Conditions: Non-Small Cell Lung Cancer
Keywords: Programmed Cell Death-1 (PD1, PD-1) Programmed Death-Ligand 1 (PDL1, PD-L1) Programmed Cell Death Receptor Ligand 2 (PDL2, PD-L2)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 448
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the efficacy and safety of stereotactic body radiotherapy (SBRT) plus pembrolizumab (MK-3475) in the treatment of adult participants with unresected Stage I or II (Stage IIB N0, M0) non-small cell lung cancer (NSCLC).

The primary study hypothesis is SBRT plus pembrolizumab prolongs Event-free Survival (EFS) compared to SBRT plus placebo (normal saline solution).

Detailed description:
As of protocol amendment 8, the study was stopped due to an interim analysis that did not support the study primary and key secondary endpoints. All study participants stopped ongoing treatment with pembrolizumab/placebo, and must complete end of trial and safety follow-up visits.

Arms:
arm 1: Participants receive SBRT once every 3 days for 3, 4, 5, or 8 fractions (dependent on tumor type/location; 45-70 Gray \[Gy\] total) over approximately 2 weeks PLUS pembrolizumab 200 mg via intravenous (IV) infusion once every 3 weeks for up to 17 cycles (up to approximately 1 year). Each cycle is 21 days. arm 2: Participants receive SBRT once every 3 days for 3, 4, 5, or 8 fractions (dependent on tumor type/location; 45-70 Gy total) over approximately 2 weeks PLUS placebo (normal saline solution) via IV infusion once every 3 weeks for up to 17 cycles (up to approximately 1 year). Each cycle is 21 days.

Interventions: intervention 1: Stereotactic Body Radiotherapy (SBRT) intervention 2: Pembrolizumab intervention 3: Placebo
Intervention descriptions: intervention 1: SBRT will be administered once every 3 days for 3, 4, 5, or 8 fractions (dependent on tumor type/location; 45-70 Gray \[Gy\] total) over approximately 2 weeks. intervention 2: Pembrolizumab will be administered at 200 mg via IV infusion once every 3 weeks for up to 17 cycles (up to approximately 1 year). intervention 3: Placebo (normal saline solution) will be administered at 200 mg via IV infusion once every 3 weeks for up to 17 cycles (up to approximately 1 year).

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 3, Randomized, Placebo-Controlled Clinical Study to Evaluate 
the Safety and Efficacy of Stereotactic Body Radiotherapy (SBRT) with 
or without Pembrolizumab (MK-3475) in Participants with Unresected 
Stage I or II Non-Small Cell Lung Cancer (NSCLC) (KEYNOTE-867)
NCT03924869
11-OCT-2024


PRODUCT: MK-3475
1
PROTOCOL/AMENDMENT NO.: 867-08
MK-3475-867-08 FINAL PROTOCOL
11-OCT-2024
TITLE PAGE
THIS PROTOCOL 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 3, Randomized, Placebo-Controlled Clinical Study to Evaluate the Safety and 
Efficacy of Stereotactic Body Radiotherapy (SBRT) with or without Pembrolizumab (MK-
3475) in Participants with Unresected Stage I or II Non-Small Cell Lung Cancer (NSCLC) 
(KEYNOTE-867)
Protocol Number: 867-08
Compound Number: MK-3475
Sponsor Name: Merck Sharp & Dohme LLC
(hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
NCT
NCT04380636
EU CT
2022-500413-11-00
EudraCT
2018-004320-11
JRCT
JRCT2080224826
WHO
Not applicable
UTN
U1111-1275-8515
IND
116,833
Approval Date: 11 October 2024
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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PROTOCOL/AMENDMENT NO.: 867-08
MK-3475-867-08 FINAL PROTOCOL
11-OCT-2024
DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 8
11-OCT-2024
This change was made to address new data and 
recommendations of the eDMC after an interim 
review of the data; specifically, to stop the study as 
pembrolizumab in combination with SBRT did not 
demonstrate an improvement in event-free survival 
or overall survival, the study’s primary endpoint 
and key secondary endpoint, respectively, 
compared to placebo plus SBRT, and the 
benefit/risk profile of the combination did not 
support continuing the trial. 
Amendment 7
24-APR-2024
Update definitions of disease recurrence and biopsy 
information to capture event-free survival events 
more accurately.
