points for all safety assessments are provided in the SoA.
Physical Examinations
Full Physical Examination
The investigator or qualified designee will perform a complete physical examination during 
the Screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  The time points for full physical exams are described in Section 2.  After the first 
dose of trial treatment, new clinically significant abnormal findings should be recorded as 
AEs.
Directed Physical Examination
The investigator or qualified designee will perform a directed physical examination as 
clinically indicated prior to the administration of the trial treatment. Cycles that do not
require a full physical examination are defined in Section 2. New clinically significant 
abnormal findings should be recorded as AEs.
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of study treatment, and during the Follow-up period as specified 
in the SoA. Vital signs include temperature, pulse, respiratory rate, weight, and blood 
pressure. Height will be measured at Screening only.
Electrocardiograms
A standard 12-lead ECG will be performed using local standard procedures once at 
screening. Clinically significant abnormal findings should be recorded as medical history. 
Additional time points may be performed as clinically necessary. 
Clinical Safety Laboratory Assessments
Refer to Appendix 6: Clinical Laboratory Tests for the list of clinical laboratory tests to be 
performed and to the SoA for the timing and frequency. 
●
The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
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.
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●
All protocol-required laboratory assessments, as defined in Appendix 6, must be 
conducted in accordance with the Laboratory Manual and the SoA.
●
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).
●
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. 
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified Appendix 6. Refer to 
the SoA for the timing of laboratory assessments.
Pregnancy Test

Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 6.1.
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at monthly intervals during intervention.
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted for the time required to eliminate systemic exposure after the last dose of 
each study intervention(s) as noted in Section 6.1. The length of time required to 
continue pregnancy testing for each study intervention is as follows:
◦
Chemotherapy: 180 days
◦
MK-3475: 120 days
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the participant’s participation in the study.
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status at screening (within 10 days 
prior to randomization), prior to the administration of each dose of study treatment, and 
during the Follow-up period as specified in the SoA. The ECOG performance scale is 
outlined in Appendix 5.
Pharmacokinetics
PK parameters will not be evaluated in this study.
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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 Genetic Analyses

Blood for RNA Analyses

Blood for Serum Biomarker Analysis

Blood for Plasma Biomarker Analysis

Blood for ctDNA

Tissue for Biomarker Analysis
Sample collection, storage and shipment instructions for the exploratory biomarker 
specimens will be provided in the Laboratory Manual.
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. 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 these purposes. If the sample is collected, 
leftover extracted DNA will be stored for FBR if the participant provides documented 
informed consent for FBR. If the planned genetic analysis is not approved, but FBR is 
approved and consent is given, this sample will be collected for the purpose of FBR.
Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be in the Operations/Laboratory Manual.
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:

Leftover DNA

Leftover RNA

Leftover main trial tumor tissue

Leftover plasma from plasma biomarker analyses

Leftover serum from serum biomarker analyses

Leftover plasma or derivative for ctDNA
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Visit Requirements
Visit requirements are outlined in Section 2 – Schedule of Activities (SoA).  Specific 
procedure-related details are provided above in Section 9 – Study Assessments and 
Procedures.
Screening
Approximately 28 days prior to treatment allocation/randomization, potential participants 
will be evaluated to determine that they fulfill the entry requirements as set forth in Sections 
6.1 and 6.2. 
Documented consent must be obtained prior to performing any protocol-specific procedure. 
Results of a test performed prior to the participant signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. Screening procedures are to be completed within approximately 28 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 testing (only required if indicated by local health 
authority), which may be done up to 28 days prior to the first dose of study treatment.

Evaluation of ECOG is to be performed within 10 days prior to randomization.

For women of reproductive potential, a urine or serum pregnancy test will be 
performed within 24 hours prior to the first dose of study treatment in both the 
neoadjuvant and adjuvant treatment phases. If urine 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 28 days prior 
to the first dose of study treatment. Newly obtained tumor tissue may be obtained 
within 90 days prior to randomization.

Baseline imaging must be done within 60 days, except for repeat CT of chest and 
abdomen, which must be done within 28 days.
Participants may be rescreened once after initially failing to meet the inclusion/exclusion 
criteria or failing to complete the required testing within the 28 day Screening Period, and 
will retain their original screening number.
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 are met. 
Treatment Period
Visit requirements are outlined in Section 2—Schedule of Activities (SoA). Specific 
procedure-related details are provided above in Section 9—Study Assessments and 
Procedures. Unless otherwise specified, assessments/procedures are to be performed prior to 
the first dose of treatment for each cycle. Neoadjuvant visits can occur from 21 days up to 12 
weeks after the prior cycle, so that the neoadjuvant visit is at least a minimum of 21 days 
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from the prior cycle (to avoid the dose overlap). The total duration of the neoadjuvant period 
should not exceed 20 weeks. During the adjuvant phase the visit window is ±3 days.
Treatment in the neoadjuvant phase will occur every 21 days (1 cycle) for 4 cycles. 
Treatment in the adjuvant phase will occur every 21 days (1 cycle) up to a maximum of 13 
cycles. 
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study treatment or before the initiation of a new anticancer treatment, whichever 
comes first.  If the participant has a discontinuation visit ≥27 days after the last dose of study 
treatment, the Safety Follow-up visit is not required.
Follow-up Visits
Participants who discontinue study treatment for a reason other than biopsy-proven or 
radiologically documented progressive disease (PD) will move into the Follow-up Phase and 
should be assessed with imaging every 16 weeks through year 3, every 6 months through 
years 4-5, and then every 12 months (± 28 days) thereafter. The Sponsor may request vital
status to be assessed at additional time points during the course of the study (not to exceed 
approximately every 12 weeks). Every effort should be made to collect imaging (including in 
those participants who start anticancer therapy) until biopsy-proven progression or recurrence
or death. Information regarding post-study anticancer treatment will be collected if new 
treatment is initiated.
Survival Follow-up
Participants who experience local progression that precludes surgery during the neoadjuvant 
phase, metastases during the neoadjuvant phase, unresectable disease (as determined during 
surgery) and recurrent disease during the adjuvant phase or EOT Follow-up Phase as outlined 
in Section 5.6 will move into the Survival Follow-up Phase and should be contacted by 
telephone approximately every 12 weeks to assess for vital status until death, withdrawal of 
consent, or the end of the trial, whichever occurs first.
Participants may withdraw their consent at any time from any or all portions of the study. 
Participants who withdraw consent for treatment and/or imaging are encouraged to remain on 
the noninvasive Survival Follow-up portion of the study. The only procedures associated 
with this phase are telephone contacts to assess vital status and the current state of the 
participant’s NSCLC. Although per-protocol scheduled imaging ends when participants enter 
Survival Follow-up, all imaging that is conducted thereafter should be submitted. The 
noninvasive nature and societal benefit of Survival Follow-up should be explained to the 
participant by the site staff, particularly when discontinuing treatment and imaging.
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Vital Status
To ensure current and complete survival information (vital status) is available at the time of 
database locks, updated vital status may be requested during the study by the Sponsor.  For 
example, updated vital status may be requested before but not limited to an 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 vital status.
10. Statistical Analysis Plan
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, but prior to any unblinding/final database lock, changes made to 
primary and/or key secondary hypotheses, or the statistical methods related to those 
hypotheses, then the protocol will be amended (consistent with ICH Guideline E-9).  
Changes to exploratory or other non-confirmatory analyses made after the protocol has been 
finalized, but prior to unblinding/final database lock, will be documented in a supplemental 
SAP (sSAP) and referenced in the Clinical Study Report (CSR) for the study.  Post hoc 
exploratory analyses will be clearly identified in the CSR.  Separate analysis plans (i.e.,
separate documents from the sSAP) will be developed to detail biomarker analyses. The PRO 
analysis plan will be included in the sSAP. 
Statistical Analysis Plan Summary
Key elements of the Statistical Analysis Plan are summarized below; the comprehensive plan 
is provided in Sections 10.2 -Responsibility for Analyses/In-house Blinding through 10.12 –
Extent of Exposure.
Study Design Overview
A Phase III, randomized, double-blind trial of pembrolizumab plus 
chemotherapy versus placebo plus chemotherapy as neoadjuvant/adjuvant 
therapy for participants with resectable Stage II through IIIA-B (N2) NSCLC
Treatment Assignment
Approximately 786 participants will be randomized in a 1:1 ratio between 2
treatment arms: 
(Arm A) Neoadjuvant pembrolizumab plus platinum doublet chemotherapy 
(4 cycles) followed by surgery and adjuvant pembrolizumab (13 cycles)
(referred to as pembrolizumab plus chemotherapy arm)
(Arm B) Neoadjuvant placebo plus platinum doublet chemotherapy (4 cycles) 
followed by surgery and adjuvant placebo (13 cycles) (referred to as placebo
plus chemotherapy arm)
Stratification factors are as follows:
1) Stage (II, III)
2) TPS (<50%, ≥50%)
3) Histology (Squamous, Nonsquamous)
4) Geographic Region (East Asia, non-East Asia)
Analysis Populations
Efficacy: Intention-to-Treat (ITT)
Safety: All Participants as Treated (APaT)
PRO: Full Analysis Set (FAS)
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Primary Endpoint(s)

Event-free survival (EFS)

Overall survival (OS)
Secondary Endpoints

Major pathological response (mPR) rate

Pathological complete response (pCR) rate

PRO outcome 

Safety and tolerability
Statistical Methods for 
Key Efficacy Analyses
The hypotheses will be evaluated by comparing pembrolizumab plus 
chemotherapy to placebo plus chemotherapy with respect to EFS and OS using
a stratified log-rank test, and with respect to mPR and pCR rates using the 
stratified Miettinen and Nurminen method. For EFS and OS, hazard ratios 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 
difference in mPR rate and pCR rate will be estimated using the stratified 
Miettinen and Nurminen method with strata weighting by sample size.
Statistical Methods for 
Key Safety Analyses
The analysis of safety results will follow a tiered approach.  The tiers differ with 
respect to the analyses that will be performed.  There are no events of interest 
that warrant elevation to Tier 1 events in this study.  Tier 2 parameters will be 
assessed via point estimates with 95% confidence intervals (CIs) provided for 
between-group comparisons; only point estimates by treatment group are 
provided for Tier 3 safety parameters.  The 95% CIs for the between-treatment 
differences in percentages will be provided using the unstratified Miettinen and 
Nurminen method.
Interim Analyses
Four interim analyses and one final analysis are planned for this study.  Results 
will be reviewed by an external DMC. Details are provided in Section 10.7-
Interim Analyses. 