Amendment 6
29-NOV-2023
The primary purpose of this amendment is to 
update the statistical analysis plan based on new 
data from literature.
Amendment 5
07-JUN-2022
Update to include female contraception 
requirements following radiotherapy.
Amendment 4
14-DEC-2021
Update inclusion criteria to include male 
contraception requirements.
Amendment 3
24-AUG-2021
Update inclusion criteria and stratification factors 
from Stage I-IIA to Stage I-II. Also, update SBRT 
regimens to better reflect current global standard of 
care in the study population. To update the dose 
modification and toxicity management guidelines 
for immune-related adverse events (irAEs).
Amendment 2
26-FEB-2021
Update inclusion criteria and stratification factors 
to include patients who are medically operable but 
refuse surgery to the study population.
Amendment 1
16-SEP-2019
Expansion of the available SBRT regimens for 
peripheral tumors.
Original Protocol
14-FEB-2019
Not applicable.
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 08
Overall Rationale for the Amendments:
This change was made to address new data and recommendations of the eDMC after an 
interim review of the data; specifically, to stop the study as pembrolizumab in combination 
with SBRT did not demonstrate an improvement in event-free survival or overall survival, 
the study’s primary endpoint and key secondary endpoint, respectively, compared to placebo 
plus SBRT, and the benefit/risk profile of the combination did not support continuing the 
trial. 
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Primary Reason for Amendment
Section 1.1, Synopsis
Hypotheses, Objectives, and 
Endpoints: Added NOTE to confirm 
that based on the data from an interim 
safety and efficacy analysis, the study 
will be stopped. Safety endpoints 
analyses will be performed at the end 
of the study. No further analyses of 
efficacy and ePRO endpoints will 
occur after the IA1 cutoff date.
Participants who are still on study 
treatment will no longer need to 
provide some samples and 
assessments. Follow-up and Survival 
Follow-up visits will no longer be 
conducted.
This change was made to address new data and 
recommendations of the eDMC after an interim 
review of data.
Section # and Name
Description of Change 
Brief Rationale 
Other Changes in Amendment
Section 1.1, Synopsis
Study Governance Committees: 
Executive Oversight Committee and 
eDMC are no longer applicable.
Refer to Section 1.1 rationale above..
Section 1.3, Schedule of 
Activities (SoA)
Added text that participants who are 
still on study treatment will no longer 
need to provide some samples and 
assessments. Follow-up and Survival 
Follow-up visits will no longer be 
conducted.
Refer to Section 1.1 rationale.
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Section # and Name
Description of Change 
Brief Rationale 
Other Changes in Amendment
Section 2.3, Benefit/Risk 
Assessment
Added NOTE to confirm that based 
on the data from an interim safety and 
efficacy analysis, the study will be 
stopped. Safety endpoints analyses 
will be performed at the end of the 
study. No further analyses of efficacy 
and ePRO endpoints will occur after 
IA1 cutoff date.
Refer to Section 1.1 rationale.
Section 3, HYPOTHESES, 
OBJECTIVES, AND 
ENDPOINTS
Added NOTE to confirm that based 
on the data from an interim safety and 
efficacy analysis, the study will be 
stopped. Safety endpoints analyses 
will be performed at the end of the 
study. No further analyses of efficacy 
and ePRO endpoints will occur after 
IA1 cutoff date. Participants who are 
still on study treatment will no longer 
collect some samples and 
assessments. Follow-up and Survival 
Follow-up visits will no longer be 
conducted.
Refer to Section 1.1 rationale.
Section 4.1, Overall Design
Added NOTE to confirm that based 
on the data from an interim safety and 
efficacy analysis, the study will be 
stopped. Safety endpoints analyses 
will be performed at the end of the 
study. No further analyses of efficacy 
and ePRO endpoints will occur after 
IA1 cutoff date. Participants who are 
still on study treatment will no longer 
collect some samples and 
assessments. Follow-up and Survival 
Follow-up visits will no longer be 
conducted. 
Refer to Section 1.1 rationale.
Added text that early study 
termination as part of participants 
who discontinue.
To align with text in section 8.11.4.1 and 
8.11.4.2.
Section 6.1, Study 
Intervention(s) 
Administered
Added text that participants who are 
still on study treatment will no longer 
collect some samples and 
assessments. Follow-up and Survival 
Follow-up visits will no longer be 
conducted.
Refer to Section 1.1 rationale.
Section 6.3.3, Blinding
Added text that the study was 
unblinded.
Refer to Section 1.1 rationale.
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Section # and Name
Description of Change 
Brief Rationale 
Other Changes in Amendment
Section 7.1, Discontinuation 
of Study Intervention
Added NOTE to confirm that based 
on the data from an interim safety and 
efficacy analysis, the study will be 
stopped. Safety endpoints analyses 
will be performed at the end of the 
study. No further analyses of efficacy 
and ePRO endpoints will occur after 
IA1 cutoff date. Participants who are 
still on study treatment will no longer 
collect some samples and 
assessments. Follow-up and Survival 
Follow-up visits will no longer be 
conducted.
Refer to Section 1.1 rationale.
Section 8.2.1, Tumor 
Imaging and Assessment of 
Disease
Added text that Central tumor 
response assessments will be 
discontinued, and local tumor 
imaging should continue per SOC 
schedule. 
Refer to Section 1.1 rationale.
Section 8.2.1.3, Assessment 
of Disease Recurrence
Added text that Disease recurrence 
assessments will be discontinued.
Refer to Section 1.1 rationale.
Section 8.8, Biomarkers
Text added that Biomarker sample 
collections will be discontinued. 
Refer to Section 1.1 rationale.
Section 9, Statistical 
Analysis Plan
Amended the SAP and added NOTE 
to confirm that based on the data from 
an interim safety and efficacy 
analysis, the study will be stopped. 
Safety endpoints analyses will be 
performed at the end of the study. No 
further analyses of efficacy and ePRO 
endpoints will occur after IA1 cutoff 
date.
Refer to Section 1.1 rationale.
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11-OCT-2024
Section # and Name
Description of Change 
Brief Rationale 
Other Changes in Amendment
Section 9.1, Statistical 
Analysis Plan Summary
Added text that all the prespecified 
interim analyses after IA1 and final 
analysis of the study described in the 
SAP will not be performed. Safety 
analysis will be performed at the end 
of the study; there will be no further 
analyses of efficacy and ePRO 
endpoints collected from participants 
after IA1 cutoff date.
Refer to Section 1.1 rationale.
Interim Analyses: Added text that all 
the prespecified interim analyses after 
IA1 and final analysis of the study 
described in the SAP will not be 
performed.
Refer to Section 1.1 rationale.
Sample Size and Power: Added text 
that all the prespecified interim 
analyses after IA1 and final analysis 
of the study described in the SAP will 
not be performed.
Refer to Section 1.1 rationale.
Section 9.6, Statistical 
Methods
Added text that all the prespecified 
interim analyses after IA1 and final 
analysis of the study described in the 
SAP will not be performed. Safety 
analysis will be performed at the end 
of the study; there will be no further 
analyses of efficacy and ePRO 
endpoints collected from participants 
after IA1 cutoff date.
Refer to Section 1.1 rationale.
Section 9.7, Interim 
Analyses
Added text that all the prespecified 
interim analyses after IA1 and final 
analysis of the study described in the 
SAP will not be performed.
Refer to Section 1.1 rationale.
Section 9.8, Multiplicity
Added text that all the prespecified 
interim analyses after IA1 and final 
analysis of the study described in the 
SAP will not be performed.
Refer to Section 1.1 rationale.
Section 9.9, Sample Size 
and Power Calculations
Added text that all the prespecified 
interim analyses after IA1 and final 
analysis of the study described in the 
SAP will not be performed.
Refer to Section 1.1 rationale.
Section 10.1.1, Code of 
Conduct for Interventional 
Clinical Trials
Expanded MSD. 
To reflect entity name.
Added EU CTR number.
Refer to Section 4.4 rationale for EU CTR.
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PROTOCOL/AMENDMENT NO.: 867-08
MK-3475-867-08 FINAL PROTOCOL
11-OCT-2024
Section # and Name
Description of Change 
Brief Rationale 
Other Changes in Amendment
Section 10.1.3, Data 
Protection
Specified that the Sponsor will 
conduct this study in compliance with 
all applicable data and information of 
EU-approved rules.
Refer to Section 4.4 rationale for EU CTR.
Section 10.1.6, Compliance 
with Study Registration and 
Results Posting 
Requirements
Added EU CTR number and 
corresponding website.