Interim analysis (IA1): when approximately 326 EFS events have been 
observed and ~ 5 months after the last participant is randomized
(~48months after the first participant is randomized)  
o
Purpose: mPR rate analysis, pCR rate analysis, interim EFS analysis
(~78% of target EFS events) and interim OS analysis (~41% of target 
OS events)

Interim analysis (IA2): when approximately 416 EFS events have been 
observed (~60 months after the first participant is randomized)
o
Purpose: final EFS analysis and interim OS analysis (~58% of target 
OS events)

Interim analysis (IA3): when approximately 285 deaths have been observed 
(~72 months after the first participant is randomized)
o
Purpose: interim OS analysis (~74% of target OS events)

Interim analysis (IA4): when approximately 340 deaths have been observed 
(~84 months after the first participant is randomized)
o
Purpose: interim OS analysis (~88% of target OS events)

Final analysis (FA): when approximately 386 deaths have been observed 
(~96 months after the first participant is randomized)
o
Purpose: final OS analysis 
Note that for IA3 and IA4, if the OS events accrue slower than expected, the 
Sponsor may conduct the analysis with additional 3 months of follow-up, or
when the specified number of events is observed, whichever occurs first. If the 
final targeted OS events cannot be reached by the end of year 5 after last 
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participant randomized, the final OS analysis will be conducted at the end of 
year 5 after last participant randomized at the latest.
Multiplicity
The overall Type I error rate over the multiple endpoints will be strongly 
controlled at 2.5% (one-sided). A 0.01% (one-sided) Type I error rate will be 
initially allocated to test mPR rate, 0.01% (one-sided) allocated to test pCR rate,
1.0% (one-sided) allocated to test EFS and 1.48% (one-sided) allocated to test 
OS.   The graphical approach of Maurer and Bretz [Maurer, W. and Bretz, F. 
2013] will be applied to re-allocate alpha among the hypotheses for mPR rate, 
pCR rate, EFS and OS. Group sequential methods will be used to allocate alpha 
among the interim and final analyses for the EFS and OS endpoints.
Sample Size and Power 
The planned sample size is approximately 786 participants. The trial is event-
driven and completes after substantial efficacy evidence of EFS and/or OS are 
observed. With 416 EFS events, the study has 90% power for detecting a hazard 
ratio (HR) of 0.7 at a 1.0% (one-sided) significance level. With 386 deaths, the 
study has 90% power for detecting a HR of 0.7 at a 1.48% (one-sided) 
significance level. Based on the time that approximately 326 EFS events have 
been observed, the study has 99.1% power for detecting a 20 percent point
difference in mPR rate and 99.3% power for detecting a 16 percent point 
difference in pCR rate at a 0.01% (one-sided) significance 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.
This study will be conducted as a double-blinded study under in-house blinding procedures. 
The official, final database will not be unblinded until medical or scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete. 
The Sponsor will generate the randomized allocation schedule(s) for study treatment 
assignment for this protocol. Randomization will be implemented in IVRS/IWRS.
Planned interim analyses are described in Section 10.7 – Interim Analyses. Blinding to 
treatment assignment will be maintained at all investigational sites. Treatment-level results of
the planned interim analyses will be provided by the external unblinded statistician to the 
DMC. Limited additional Sponsor personnel may be unblinded to the treatment-level results 
of the interim analyses, if required, in order to act on the recommendations of the DMC (e.g., 
interaction with regulatory agencies). The extent to which individuals are unblinded with 
respect to results of interim analyses will be documented by the external unblinded
statistician.
The DMC will serve as the primary reviewer of the results of the interim analyses and will 
make recommendations for discontinuation of the study or modification to an EOC of the 
Sponsor. Depending on the recommendation of the DMC, the Sponsor may prepare a 
regulatory submission. If the DMC recommends modifications to the design of the protocol 
or discontinuation of the study, this EOC and limited additional Sponsor personnel may be 
unblinded to results at the treatment level in order to act on these recommendations. The 
DMC responsibilities, review schedules, and additional logistical details will be provided in 
the DMC Charter.
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Prior to final study unblinding, the external unblinded statistician will not be involved in any 
discussions regarding modifications to the protocol, statistical methods, identification of 
protocol deviations, or data validation efforts after the interim analyses.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 4 – Objectives/Hypotheses and 
Endpoints.
Analysis Endpoints
Primary and secondary efficacy, safety and PRO endpoints that will be evaluated for within-
and/or between-treatment differences are listed below.  Exploratory endpoints will be 
described in the sSAP.
Efficacy Endpoints
Primary
Event-free Survival
EFS is defined as the time from randomization to the first of the following events:

Radiographic disease progression per RECIST 1.1 (for participants who have not had 
or will not have surgery, or participants who have gross residual disease after an 
incomplete resection [R2 resection])

Local progression (primary tumor or regional lymph nodes) precluding planned
surgery

Inability to resect the tumor

Local or distant recurrence (for participants who are disease free after surgery or 
participants with microscopic positive margins [R1 resection]) 

Death due to any cause
Imaging and biopsy are investigator-assessed. For radiographic progression/recurrence, the 
EFS event will be declared when:

Only imaging is performed, and progression/recurrence confirmed

Only pathology is done, and progression/recurrence confirmed

Both pathology and imaging are done, and progression/recurrence confirmed (by at 
least one). In this case, whatever examination comes first, the first date is considered 
as the EFS event date. 
In the event that biopsy is not diagnostic or does not reveal malignancy, the investigator 
should reassess the corresponding radiographic progression/recurrence.
See Section 10.6.1 for the definition of censoring.
Overall Survival
OS is defined as the time from randomization to death due to any cause.
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Secondary
Major Pathological Response (mPR) Rate
The mPR rate is defined as the proportion of participants having ≤10% viable tumor cells in 
the resected primary tumor and all resected lymph nodes.
Pathological Complete Response (pCR) Rate
The pCR rate is defined as the proportion of participants having an absence of residual 
invasive cancer on hematoxylin and eosin stained slides of the resected lung specimen and 
lymph nodes following completion of neoadjuvant therapy (ie, ypT0/Tis ypN0).
Safety Endpoints
Safety measurements are described in Section 5.4.1.2 - Rationale for Safety Endpoints and 
Section 9.5- Safety. 
Patient-reported Outcome (PRO) Endpoints
Change from baseline (C1 in neoadjuvant phase) to follow up assessments in the neoadjuvant 
phase and in the adjuvant phase in global health status/QoL score using the EORTC QLQ-
C30 (items 29-30) questionnaire will be assessed.
Exploratory PRO endpoints as described in Section 5.4.1.3 will also be evaluated. Details 
will be provided in the sSAP.
Analysis Populations
Efficacy Analysis Population
The Intention-to-Treat (ITT) population will serve as the population for primary efficacy 
analyses. All randomized participants will be included in this population. Participants will be 
included in the treatment group to which they are randomized.
Details on the approach to handling missing data are provided in Section 10.6 – Statistical 
Methods.
Safety Analysis Population
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. For the analysis of perioperative complications, the All 
Participants receiving Surgery (APrS) population will be used, which consists of all 
randomized participants who receive at least one dose of neoadjuvant study treatment and 
also undergo on-study surgery. For both the APaT and APrS populations, participants will be 
included in the treatment group corresponding to the study treatment they actually received. 
For most participants, this will be the treatment group to which 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 correct treatment group and a 
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narrative will be provided for any events that occur during the cycle for which the participant 
is incorrectly dosed.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in 
Section 10.6 – Statistical Methods.
PRO Analysis Population
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
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the sSAP.
Statistical Methods for Efficacy Analyses
Efficacy results that will be deemed to be statistically significant after consideration of the 
Type I error control strategy are described in Section 10.8 – Multiplicity. Nominal p-values 
will be computed for other efficacy analyses, but should be interpreted with caution due to 
potential issues of multiplicity.
The stratification factors used for randomization will be applied to all stratified efficacy 
analyses, including stratified log-rank test, stratified Cox model, and stratified Miettinen and 
Nurminen method. In the event that some strata are of small size, they may be pooled for 
analyses in a meaningful way. Details regarding the pooling of strata will be specified in the 
sSAP prior to database lock for the first interim efficacy analysis. 
Event-free Survival
The non-parametric Kaplan-Meier method will be used to estimate the EFS curve in each 
treatment group.  The treatment difference in EFS will be assessed by the stratified log-rank 
test.  A stratified Cox proportional hazard model with Efron's method of tie handling will be 
used to assess the magnitude of the treatment difference (i.e., hazard ratio) between the 
treatment arms.  The hazard ratio and its 95% CI from the stratified Cox model with Efron's 
method of tie handling and with a single treatment covariate will be reported. The 
stratification factors used for randomization (See Section 7.3.1 – Stratification) will be 
applied to both the stratified log-rank test and the stratified Cox model. 
For the primary EFS analysis, the true date of event will be approximated by the date of the 
first assessment at which event is objectively documented. Participants who do not 
experience an event at the time of analysis will be censored at the last disease assessment. 
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The primary approach for EFS will be based on investigator assessment.  A sensitivity 
analysis by using the central review of imaging and biopsy will also be conducted. Other 
sensitivity analyses may be conducted using different censoring rules and will be 
documented in the sSAP.
In case the proportional hazards assumption is not valid, the Restricted Mean Survival Time 
(RMST) method may be conducted for EFS to account for the possible non-proportional 
hazards effect as a sensitivity analysis.
Overall Survival
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. A stratified 
Cox proportional hazard model with Efron's method of tie handling will be used to assess the 
magnitude of the treatment difference (i.e., the hazard ratio). The hazard ratio and its 95% CI 
from the stratified Cox model with a single treatment covariate will be reported. The 
stratification factors used for randomization (See Section 7.3.1– Stratification) will be 
applied to both the stratified log-rank test and the stratified Cox model. Participants without 
documented death at the time of analysis will be censored at the date of last known contact.
In case the proportional hazards assumption is not valid, the Restricted Mean Survival Time 
(RMST) method may be conducted for OS to account for the possible non-proportional 
hazards effect as a sensitivity analysis.
Major Pathological Response Rate
The stratified Miettinen and Nurminen’s method will be used for comparison of the mPR 
rates between the 2 treatment groups. The difference in mPR rates and its 95% CI from the 
stratified Miettinen and Nurminen method with strata weighting by sample size will be 
provided. The stratification factors used for randomization (see Section 7.3.1-Stratification) 
will be applied to the analysis.
Participants who are discontinued from the study treatment but receive other neoadjuvant 
treatment not specified by the study prior to surgery will be classified as not having an mPR 
(nonresponders) in the efficacy analyses, regardless of the results obtained from the surgery.  
Participants who are discontinued from study treatment due to reasons that preclude surgery 
are considered nonresponders. 
Pathological Complete Response Rate
The stratified Miettinen and Nurminen’s method will be used for comparison of the pCR 
rates between the 2 treatment groups. The difference in pCR rates and its 95% CI from the 
stratified Miettinen and Nurminen method with strata weighting by sample size will be 
provided. The stratification factors used for randomization (see Section 7.3.1-Stratification) 
will be applied to the analysis.
Participants who are discontinued from the study treatment but receive other neoadjuvant 
treatment not specified by the study prior to surgery will be classified as not having an pCR 
(nonresponders) in the efficacy analyses, regardless of the results obtained from the surgery.  
Participants who are discontinued from study treatment due to reasons that preclude surgery 
are considered nonresponders. 
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Summary of Primary Analysis Approach for Key Efficacy Endpoints
Table 10 summarizes the primary analysis approach for key efficacy endpoints.
Table 10
Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
(Description, Time Point)
Statistical Method†
Analysis 
Population
Missing Data Approach
Primary 
EFS 
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
Censored at the last disease 
assessment
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
Censored at last known alive 
date
Secondary
mPR rate
Stratified Miettinen and 
Nurminen method with sample 
size weights
ITT
Participants with relevant 
data missing are considered 
nonresponders 
pCR rate
Stratified Miettinen and 
Nurminen method with sample 
size weights
ITT
Participants with relevant 
data missing are considered 
nonresponders 
†Statistical models are described in further detail in the text. For stratified analyses, the stratification factors used for 
randomization (Section 7.3.1– Stratification) will be applied to the analysis.
The strategy to address multiplicity issues with regard to multiple efficacy endpoints, and 
interim analyses is described in Section 10.7 – Interim Analyses and in Section10.8 –
Multiplicity.
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, vital signs, surgical complications, etc.
The analysis of safety results will follow a tiered approach (Table 11). The tiers differ with 
respect to the analyses that will be performed. Adverse events (specific terms as well as 
system organ class terms), surgical complications, and events that meet predefined limits of 
change in laboratory, vital signs, and ECG parameters are either pre-specified as “Tier 1” 
endpoints or will be classified as belonging to “Tier 2” or “Tier 3” based on observed 
proportions of participants with an event. 
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Tier 1 Events
Safety parameters or AEs of special interest (AEOSIs) that are identified a priori constitute 
“Tier 1” safety endpoints that will be subject to inferential testing for statistical significance 
with p -values and 95% CIs provided for between-group comparisons. AEOSIs that are 
immune-mediated or potentially immune-mediated are well-documented and will be 
evaluated separately; however, these events have been characterized consistently throughout 
the pembrolizumab clinical development program and determination of statistical 
significance is not expected to add value to the safety evaluation. Based on toxicity data 
across the pembrolizumab program, the combination of pembrolizumab with chemotherapy 
is not anticipated to produce toxicity beyond what is expected for these therapies alone. Thus, 
there are no events of interest that warrant elevation to Tier 1 in this study.  
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events using the unstratified Miettinen and Nurminen 
method (1985) [Miettinen, O. and Nurminen, M. 1985], an unconditional, asymptotic 
method.
Membership in Tier 2 requires that at least 10% of participants in any treatment group exhibit 
the event. The threshold of at least 10% of participants was chosen for Tier 2 event because 
the population enrolled in this study is in critical conditions and usually experiences various 
AEs 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. In addition, Grade 3 to 5 AE 
(≥5% of participants in 1 of the treatment groups) and SAE (≥5% of participants in 1 of the 
treatment groups) will be considered Tier 2 endpoints. Because many 95% CIs may be 
provided without adjustment for multiplicity, the CIs should be regarded as a helpful 
descriptive measure to be used in safety review, not a formal method for assessing the 
statistical significance of the between-group differences.
Tier 3 Events
Safety parameters 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
Continuous measures such as changes from baseline in laboratory, vital signs, and ECG 
parameters that are not pre-specified as Tier 1 endpoints will be considered Tier 3 safety 
parameters. Summary statistics for baseline, on-treatment, and change from baseline values 
will be provided by treatment group in table format.
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Table 11
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Specific AE (≥10% of participants in one of the 
treatment groups) 
X
X
Any Serious AE (≥5% of participants in one of the 
treatment groups)
X
X
Any Grade 3-5 AE (≥5% of participants in one of the 
treatment groups)
X
X
Tier 3
Any AE, surgical complications1
X
Change from Baseline Results (Labs, ECGs, Vital Signs)
X
1 Analyses for perioperative complications are based on the APrS population as defined in Section 10.5.2.
Statistical Methods for PRO Analyses: EORTC QLQ-C30 Global Health 
Status/QoL Score
To assess the treatment effect on the EORTC QLQ-C30 global health status/QoL score, a 
constrained longitudinal data analysis (cLDA) model will be applied, with this PRO score as 
the response variable, and treatment by time interaction as well as stratification factors as 
covariates. The least square mean change from baseline will be summarized.  Treatment 
effect on this PRO score change from baseline will be primarily evaluated in the neoadjuvant 
phase (at last scheduled visit prior to surgery) and adjuvant phase (at approximately 6 months 
following the first dose of adjuvant therapy). 
Details of PRO analyses including the exploratory endpoints will be described in the sSAP.
Summaries of Baseline Characteristics and Demographics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs. No statistical hypothesis tests will be performed on these 
characteristics. The number and percentage of participants randomized, and the primary 
reason for discontinuation will be displayed. Demographic variables (such as age, gender) 
and baseline characteristics will be summarized by treatment either by descriptive statistics 
or categorical tables. The reasons for exclusion from the ITT population (if any) will be 
summarized.
Interim Analyses
Interim Safety Analyses
The DMC will conduct regular safety monitoring. The timing of the safety monitoring will 
be specified in the DMC charter.
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Interim Efficacy Analyses
Four interim efficacy analyses are planned in addition to the final analysis for this study. The 
analyses planned, endpoints evaluated, and drivers of timing are summarized in 
Table 12. The timing of interim analyses may be adjusted if less than 4 months of time or 
more than 12 months of time is predicted to accrue the events required performing the 
analyses. Also, the timing of interim analyses may be altered if events accrue at a 
substantially different rate than anticipated. For IA3 and IA4, if the OS events accrue slower 
than expected, the Sponsor may conduct the analysis with additional 3 months of follow-up, 
or when the specified number of events is observed, whichever occurs first. If the final 
targeted OS events cannot be reached by the end of year 5 after last participant randomized, 
the final OS analysis will be conducted at the end of year 5 after last participant randomized 
at the latest.
Table 12
Summary of Interim and Final Analyses Strategy
Analyses 
Key Endpoints 
Timing
Estimated Time after 
First Participant 
Randomized 
Primary Purpose 
of Analysis
IA1
mPR rate
pCR rate
EFS
OS*
~ 326 EFS events have 
been observed and ~ 5 
months after last 
participant is 
randomized.
~48 months 