Refer to Section 4.4 rationale for EU CTR.
Section 10.1.7, Compliance 
with Law, Audit, and 
Debarment
Added serious breach reporting 
requirements.
Refer to Section 4.4 rationale for EU CTR.
Section 10.1.8, Data Quality 
Assurance
Added EU CTR requirement 
stipulating 25-year retention period 
after end of study.
Refer to Section 4.4 rationale for EU CTR.
Updated text records and documents, 
including participants documented 
informed consent.
To provide clarity for text records and 
documents. 
Throughout
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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PROTOCOL/AMENDMENT NO.: 867-08
MK-3475-867-08 FINAL PROTOCOL
11-OCT-2024
TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................17
1.1
Synopsis.................................................................................................................17
1.2
Schema ..................................................................................................................24
1.3
Schedule of Activities (SoA)................................................................................25
2
INTRODUCTION..........................................................................................................32
2.1
Study Rationale....................................................................................................33
2.2
Background ..........................................................................................................33
2.2.1
Pharmaceutical and Therapeutic Background .............................................33
2.2.2
Preclinical and Clinical Studies ...................................................................34
2.2.3
Ongoing Clinical Studies.............................................................................34
2.2.4
Information on Other Study-related Therapy: SBRT ..................................34
2.3
Benefit/Risk Assessment......................................................................................35
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................36
4
STUDY DESIGN............................................................................................................39
4.1
Overall Design......................................................................................................39
4.2
Scientific Rationale for Study Design.................................................................41
4.2.1
Rationale for Endpoints ...............................................................................41
4.2.1.1
Efficacy Endpoints.............................................................................41
4.2.1.2
Safety Endpoints................................................................................42
4.2.1.3
Patient-reported Outcomes.................................................................42
4.2.1.3.1
EORTC QLQ-C30 ...................................................................42
4.2.1.3.2
EORTC QLQ-LC13.................................................................42
4.2.1.3.3
EuroQoL EQ-5D......................................................................43
4.2.1.4
Planned Exploratory Biomarker Research.........................................43
4.2.1.5
Future Biomedical Research..............................................................45
4.2.2
Rationale for the Use of Comparator/Placebo .............................................45
4.3
Justification for Dose...........................................................................................45
4.4
Beginning and End-of-Study Definition ............................................................46
4.4.1
Clinical Criteria for Early Study Termination .............................................47
5
STUDY POPULATION ................................................................................................48
5.1
Inclusion Criteria.................................................................................................48
5.2
Exclusion Criteria................................................................................................51
5.3
Lifestyle Considerations......................................................................................53
5.3.1
Meals and Dietary Restrictions....................................................................53
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................53
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5.4
Screen Failures.....................................................................................................53
5.5
Participant Replacement Strategy......................................................................53
6
STUDY INTERVENTION............................................................................................54
6.1
Study Intervention(s) Administered...................................................................54
6.2
Preparation/Handling/Storage/Accountability .................................................57
6.2.1
Dose Preparation..........................................................................................57
6.2.2
Handling, Storage, and Accountability........................................................57
6.3
Measures to Minimize Bias: Randomization and Blinding..............................58
6.3.1
Intervention Assignment..............................................................................58
6.3.2
Stratification.................................................................................................58
6.3.3
Blinding........................................................................................................58
6.4
Study Intervention Compliance..........................................................................58
6.5
Concomitant Therapy..........................................................................................59
6.5.1
Rescue Medications and Supportive Care ...................................................60
6.6
Dose Modification (Escalation/Titration/Other)...............................................61
6.7
Intervention After the End of the Study............................................................67
6.8
Clinical Supplies Disclosure................................................................................67
6.9
Standard Policies..................................................................................................67
6.9.1
Study Site Retention Samples......................................................................67
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................69
7.1
Discontinuation of Study Intervention...............................................................69
7.2
Participant Withdrawal From the Study...........................................................70
7.3
Lost to Follow-up .................................................................................................71
8
STUDY ASSESSMENTS AND PROCEDURES........................................................72
8.1
Administrative and General Procedures ...........................................................72
8.1.1
Informed Consent.........................................................................................72
8.1.1.1
General Informed Consent.................................................................73
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................73
8.1.2
Inclusion/Exclusion Criteria ........................................................................73
8.1.3
Participant Identification Card.....................................................................73
8.1.4
Medical History ...........................................................................................74
8.1.5
Prior and Concomitant Medications Review...............................................74
8.1.5.1
Prior Medications...............................................................................74
8.1.5.2
Concomitant Medications..................................................................75
8.1.6
Assignment of Screening Number...............................................................75
8.1.7
Assignment of Treatment/Randomization Number.....................................75
8.1.8
Study Intervention Administration ..............................................................75
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8.1.8.1
Timing of Dose Administration.........................................................75
8.1.8.1.1
Pembrolizumab or Matching Placebo......................................75
8.1.8.1.2
Stereotactic Body Radiotherapy ..............................................76
8.1.9
Discontinuation and Withdrawal .................................................................76
8.1.9.1
Withdrawal From Future Biomedical Research ................................76
8.1.10
Participant Blinding/Unblinding..................................................................77
8.1.11
Calibration of Equipment.............................................................................77
8.2
Efficacy Assessments ...........................................................................................78
8.2.1
Tumor Imaging and Assessment of Disease................................................78
8.2.1.1
Initial Tumor Scans............................................................................78
8.2.1.2
Tumor Scans During the Study..........................................................79
8.2.1.3
Assessment of Disease Recurrence....................................................79
8.2.1.3.1
Local Disease Recurrence........................................................79
8.2.1.3.2
Regional or Distant Disease Recurrence..................................80
8.2.1.4
Central Verification of Disease Recurrence ......................................80
8.2.1.5
End-of-treatment and Follow-up Tumor Scans .................................81
8.2.2
Patient-reported Outcomes...........................................................................81
8.3
Safety Assessments...............................................................................................82
8.3.1
Physical Examinations.................................................................................82
8.3.1.1
Full Physical Examination.................................................................82
8.3.1.2
Directed Physical Examination..........................................................82
8.3.2
Vital Signs....................................................................................................82
8.3.3
Electrocardiograms ......................................................................................82
8.3.4
Clinical Safety Laboratory Assessments .....................................................83
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis)..........................................................................................83
8.3.4.2
Pregnancy Test...................................................................................83
8.3.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale ...........84
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................84
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................85
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......86
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...87
8.4.4
Regulatory Reporting Requirements for SAE .............................................87
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................87
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................88
8.4.7
Events of Clinical Interest............................................................................88
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8.5
Treatment of Overdose........................................................................................88
8.6
Pharmacokinetics.................................................................................................89
8.7
Pharmacodynamics..............................................................................................89
8.8
Biomarkers ...........................................................................................................89
8.8.1
Planned Genetic Analysis Sample Collection..............................................89
8.9
Future Biomedical Research Sample Collection...............................................89
8.10
Medical Resource Utilization and Health Economics.......................................90
8.11
Visit Requirements...............................................................................................90
8.11.1
Screening......................................................................................................90
8.11.2
Treatment Period Visit.................................................................................90
8.11.3
Discontinued Participants Continuing to be Monitored in the Study ..........91
8.11.4
Posttreatment Visit.......................................................................................91
8.11.4.1
Safety Follow-up Visit.......................................................................91
8.11.4.2
Follow-up Visits.................................................................................91
8.11.4.3
Survival Follow-up ............................................................................91
8.11.5
Vital Status...................................................................................................91
9
STATISTICAL ANALYSIS PLAN .............................................................................92
9.1
Statistical Analysis Plan Summary.....................................................................92
9.2
Responsibility for Analyses/In-house Blinding .................................................94
9.3
Hypothesis/Estimation.........................................................................................94
9.4
Analysis Endpoints...............................................................................................94
9.4.1
Efficacy Endpoints.......................................................................................94
9.4.1.1
Primary Endpoints .............................................................................94
9.4.1.2
Secondary Endpoint...........................................................................95
9.4.1.3
Exploratory Endpoints .......................................................................95
9.4.2
Safety Endpoints..........................................................................................95
9.4.3
PRO Endpoints.............................................................................................96
9.4.4
Other Exploratory Endpoints.......................................................................96
9.5
Analysis Populations............................................................................................96
9.5.1
Efficacy Analysis Populations.....................................................................96
9.5.2
Safety Analysis Populations ........................................................................96
9.5.3
PRO Analysis Population ............................................................................97
9.6
Statistical Methods...............................................................................................97
9.6.1
Statistical Methods for Efficacy Analyses...................................................97