Demonstrate mPR
rate superiority

Demonstrate pCR
rate superiority

Interim evaluation 
of EFS superiority

Interim evaluation 
of OS superiority
IA2
EFS
OS*
~ 416 EFS events have 
been observed.
~60 months
Demonstrate EFS
superiority
Interim evaluation of
OS superiority
IA3
OS
~ 285 deaths have been 
observed.
~72 months
Interim evaluation of
OS superiority
IA4
OS
~ 340 deaths have been 
observed.
~84 months
Interim evaluation of
OS superiority
FA
OS
~ 386 deaths have been 
observed.
~96 months 
Demonstrate OS 
superiority
* The estimated observed OS events at IA1 and IA2 are approximately 159 and 225, respectively.  Note that IA1 
and IA2 are EFS event-driven, so there is no OS events count requirement to proceed with these 2 analyses. 
Note that for IA3 and IA4, if the OS events accrue slower than expected, the Sponsor may conduct the analysis 
with additional 3 months of follow-up, or when the specified number of events is observed, whichever occurs 
first. If the final targeted OS events cannot be reached by the end of year 5 after last participant randomized, the 
final OS analysis will be conducted at the end of year 5 after last participant randomized at the latest.
Results of the interim analyses will be reviewed by the DMC. If the EFS or OS null 
hypothesis is rejected prior to the final analysis, the DMC may recommend stopping the trial 
early for efficacy. Details on how the above planned analyses are incorporated into 
establishing Type I error control and efficacy boundaries are discussed further in Section 
10.8 – Multiplicity.
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Multiplicity
The overall Type I error rate is strongly controlled at a 0.025 (one-sided) α level. The trial 
uses the graphical method of Maurer and Bretz [Maurer, W. and Bretz, F. 2013] to provide 
strong multiplicity control for multiple hypotheses as well as interim efficacy analyses; this 
method specifically extends previous graphical multiplicity methods to cases where 
individual hypotheses are tested in a group sequential fashion using an error spending 
approach. Figure 2 shows the initial one-sided α-allocation for each hypothesis in the ellipse 
representing the hypothesis. The initial weights for reallocation from each hypothesis to the 
others are represented in the boxes on the lines connecting hypotheses. This is further 
explained below.
Figure 2
Multiplicity Graph for Type I Error Control
Major Pathological Response Rate
The trial initially allocates α=0.0001, one-sided, to test mPR rate. If the null hypothesis for 
pCR rate is rejected, Figure 2 shows that its α=0.0001 is essentially fully reallocated to mPR 
rate hypothesis testing. Only data from IA1 will be used to test the mPR rate. However, if the 
test does not reach statistical significance at IA1, the p-value from IA1 can be compared to 
an updated α-level if the null hypotheses for both EFS and OS are rejected at a later time. 
Power at the possible α-levels as well as the approximate treatment difference required to 
reach the bound (ΔmPR rate) are shown in Table 13, assuming underlying 22% and 42% 
mPR rates in the control and experimental groups, respectively. 
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Table 13
Possible α-levels and Approximate mPR Rate Difference Required to 
Demonstrate Efficacy for mPR rate
Α
~ΔmPR rate
Power
0.0001
12.38%
0.991
0.0002
11.78%
0.994
0.0249
6.53%
1.000
0.025
6.37%
1.000
Pathological Complete Response Rate
The trial initially allocates α=0.0001, one-sided, to test pCR rate. If the null hypothesis for 
mPR rate is rejected, Figure 2 shows that its α=0.0001 is essentially fully reallocated to pCR 
rate hypothesis testing. Only data from IA1 will be used to test the pCR rate. However, if the 
test does not reach statistical significance at IA1, the p-value from IA1 can be compared to 
an updated α-level if the null hypotheses for EFS, OS and mPR rate are all rejected at a later 
time. Power at the possible α-levels as well as the approximate treatment difference required 
to reach the bound (ΔpCR rate) are shown in Table 14, assuming underlying 8% and 24% 
pCR rates in the control and experimental groups, respectively. 
Table 14
Possible α-levels and Approximate pCR Rate Difference Required to Demonstrate 
Efficacy for pCR rate
Α
~ ΔpCR rate
Power
0.0001
9.73%
0.993
0.0002
9.26%
0.996
0.025
5.13%
1.000
Event-free Survival
The trial initially allocates α=0.01, one-sided to test EFS. If the null hypothesis for OS is 
rejected, Figure 2 shows that its α=0.0148 is essentially fully reallocated to EFS hypothesis 
testing. If the null hypotheses for mPR rate and pCR rate are both rejected, their 
accumulative α=0.0002 is fully reallocated to EFS hypothesis testing. The EFS null 
hypothesis may be tested at α=0.01 (if OS null hypothesis is not rejected, and not both of 
mPR and pCR null hypotheses are rejected), α=0.0102 (if both of mPR and pCR null 
hypotheses are rejected while OS null hypothesis is not), α=0.0248 (if OS null hypothesis is 
rejected while not both of mPR and pCR null hypotheses are rejected), or α=0.025 (if null 
hypotheses for mPR, pCR and OS are all rejected). Table 15 shows the boundary properties 
for α=0.01 and α=0.025 for the planned analysis testing of EFS, which were derived using a 
Lan-DeMets O'Brien-Fleming spending function. Note that the final row indicates the total 
power to reject the null hypothesis for EFS at each α-level. If the actual number of EFS 
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events at the interim analyses differ from those specified in the table, the bounds will be 
adjusted using the Lan-DeMets O'Brien-Fleming spending function accordingly.
Table 15
Efficacy Boundaries and Properties for Planned Analyses of EFS
Analysis
Value
α = 0.01
α=0.025
IA1: 78%*
N: 786
Events: 326
Month+: 48
Z statistics
2.6842
2.2772
p (1-sided)§
0.0036
0.0114
HR at boundǁ
0.7428
0.7770
P (Cross) if HR = 1†
0.0036
0.0114
P (Cross) if HR = 0.7#
0.7045
0.8264
IA2: 
N: 786
Events: 416
Month+: 60
Z statistics
2.3697
2.0207
p (1-sided) §
0.0089
0.0217
HR at boundǁ
0.7925
0.8201
P (Cross) if HR = 1†
0.0100
0.0250
P (Cross) if HR = 0.7#
0.9010
0.9495
*Percentage of total number of required events needed at each interim analysis.
§The nominal α for testing.
ǁThe approximate HR required to reach an efficacy bound.
†The probability of crossing a bound under the null hypothesis.
+The analysis timeline is projected based on blinded clinical data monitoring.
#The probability of crossing a bound under the alternative hypothesis.
Note that if the OS null hypothesis is rejected at an interim or final analysis, the previously 
computed EFS test statistics for the EFS interim or final analyses may be re-evaluated versus 
the updated bounds considering the α reallocation from the OS hypothesis.
Overall Survival
The OS hypothesis may be tested at α=0.0148 (if EFS null hypothesis is not rejected, and not 
both of mPR and pCR null hypotheses are rejected), α=0.0248 (if EFS null hypothesis is 
rejected while not both of mPR and pCR null hypotheses are rejected), or α=0.025 (if null 
hypotheses for mPR, pCR and EFS are all rejected). Table 16, analogous to the EFS table 
above, shows the boundary properties for OS hypothesis testing, which were derived using a 
Lan-DeMets O'Brien-Fleming spending function. If the actual number of OS events at the 
interim analyses differs from those specified in the table, the bounds will be adjusted using 
the Lan-DeMets O'Brien-Fleming spending function accordingly. Note that if the OS event 
accumulation is much slower than expected and the final targeted OS events cannot be 
reached by the end of year 5 after last participant randomized, the final OS analysis will be 
conducted at the end of year 5 after last participant randomized at the latest. In this situation, 
all of the remaining available alpha by then will be used in the final OS analysis.
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Table 16
Efficacy Boundaries and Properties for Planned Analyses of OS
Analysis
Value
α=0.0148
α=0.025
IA1: 41%*
Events: 159
Month+: 48
Z statistics
3.6216
3.3023
p(1-sided) §
0.0001
0.0005
HR at boundǁ
0.5630
0.5922
P(Cross) if HR = 1†
0.0001
0.0005
P(Cross) if HR = 0.7#
0.0849
0.1458
IA2: 58%*
Events: 225
Month+: 60
Z statistics
2.9968
2.7292
p(1-sided) §
0.0014
0.0032
HR at boundǁ
0.6706
0.6949
P(Cross) if HR = 1†
0.0014
0.0033
P(Cross) if HR = 0.7#
0.3759
0.4809
IA3: 74%*
Events: 285
Month+: 72
Z statistics
2.6433
2.4075
p(1-sided) §
0.0041
0.0080
HR at boundǁ
0.7310
0.7518
P(Cross) if HR = 1†
0.0046
0.0091
P(Cross) if HR = 0.7#
0.6496
0.7334
IA4: 88%*
Events: 340
Month+: 84
Z statistics
2.4109
2.1965
p(1-sided) §
0.0080
0.0140
HR at boundǁ
0.7699
0.7880
P(Cross) if HR = 1†
0.0094
0.0169
P(Cross) if HR = 0.7#
0.8183
0.8703
FA: 
Events: 386
Month+: 96
Z statistics
2.2666
2.0666
p(1-sided) §
0.0117
0.0194
HR at boundǁ
0.7939
0.8103
P(Cross) if HR = 1†
0.0148
0.0250
P(Cross) if HR = 0.7#
0.9004
0.9318
*Percentage of total number of required events needed at each interim analysis.
§The nominal α for testing.
ǁThe approximate HR required to reach an efficacy bound.
†The probability of crossing a bound under the null hypothesis.
+The analysis timeline is projected based on blinded clinical data monitoring.
#The probability of crossing a bound under the alternative hypothesis.
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Safety Analyses
The DMC has responsibility for assessment of overall risk:benefit. When prompted by safety 
concerns, the DMC can request corresponding efficacy data. DMC review of efficacy data to 
assess the overall risk:benefit to trial participants will not require a multiplicity adjustment 
typically associated with a planned efficacy interim analysis. However, to account for any 
multiplicity concerns raised by the DMC review of unplanned efficacy data prompted by 
safety concerns, a sensitivity analysis for EFS and OS adopting a conservative multiplicity 
adjustment will be pre-specified in the sSAP. This analysis will be performed if requested by 
the DMC. 
Sample Size and Power Calculations
Sample Size and Power for Efficacy Analyses
The study is event-driven, and approximately 786 participants will be randomized in a 1:1 
ratio into the pembrolizumab plus chemotherapy arm and the placebo plus chemotherapy
arm.
For EFS, based on a target number of ~416 events at IA2 (ie, FA for EFS), the study has 
power of 90.1% to detect a hazard ratio of 0.7 at α=0.01.  Power is increased to 94.9% at 
α=0.025. For OS, based on a target number of ~ 386 deaths at FA, the study has power of 
90% (α=0.0148) or 93.2% (α=0.025) to detect a hazard ratio of 0.7. The sample size and 
power calculation for EFS and OS are based on the following assumptions: 

EFS follows an exponential distribution with a median of 21 months for the control 
group and 30 months for the experimental group.

OS follows an exponential distribution with a median of 34 months for the control 
group and 48.6 months for the experimental group.

The hazard ratio for EFS and OS between the experimental and control groups is 0.7.

The enrollment period is 36 months with a ramp up period of 6 months.

The monthly drop-out rate is 1% for both EFS and OS.
Based on the 786 participants, there is 99.1% power to detect a difference in mPR rates at the 
allocated α=0.0001 assuming an underlying 22% mPR rate in the control group and 42% in 
the experimental group. There is 99.3% power to detect a difference in pCR rates at the 
allocated α=0.0001 assuming an underlying 8% pCR rate in the control group and 24% in the 
experimental group.
The sample size and power calculations were performed in EAST and R (Package 
“gsDesign”).
Sample Size and Power for Safety Analyses
For safety comparisons, risk differences between any 2 treatment groups are summarized in 
Table 17 for a variety of hypothetical observed incidence rates. The table demonstrates the 
width of the corresponding 95% confidence intervals for different incidence rates in the 
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treatment groups. These calculations assume there are 393 participants for each treatment 
group.
Table 17
Two-sided 95% Confidence Intervals of Differences in Incidence of AE Rates 
Between the Two Treatment Groups for 393 Participants in Each Treatment Arm
Incidence of Adverse Event
Risk Difference
Treatment Group A (%)
Treatment Group B (%)
Percentage Points
95% CI†
5
15
-10
(-14.2, -5.8)
15
25
-10
(-15.8,-4.6)
25
35
-10
(-16.3,-3.5)
45
55
-10
(-17.1, -3.2)
55
65
-10
(-16.7, -3.1)
Incidences presented here are hypothetical and do not represent actual adverse experiences in either group.
† Based on an asymptotic method [Farrington, C. P. and Manning, G. 1990].
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
between-group treatment effect (with a nominal 95% CI) for the primary endpoint will be 
estimated and plotted by treatment group within each category of the following classification 
variables:

Tumor stage (II, III)

TPS (<50%, ≥50%)

Histology (squamous, nonsquamous)

Geographic region (East Asia, non-East Asia)

Age category (<65, ≥65 years)

Sex (female, male)

Race (white, non-white)

Smoking status (never, former, current)

Known EGFR activating mutation status (Yes, No)

ALK translocation status (Yes, No)
The consistency of the treatment effect will be assessed descriptively via summary statistics 
by category for the classification variables listed above.
Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study. Any deviation 
from protocol-directed administration will be reported.
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Extent of Exposure
Extent of exposure for a participant is defined as number of cycles in which the participant 
receives the study medication infusion. Summary statistics will be provided on extent of 
exposure for the APaT population.
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]
[Brunelli, A., et al 2013]
Brunelli A, Kim AW, Berger KI, Addrizzo-Harris 
DJ. Physiologic evaluation of the patient with 
lung cancer being considered for resectional 
surgery: Diagnosis and management of lung 
cancer, 3rd ed: American College of Chest 
Physicians evidence-based clinical practice 
guidelines. Chest. 2013 May;143(5 
Suppl):e166S-e190S.
[04QP9W]
[Chaft, J. E., et al 2016]
Chaft JE, Dunphy M, Naidoo J, Travis WD, 
Hellmann M, Woo K, et al. Adaptive neoadjuvant 
chemotherapy guided by (18)F-FDG PET in 
resectable non-small cell lung cancers: The 
NEOSCAN Trial. J Thorac Oncol. 2016 
Apr;11(4):537-44.
[04Q3NC]
[Chaft, J. E., et al 2017]
Chaft JE, Forde PM, Smith KN, Anagnostou V, 
Cottrell T, Taube JM. et al. E1505: Neoadjuvant 
nivolumab in early-stage, resectable non-small 
cell lung cancers. [abstract]. Abstracts of the 2017 
ASCO Annual Meeting; 2017 Jun 2 - 6; Chicago, 
IL: ASCO; 2017. P. 2.
[04Q3F3]
[Chansky, K., et al 2017]
Chansky K, Detterbeck FC, Nicholson AG, 
Rusch VW, Vallieres E, Groome P, et al. The 
IASLC Lung Cancer Staging Project: external 
validation of the revision of the TNM stage 
groupings in the eighth edition of the TNM 
classification of lung cancer. J Thorac Oncol. 
2017 Jul;12(7):1109-21.
[057MBQ]
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[Chew, V., et al 2010]
Chew V, Tow C, Teo M, Wong HL, Chan J, 
Gehring A, et al. Inflammatory tumor 
microenvironment is associated with superior 
survival in hepatocellular carcinoma patients. J 
Hepatol 2010;52:370-9.
[00VMQK]
[Detterbeck, F. 2008]
Detterbeck F. What to do with "Surprise" N2?: 
intraoperative management of patients with non-
small cell lung cancer. J Thorac Oncol. 2008 
Mar;3(3):289-302.
[04Q3F6]
[Disis, M. L. 2010]
Disis ML. Immune regulation of cancer. J Clin 
Oncol 2010;28(29):4531-8.
[058SQL]
[Dudley, M. E., et al 2005]
Dudley ME, Wunderlich JR, Yang JC, Sherry 
RM, Topalian SL, Restifo NP, et al. Adoptive cell 
transfer therapy following non-myeloablative but 
lymphodepleting chemotherapy for the treatment 
of patients with refractory metastatic melanoma. J 
Clin Oncol 2005;23(10):2346-57.
[00VMPR]
[Farrington, C. P. and 
Manning, G. 1990]
Farrington CP, Manning G. Test statistics and 
sample size formulae for comparative binomial 
trials with null hypothesis of non-zero risk 
difference or non-unity relative risk. Stat Med 
1990;9:1447-54.
[03QK0P]
[Garon, E. B., et al 2015]
Garon EB, Rizvi NA, Hui R, Leighl N, 
Balmanoukian AS, Eder JP, et al. Pembrolizumab 
for the treatment of non-small-cell lung cancer. N 
Engl J Med. 2015 May 21;372(21):2018-28.
[045H0L]
[Greenwald, R. J., et al 
2005]
Greenwald RJ, Freeman GJ, Sharpe AH. The B7 
family revisited. Annu Rev Immunol 
2005;23:515-48.
[00VMQL]
[Hamid, Omid, et al 2013]
Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, 
Kefford R, et al. Safety and Tumor Responses 
with Lambrolizumab (Anti-PD-1) in Melanoma. 
N Engl J Med 2013;369(2):134-44.
[03N3VT]
[Hellmann, M. D. 2014]
Hellmann MD, Chaft JE, William WN Jr, Rusch 
V, Pisters KM, Kalhor N, et al. Pathological 
response after neoadjuvant chemotherapy in 
resectable non-small-cell lung cancers: proposal 
for the use of major pathological response as a 
surrogate endpoint. Lancet Oncol. 2014 
Jan;15(1):e42-50.
[04NY27]
0869J0
089P9J
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128
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Confidential
[Hellmann, M. D., et al 
2014]
Hellmann MD, Chaft JE, William WN Jr, Rusch 
V, Pisters KM, Kalhor N, et al. Pathological 
response after neoadjuvant chemotherapy in 
resectable non-small-cell lung cancers: proposal 
for the use of major pathological response as a 
surrogate endpoint. Lancet Oncol. 2014 
Jan;15(1):e42-50.
[04LK2F]
[Hunder, N. N., et al 2008]
Hunder NN, Wallen H, Cao J, Hendricks DW, 
Reilly JZ, Rodmyre R, et al. Treatment of 
metastatic melanoma with autologous CD4+ T 
cells against NY-ESO-1. N Engl J Med 
2008;358(25):2698-703.
[00VMPX]
[Junker, K., et al 2001]
Junker K, Langner K, Klinke F, Bosse U, Thomas 
M. Grading of tumor regression in non-small cell 
lung cancer : morphology and prognosis. Chest. 
2001 Nov;120(5):1584-91.
[04PZ4K]
[Kassis, E. S. 2008]
Kassis ES, Vaporciyan AA. Defining N2 disease 
in non-small cell lung cancer. Thorac Surg Clin. 
2008 Nov;18(4):333-7.
[04Q3DZ]
[Langer, C. J., et al 2016]
Langer CJ, Gadgeel SM, Borghaei H, 
Papadimitrakopoulou VA, Patnaik A, Powell SF, 
et al. Carboplatin and pemetrexed with or without 
pembrolizumab for advanced, non-squamous 
non-small-cell lung cancer: a randomised, phase 2 
cohort of the open-label KEYNOTE-021 study. 
Lancet Oncol. 2016 Oct 9. [Epub ahead of print].
[04JNLW]
[Leffers, N., et al 2009]
Leffers N, Gooden MJM, de Jong RA, 
Hoogeboom B-N, ten Hoor KA, Hollema H, et al. 
Prognostic significance of tumor-infiltrating T-
lymphocytes in primary and metastatic lesions of 
advanced stage ovarian cancer. Cancer Immunol 
Immunother 2009;58(3):449-59.
[00VMQ3]
[Liotta, F., et al 2011]
Liotta F, Gacci M, Frosali F, Querci V, Vittori G, 
Lapini A, et al. Frequency of regulatory T cells in 
peripheral blood and in tumour-infiltrating 
lymphocytes correlates with poor prognosis in 
renal cell carcinoma. BJU Int 2011;107(9):1500-
6.
[00VMQM
]
[Maurer, W. and Bretz, F. 
2013]
Maurer W and Bretz F. Multiple testing in group 
sequential trials using graphical approaches. Stat 
Biopharm Res 2013;5(4):311-20.
[03XQVB]
0869J0
089P9J
08JZLF

Product:  MK-3475 
129
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MK-3475-671-11 Final Protocol
29-Nov-2022
Confidential
[Miettinen, O. and 
Nurminen, M. 1985]
Miettinen O and Nurminen M. Comparative 
analysis of two rates. Stat Med 1985;4:213-26.
[00QHZT]
[Mouillet, G., et al 2012]
Mouillet G, Monnet E, Milleron B, Puyraveau M, 
Quoix E, David P, et al. Pathologic complete 
response to preoperative chemotherapy predicts 
cure in early-stage non-small-cell lung cancer: 
combined analysis of two IFCT randomized 
trials. J Thorac Oncol. 2012 May;7(5):841-9.
[04PX5K]
[Nanda, R., et al 2017]
Nanda R, Liu MC, Yau C, Asare S, Hylton N, 
Veer LV. Et al. Pembrolizumab plus standard 
neoadjuvant therapy for high-risk breast cancer 
(BC): Results from I-SPY 2. [abstract]. Abstracts 
of the 2017 ASCO Annual Meeting; 2017 Jun 2 -
6; Chicago, IL: ASCO; 2017. P. 2.
[04Q3F4]
[National Comprehensive 
Cancer Network 2017]
National Comprehensive Cancer Network 
(NCCN). Clinical Practice Guidelines in 
Oncology: Non-small cell lung cancer: version 
5.2017. Fort Washington, PA: NCCN; 2017.
[04PX5S]
[Nishimura, H., et al 2000]
Nishimura H, Honjo T, Minato N. Facilitation of 
beta selection and modification of positive 
selection in the thymus of PD-1-deficient mice. J 
Exp Med. 2000 Mar 6;191(5):891-8.
[00VMQ4]
[Nobili, C., et al 2008]
Nobili C, Degrate L, Caprotti R, Franciosi C, 
Leone BE, Trezzi R, et al. Prolonged survival of a 
patient affected by pancreatic adenocarcinoma 
with massive lymphocyte and dendritic cell 
infiltration after interleukin-2 immunotherapy. 
Report of a case. Tumori 2008;94(3):426-30.
[00VMP9]
[Okazaki, T., et al 2001]
Okazaki T, Maeda A, Nishimura H, Kurosaki T, 
Honjo T. PD-1 immunoreceptor inhibits B cell 
receptor-mediated signaling by recruiting src 
homology 2-domain-containing tyrosine 
phosphatase 2 to phosphotyrosine. Proc Natl 
Acad Sci U S A 2001;98(24):13866-71.
[00VMQ6]
[Peters, S., et al 2012]
Peters S, Adjei AA, Gridelli C, Reck M, Kerr K, 
Felip E, et al. Metastatic non-small-cell lung 
cancer (NSCLC): ESMO Clinical Practice 
Guidelines for diagnosis, treatment and follow-
up. Annals Oncol 2012;23(Supplement 7):vii56-
vii64.
[03NFH6]
0869J0
089P9J
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130
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MK-3475-671-11 Final Protocol
29-Nov-2022
Confidential
[Pickard, A. S., et al 2007]
Pickard AS, Neary MP, Cella D. Estimation of 
minimally important differences in EQ-5D utility 
and VAS scores in cancer. Health Qual Life 
Outcomes 2007;5:1-8.
[00W0FM]
[Pignon, J. P., et al 2008]
Pignon JP, Tribodet H, Scagliotti GV, Douillard 
JY, Shepherd FA, Stephens RJ, et al. Lung 
adjuvant cisplatin evaluation: a pooled analysis 
by the LACE Collaborative Group. J Clin Oncol. 
2008 Jul 20;26(21):3552-9.
[040JV3]
[Pölcher, M., et al 2010]
Pölcher M, Braun M, Friedrichs N, Rudlowski C, 
Bercht E, Fimmers R, et al. Foxp3(+) cell 
infiltration and granzyme B(+)/Foxp3(+) cell 
ratio are associated with outcome in neoadjuvant 
chemotherapy-treated ovarian carcinoma. Cancer 
Immunol Immunother 2010;59(6):909-19.
[00VMQ8]
[Rabin, R. and de Charro, 
F. 2001]
Rabin R, de Charro F. EQ-5D: a measure of 
health status from the EuroQol group. Ann Med 
2001;33:337-43.
[03QM46]
[Ropponen, K. M., et al 
1997]
Ropponen KM, Eskelinen MJ, Lipponen PK, 
Alhava E, Kosma V-M. Prognostic value of 
tumour-infiltrating lymphocytes (TILs) in 
colorectal cancer. J Pathol 1997;182(3):318-24.
[00VMQT]
[Sandler, A. B., et al 2000]
Sandler AB, Nemunaitis J, Denham C, von Pawel 
J, Cormier Y, Gatzemeier U, et al. Phase III Trial 
of Gemcitabine Plus Cisplatin Versus Cisplatin 
Alone in Patients With Locally Advanced or 
Metastatic Non-Small-Cell Lung Cancer. J Clin 
Oncol 2000;18(1):122-30.
[03NFHC]
[Sasaki, A., et al 2008]
Sasaki A, Tanaka F, Mimori K, Inoue H, Kai S, 
Shibata K, et al. Prognostic value of tumor-
infiltrating FOXP3+ regulatory T cells in patients 
with hepatocellular carcinoma. EJSO 
2008;34:173-9.
[00VMPF]
[Scagliotti, G. V., et al 
2008]
Scagliotti GV, Parikh P, von Pawel J, Biesma B, 
Vansteenkiste J, Manegold C, et al. Phase III 
study comparing cisplatin plus gemcitabine with 
cisplatin plus pemetrexed in chemotherapy-naive 
patients with advanced-stage non-small-cell lung 
cancer. J Clin Oncol 2008;26(21):3543-51.
[00VSVP]
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[Scagliotti, G. V., et al 
2008]
Scagliotti GV, Parikh P, von Pawel J, Biesma B, 
Vansteenkiste J, Manegold C. et al. Phase III 
study comparing cisplatin plus gemcitabine with 
cisplatin plus pemetrexed in chemotherapy-naive 
patients with advanced-stage non-small-cell lung 
cancer. J Clin Oncol. 2008 Jul 20;26(21):3543-
51.
[04Q3DV]
[Scagliotti, G. V., et al 
2012]
Scagliotti GV, Pastorino U, Vansteenkiste JF, 
Spaggiari L, Facciolo F, Orlowski TM. Et al. 
Randomized phase III study of surgery alone or 
surgery plus preoperative cisplatin and 
gemcitabine in stages IB to IIIA non-small-cell 
lung cancer. J Clin Oncol. 2012 Jan 10;30(2):172-
8.
[04Q3DX]
[Scagliotti, G. V., et al 
2012]
Scagliotti GV, Pastorino U, Vansteenkiste JF, 
Spaggiari L, Facciolo F, Orlowski TM, et al. 
Randomized phase III study of surgery alone or 
surgery plus preoperative cisplatin and 
gemcitabine in stages IB to IIIA non-small-cell 
lung cancer. J Clin Oncol. 2012 Jan 10;30(2):172-
8.
[04NY35]
[Shen, Z., et al 2010]
Shen Z, Zhou S, Wang Y, Li R, Zhong C, Liang 
C, et al. Higher intratumoral infiltrated Foxp3+ 
Treg numbers and Foxp3+/CD8+ ratio are 
associated with adverse prognosis in resectable 
gastric cancer. J Cancer Res Clin Oncol 
2010;136:1585-95.
[00VMPG]
[Spaggiari, L., et al 2016]
Spaggiari L, Casiraghi M, Guarize J, Brambilla 
D, Petrella F, Maisonneuve P, et al. Outcome of 
Patients With pN2 "Potentially Resectable" 
Nonsmall Cell Lung Cancer Who Underwent 
Surgery After Induction Chemotherapy. Semin 
Thorac Cardiovasc Surg. 2016 
Summer;28(2):593-602.
[04NY3S]
[Suzuki, H., et al 2010]
Suzuki H, Chikazawa N, Tasaka T, Wada J, 
Yamasaki A, Kitaura Y, et al. Intratumoral CD8+ 
T/FOXP3+ cell ratio is a predictive marker for 
survival in patients with colorectal cancer. Cancer 
Immunol Immunother 2010;59:653-61.
[00VMQD]
[Talmadge, J. E., et al 
2007]
Talmadge JE, Donkor M, Scholar E. 
Inflammatory cell infiltration of tumors: Jekyll or 
Hyde. Cancer Metastasis Rev 2007;26(3-4):373-
400.
[00VMPH]
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[Torre, L. A., et al 2015]
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-
Tieulent J, Jemal A. Global cancer statistics, 
2012. CA Cancer J Clin. 2015 Mar;65(2):87-108.
[043HKG]
[Usubütün, A., et al 1998]
Usubütün A, Ayhan A, Uygur MC, Özen H, 
Toklu C, Ruacan S. Prognostic factors in renal 
cell carcinoma. J Exp Clin Cancer Res 
1998;17(1):77-81.
[00VMPJ]
[van Meerbeeck, J. P., et al 
2007]
van Meerbeeck JP, Kramer GW, Van Schil PE, 
Legrand C, Smit EF, Schramel F, et al. 
Randomized controlled trial of resection versus 
radiotherapy after induction chemotherapy in 
stage IIIA-N2 non-small-cell lung cancer. J Natl 
Cancer Inst. 2007 Mar 21;99(6):442-50.
[04Q3NF]
[Van Zandwijk, N., et al 
2000]
Van Zandwijk N, Smit EF, Kramer GW, 
Schramel F, Gans S, Festen J, et al. Gemcitabine 
and cisplatin as induction regimen for patients 
with biopsy-proven stage IIIA N2 non-small-cell 
lung cancer: a phase II study of the European 
Organization for Research and Treatment of 
Cancer Lung Cancer Cooperative Group (EORTC 
08955). J Clin Oncol. 2000 Jul;18(14):2658-64.
[04Q3N8]
[Wakelee, H. A., et al 
2016]
Wakelee HA, Dahlberg SE, Keller SM, Tester 
WJ, Gandara WR, Graziano SL.et al. E1505: 
Adjuvant chemotherapy +/- bevacizumab for 
early stage NSCLC-outcomes based on 
chemotherapy subsets. [abstract]. Abstracts of the 
2016 ASCO Annual Meeting; 2016 Jun 3 - 7; 
Chicago, IL: ASCO; 2016. P. 2.
[04Q3F2]
[Zatloukal, Petr, et al 2003]
Zatloukal P, Petruzelka L, Zemanova M, Kolek 
V, Skrickova J, Pesek M, et al. Gemcitabine plus 
cisplatin vs. gemcitabine plus carboplatin in stage 
IIIb and IV non-small cell lung cancer: a phase III 
randomized trial. Lung Cancer 2003;41(3):321-
31.
[03NFHG]
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12. Appendices
Appendix 1: Study Governance Considerations
MSD Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I.
Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted in 
compliance with local and/or national regulations (including all applicable data protection laws and regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or which 
are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the full control 
of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial.
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease-related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities and 
staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, sites are 
evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to successfully conduct 
the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts to 
raise awareness of clinical trial opportunities in various communities. MSD will seek to engage underrepresented 
groups and those disproportionately impacted by the disease under study. MSD will support clinical trial 
investigators to enroll underrepresented groups and expand access to those who will ultimately use the products 
under investigation.
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 
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reported, such matters are investigated. When necessary, appropriate corrective and/or preventative actions are 
defined and regulatory authorities and/or ethics review committees are notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the extent 
scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important to patients, 
physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather than 
hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be underpowered 
and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named authors 
must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority acceptance/authorization 
prior to implementation of the trial or amendment, in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance with 
local and/or national regulations. Changes to the protocol that are required urgently to eliminate an immediate hazard 
and to protect participant safety may be enacted in anticipation of ethics committee approval. MSD will inform 
regulatory authorities of such new measures to protect participant safety, in compliance with local and/or national 
regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a 
minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is obtained. 
Participants may withdraw from an MSD trial at any time, without any influence on their access to, or receipt of, 
medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all applicable 
data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on behalf of 
MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records that might 
identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an ethics 
committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to enroll 
participants in its trials. However, when enrollment is particularly challenging, additional payments may be made to 
compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent on 
chart review and medical evaluation to identify potentially eligible participants.
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B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may wish to 
alter the wording of the disclosure statement to be consistent with financial practices at that institution. As noted 
above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
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
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. 
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 institutional review board, ethics review committee (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 trial will be considered confidential by the investigator, 
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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 trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the participant 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form 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 trial 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 trial.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH-GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Committees Structure
Trial Steering Committee
This trial will be conducted in consultation with a Trial Steering Committee.  The Trial 
Steering Committee comprises:

Sponsor personnel 

Investigators participating in the trial 

Consulting therapeutic-area experts and clinical trialists 
The Trial Steering Committee will provide guidance on the operational aspects of the trial.  
Specific details regarding responsibilities and governance of the Trial Steering 
Committee will be described in a separate charter.
Executive Oversight Committee
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management.  The EOC will receive and decide upon any recommendations made by the 
Data Monitoring Committee (DMC) or Trial Steering Committee regarding the study.
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (DMC) will monitor the interim data from this trial.  The voting 
members of the committee are external to the Sponsor.  The members of the DMC must not 
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be involved with the trial in any other way (eg, they cannot be trial investigators) and must 
have no competing interests that could affect their roles with respect to the trial. 
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the trial.  Also, the DMC will review interim trial 
results, consider the overall risk and benefit to trial participants (see Section 10.7 - Interim 
Analyses) and recommend to the EOC if the trial should continue in accordance with the 
protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the KN671 team; meeting facilitation; the 
trial 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 Trial 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 trial is solely responsible for determining whether the trial 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 trial, 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 trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.  
By signing this protocol, the investigator acknowledges that the statutory obligations under 
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 trial or its results to those 
registries.
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Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (eg, International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use Good Clinical Practice: Consolidated 
Guideline and other generally accepted standards of Good Clinical Practice); and all
applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the MSD 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 trial 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
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 trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
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. 
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
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requested by the Sponsor or regulatory authority as a result of an audit or inspection to cure 
deficiencies in the trial documentation and worksheets/case report forms.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
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 participant’s 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 trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
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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 trial as outlined in Section 9.9 – Future 
Biomedical Research Sample Collection will be used in various experiments to 
understand:

The biology of how drugs/vaccines work

Biomarkers responsible for how a drug/vaccine enters and is removed by the body

Other pathways drugs/vaccines may interact with

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 trial will be considered for enrollment in the 
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 
trial 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 
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the SoA.  If delayed, present consent at next possible Participant Visit.  Consent 
forms signed by the participant will be kept at the clinical trial site under secure 
storage for regulatory reasons.  
A template of each trial 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 electronic Case Report Forms (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 trial purposes.
4. Confidential Participant Information for Future Biomedical Research3,4
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing participant 
characteristics like 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 trial 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 trial 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 
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withdraw consent at any time by contacting the principal investigator for the main trial. If 
medical records for the main trial are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@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 trial data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main trial are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the 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 trial 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 
trial, the trial 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 trial 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 trials 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: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA AND SAMPLE CODING CATEGORIES - E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
3. Industry Pharmacogenomics Working Group. 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. Pharmacogenomics Informational 
Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
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Appendix 3: Contraceptive Guidance
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:

Premenarchal

Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
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Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.

Progestogen-only subdermal contraceptive implantb,c

IUSc

Non-hormonal IUD

Bilateral tubal occlusion

Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner 
of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review 
of the participant’s medical records, medical examination, or medical history interview.
Sexual Abstinence

Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.
a
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited 
to those which inhibit ovulation.
c
IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
- Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
- Male condom with cap, diaphragm, or sponge with spermicide.
- Male and female condom should not be used together (due to risk of failure with friction).
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Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definition of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
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 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, or are 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 treatment administration even though it 
may have been present before the start of the study.
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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 adverse 
event, the AE term should reflect the clinical symptoms or abnormal test result.  An 
overdose without any associated clinical symptoms or abnormal laboratory results is 
reported using the terminology “accidental or intentional overdose without adverse 
effect.”
●
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 
9.3.5 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 9.3.5 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.
A 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.
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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 a serious adverse event.  A pre-existing condition is a clinical condition 
that is diagnosed prior to the use of a 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.
●
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 room 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, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
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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 Adverse Event case 
report forms/worksheets at each examination.
●
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 for Adverse Events 
(CTCAE), version 4. Any adverse event which changes CTCAE grade over the course of 
a given episode will have each change of grade recorded on the adverse event case report 
forms/worksheets.
●
Grade 1: Mild; asymptomatic or mid symptoms; clinical or diagnostic observations 
only; intervention not indicated.
●
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.
●
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation or hospitalization indicated; disabling; limiting self-
care ADL.
●
Grade 4: Life threatening consequences; urgent intervention indicated.
●
Grade 5: Death related to AE.
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Assessment of Causality
●
Did the Sponsor's product cause the adverse event?
●
The determination of the likelihood that the Sponsor's product caused the adverse 
event will be provided by an investigator who is a qualified physician.  The 
investigator’s signed/dated initials on the source document or worksheet that supports 
the causality noted on the AE form, ensures that a medically qualified assessment of 
causality was done.  This initialed document must be retained for the required 
regulatory time frame.  The criteria below are intended as reference guidelines to 
assist the investigator in assessing the likelihood of a relationship between the test 
product and the adverse event based upon the available information
●
The following components are to be used to assess the relationship between the 
Sponsor's product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor's 
product caused the adverse event:
●
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 trials with investigational medicinal 
product)?
●
Likely Cause:  Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors
●
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 trial is a single-dose drug trial); 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 
trial?
●
If yes, did the AE recur or worsen?
●
If yes, this is a positive rechallenge. 
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●
If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or 
permanent disability, or (2) the trial is a single-dose drug trial); or (3) Sponsor's 
product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS 
SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY THE SPONSOR'S PRODUCT, 
OR IF 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 INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS 
COMMITTEE.
●
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 case report forms /worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
●
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.)
●
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
●
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 his/her 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.
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●
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each adverse event causality to the combination regimen or 
to a single agent of the combination.  In general, causality attribution should be assigned 
to the combination regimen (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 adverse event to the single agent.
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 AE, SAE, 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 9.3.1 – Time Period and Frequency for Collecting AE and SAE 
and Other Reportable Safety Event Information 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 electronic data collection 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 electronic data collection 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 electronic data collection 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: ECOG Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(e.g., light housework, office work).
2
In bed < 50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% of 
waking hours.
3
In bed > 50% of the time. Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.:  Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden 
ET, Carbone PP: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin 
Oncol. 1982;5:649-655. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair.
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Appendix 6: Clinical Laboratory Tests

The tests detailed in Table 18 will be performed by the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator, required by local regulations, or as per the approved 
chemotherapy package insert guidelines.
Table 18
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
% Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
PT/INR and aPTT/PTT
Chemistry
Blood Urea 
Nitrogen (BUN)1
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
Bicarbonate or 
Carbon Dioxide2
Chloride
Phosphorous
Creatinine
Sodium
Alanine 
Aminotransferase 
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase (SGPT)
Total Protein
Glucose, nonfasting
Calcium
Alkaline phosphatase
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones

Microscopic examination (if blood or protein is abnormal)

Pregnancy test, as needed for women of childbearing potential (WOCBP) during 
screening and and/or within 24 hours of first dose (neoadjuvant and adjuvant 
treatment phases)
Other Tests

Serology: HIV antibody, hepatitis B surface antigen (HBsAg), and hepatitis C virus 
antibody, if mandated by local health authority

Thyroid panel: TSH, T3/FT3, and T4/FT4
1. Urea sample will be analyzed if the site cannot perform BUN.
2. If this test is not done as part of local standard of care, this test does not need to be performed.
Investigators must document their review of each laboratory safety report.
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Appendix 7: Country-specific Requirements
Germany-specific Requirements
Section 2.1 Trial Screening Procedures:

HIV, hepatitis B and C screen, and TB testing is required during Screening.

Pancreatic function (amylase and lipase) test is required (within 10 days prior to the 
start of study treatment).  
Section 2.3 Postoperative (Adjuvant Treatment): Pancreatic function (amylase and lipase) 
test is required.
Section 2.4 End of Treatment and Follow-up Visits (Arm A and B):

Pancreatic function (amylase and lipase) test is required as clinically indicated.
Section 6.1 Inclusion Criteria 

Inclusion Criterion # 9: Amylase and lipase ≤1.5 ULN is required for inclusion.
Section 6.2 Exclusion Criteria

Exclusion Criterion #9: HIV testing is required.

Exclusion Criterion #10: Hepatitis B and hepatitis C testing is required.

Exclusion Criterion #11: TB testing is required.
Section 12.6 Appendix 6: Clinical Laboratory Tests

TB testing is required.

Amylase and lipase tests are required.
China-specific Requirements
Biomarker sample collection, testing, and analysis as described in the following sections will 
be dependent on approval by the Human Genetic Resources Administration of China for 
participants enrolled in China:
Section 2 Schedule of Activities
Section 5.4.1.4 Planned Exploratory Biomarker Research
Section 6 Study Population
Section 9.8 Biomarkers
Future Biomedical Research will not be conducted in China.
Section 5.1 Overall Design
After enrollment of the global study is complete, the study may remain open to enrollment in 
China until the target number of participants in China has been enrolled to meet local 
requirements.
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Section 7.1 Treatments Administered
All study interventions will be administered on an outpatient basis; however, hospitalization 
is acceptable if it is standard procedure for the local site.
Appendix 6 Clinical Laboratory Tests
Routine urinalysis by dipstick: A urine leukocyte is acceptable when the leukocyte esterase 
by dipstick cannot be performed.
Section 2.1 Trial Screening Procedures:
•
EGFR/ALK testing results: In China, results will be collected from participants with 
nonsquamous histology and entered into the EDC collector.
Section 7.1 Treatment Administered
•
Cisplatin unit dose strength is 20mg/vial.
•
Cisplatin and pemetrexed dose formulation are lyophilized powder.
Section 10.5.1 Efficacy Analysis Populations:
•
Participants in China randomized in the extension portion of the study will not be 
included in the above primary efficacy analysis population. The ITT participants in 
China, including all participants in China randomized in the global study and the 
extension portion of the study will be analyzed.
Section 10.5.2 Safety Analysis Populations:
•
The participants in China randomized and treated in the extension portion of the study 
will not be included in the primary safety analysis population. The APaT participants 
in China, including all randomized participants in China (in the global study and 
extension portion of the study) who received at least 1 dose of study treatment, as 
well as the APrS participants in China, including all randomized participants in China 
(in the global study and extension portion of the study) who receive at least 1 dose of 
neoadjuvant study treatment and also undergo on-study surgery, will be analyzed per 
local regulatory requirements.
Japan-specific Requirements
Section 2 Schedule of Activities (footnotes)
•
For the assistance to early diagnosis of pneumonitis/interstitial lung disease in study 
participants, the following items, such as SpO2, CRP, KL-6, and SP-D, will be 
measured in this study. These items should be measured as follows:
SpO2 at the timing of vital sign assessment.
CRP, KL-6, and SP-D at screening*, predose on Day 1 of every cycle, EOT, and the 
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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If pneumonitis/ILD occurs, regardless of causality with study intervention, 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.
Section 7.1 Treatments Administered
Table 2 Study Interventions
Pemetrexed used in this study is categorized as “test product(s)” in Japan.
Intravenous solution, not provided by the Sponsor, as placebo for pembrolizumab in 
this protocol is not categorized as “product(s) used in the clinical trial” in Japan.
Ireland
Section 2.1 Trial Screening Procedures:

HIV, hepatitis B and C screen, and TB testing is required during Screening.
Section 7.7 Concomitant Therapy 
•
Listed below are specific concomitant therapies or vaccinations that are prohibited 
during the study (exceptions noted):
Live vaccines must not be administered for 90 days after the last dose of study 
intervention. Refer to Section 7.7.3 for information on COVID-19 vaccines.
United Kingdom
Section 6.1 Inclusion Criteria - Demographics 
Participants assigned male sex at birth are to be advised to seek counselling on sperm storage 
before starting treatment with pemetrexed, etoposide, and/or platinum-based therapy as per 
respective SmPCs.
Section 7.7 Concomitant Therapy 
•
Listed below are specific concomitant therapies or vaccinations that are prohibited 
during the study (exceptions noted):
Live vaccines must not be administered for 90 days after the last dose of study 
intervention. Refer to Section 7.7.3 for information on COVID-19 vaccines.
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Appendix 8: List of Abbreviations
Abbreviation/Term
Definition
1L
first-line
3X
3 times
AE
adverse event
AEOSI
adverse event of special interest
ACTH
adrenocorticotropic hormone
ADA
anti-drug antibodies
ALT
alanine aminotransferase
ALK
anaplastic lymphoma kinase
APaT
all participants as treated
APrS
all participants receiving surgery
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
β-HCG
beta-human chorionic gonadotropin
BCG
Bacillus Calmette-Guérin
BICR
Blind, independent committee review
BSA
Body Surface Area
CBC
complete blood count
CPET
cardiopulmonary exercise test 
CI
confidence interval
Cmax
serum maximum concentration
CR
complete response
CrCl
calculated creatinine clearance
CRF
case report form
CRP
C-reactive protein
C-Path
Critical Path Institute
CSR
clinical study report
CT
computed tomography
CTCAE
Common Toxicity Criteria for Adverse Events
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DOR
duration of response
ePRO
electronic patient-reported outcome
ECIs
events of clinical interest
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EEA
European Economic Area
EFS
Event-free survival
EGFR
epidermal growth factor receptor
EMA
European Medicines Agency
EOC
Executive Oversight Committee
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Abbreviation/Term
Definition
EOI
end of infusion
EORTC
European Organization for Research and Treatment of Cancer
EORTC-QLQ-C30
European Organization for Research and Treatment of Cancer Quality 
of Life Questionnaire, Core 30
EORTC-QLQ-
LC13
European Organization for Research and Treatment of Cancer Quality 
of Life Questionnaire, Lung Cancer 13
EOT
end of treatment
ERC
Ethics Review Committee
FA
final analysis
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDG-PET
fluorodeoxyglucose-positron emission tomography
FFPE
formalin-fixed paraffin-embedded
FSH
follicle-stimulating hormone
FSR
first site ready
FEV1
forced vital capacity
GCP
Good Clinical Practice
GFR
glomerular filtration rate
Gy
Gray
HCV
hepatitis c virus
HIV
human immunodeficiency virus
HOSP
Hospitalization form
HPRA
Health Products Regulatory Authority
HR
hazard ratio
HRQoL
health-related quality of life
HSU
hospital specialty unit
IA1
interim analysis 1
IA2
interim analysis 2
IA3
interim analysis 3
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
IHC
immunohistochemistry
ILD
interstitial lung disease
INR
international normalized ratio
IC
investigator's choice
IEC
Independent Ethics Committees
IRB
Institutional Review Board
ITT
intent-to-treat
IV
Intravenous
IVRS
interactive voice response system
IWRS
integrated web response system
KL-6
Krebs von den Lungen 6
KN
Keynote
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Abbreviation/Term
Definition
MASCC
Multinational Association of Supportive Care in Cancer
mPR
Major pathological response
MRI
magnetic resonance imaging
MSD K.K.
Merck Sharp & Dohme Kabushiki Kaisya
MSI
microsatellite instability
N2
mediastinal lymph node
NCI
National Cancer Institute
NSCLC
non-small cell lung cancer
NSCLC-SAQ
The Non-small Cell Lung Cancer Symptom Assessment Questionnaire
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
pCR
Pathological complete response
PD
Progressive disease
PD-1
programmed cell death protein-1
PFS
progression-free survival
PK
pharmacokinetic
PD-L1
programmed death-ligand 1
PD-L2
programmed death-ligand 2
PPO
predicted post-operative
PPO DLCO
percent predicted postoperative diffusing capacity for carbon monoxide
PRO
patient-reported outcome
PR
partial response
PS
performance scale
PT
prothrombin time
QLQ-LC13
Quality of Life Questionnaire and Lung Cancer Module 13
QLQ-C30
Quality of Life Questionnaire Core 30
QoL
Quality of life
Q2W
Every 2 weeks
Q3W
Every 3 weeks
Q6W
Every 6 weeks
Q12W
Every 12 weeks
RNA
Ribonucleic acid
RECIST
Response Evaluation Criteria in Solid Tumors Version 1.1
RMST
restricted mean survival time
RR
response rate
RT
radiation therapy
SAE
serious adverse events
SAP
Statistical Analysis Plan
SD
stable disease
SGOT
serum glutamic-oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SOA
schedule of activities
SOC
standard of care
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Abbreviation/Term
Definition
SOP
Standard operating procedure
SP-D
surfactant protein-D
SpO2
peripheral capillary oxygen saturation
sSAP
supplemental Statistical Analysis Plan
TB
Tuberculosis
TPS
tumor proportion score
TSH
Thyroid-stimulating hormone
ULN
upper limit of normal
US
United States
VO2 max
maximal oxygen consumption
WOCBP
Woman of childbearing potential
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Appendix 9: MASCC 2016 Guidelines
Table 19
Recommended Doses of Corticosteroids* (Dexamethasone)
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.
Investigators may use local equivalent or more current guidelines, if available.
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