9.6.1.1
Event-free Survival (EFS)..................................................................97
9.6.1.2
Overall Survival.................................................................................98
9.6.1.3
Time to Death or Distant Metastases (TDDM)..................................98
9.6.1.4
Analysis Strategy for Key Efficacy Endpoints..................................99
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9.6.2
Statistical Methods for Safety Analyses ......................................................99
9.6.3
Analysis Methods for PRO Endpoints.......................................................101
9.6.4
Demographic and Baseline Characteristics ...............................................101
9.7
Interim Analyses ................................................................................................102
9.7.1
Efficacy Interim Analyses..........................................................................102
9.8
Multiplicity .........................................................................................................103
9.8.1
Multiplicity Control for Efficacy Interim Analyses...................................104
9.8.1.1
Event-free Survival (EFS)................................................................104
9.8.1.2
Overall Survival...............................................................................105
9.9
Sample Size and Power Calculations ...............................................................106
9.10
Subgroup Analyses.............................................................................................107
9.11
Compliance (Medication Adherence)...............................................................107
9.12
Extent of Exposure.............................................................................................107
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................108
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......108
10.1.1
Code of Conduct for Clinical Trials...........................................................108
10.1.2
Financial Disclosure...................................................................................110
10.1.3
Data Protection...........................................................................................110
10.1.3.1
Confidentiality of Data ....................................................................111
10.1.3.2
Confidentiality of Participant Records.............................................111
10.1.3.3
Confidentiality of IRB/IEC Information..........................................111
10.1.4
Committees Structure.................................................................................111
10.1.4.1
External Data Monitoring Committee .............................................111
10.1.4.2
Executive Oversight Committee......................................................112
10.1.5
Publication Policy......................................................................................112
10.1.6
Compliance with Study Registration and Results Posting Requirements .112
10.1.7
Compliance with Law, Audit, and Debarment ..........................................113
10.1.8
Data Quality Assurance .............................................................................113
10.1.9
Source Documents .....................................................................................114
10.1.10
Study and Site Closure...............................................................................115
10.2
Appendix 2: Clinical Laboratory Tests............................................................116
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................118
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................118
10.3.2
Definition of AE ........................................................................................118
10.3.3
Definition of SAE ......................................................................................119
10.3.4
Additional Events Reported in the Same Manner as SAE.........................120
10.3.5
Recording AE and SAE .............................................................................120
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10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................124
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................125
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................126
10.5.1
Definitions..................................................................................................126
10.5.2
Contraceptive Requirements......................................................................127
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................128
10.7
Appendix 7: Country-specific Requirements..................................................132
10.7.1
Argentina-specific Requirements: .............................................................132
10.7.2
EU Countries-specific Requirements:........................................................132
10.7.3
Germany-specific Requirements:...............................................................132
10.7.4
Japan-specific Requirements: ....................................................................132
10.7.5
South Korea-specific Requirements: .........................................................133
10.7.6
Romania-specific Requirements:...............................................................133
10.7.7
United Kingdom-specific Requirements....................................................133
10.7.8
Italy-specific Requirements .......................................................................133
10.8
Appendix 8: Eastern Cooperative Oncology Group.......................................134
10.9
Appendix 9: NSCLC Staging Definitions ........................................................135
10.10 Appendix 10: Abbreviations .............................................................................136
11
REFERENCES.............................................................................................................141
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LIST OF TABLES
Table 1
Study Schedule of Activities: Pembrolizumab & SBRT Treatment................25
Table 2
Adequate Organ Function Laboratory Values .................................................49
Table 3
Study Interventions..........................................................................................55
Table 4
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ...............................................................62
Table 5
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ........................................................................................................66
Table 6
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................86
Table 7
Censoring Rules for Primary Analysis of EFS ................................................98
Table 8
Efficacy Analysis Methods for Key Efficacy Endpoints.................................99
Table 9
Analysis Strategy for Safety Parameters........................................................101
Table 10
103
Table 11
104
Table 12
105
Table 13
Protocol-required Safety Laboratory Assessments........................................116
CCI
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LIST OF FIGURES
Figure 1
Study Schema...................................................................................................24
Figure 2
.104
Figure 3
Excerpt From AJCC v8 NSCLC Staging Guideline on Appropriate 
Staging of N0 Disease....................................................................................135
Figure 4
Excerpt From AJCC v8 NSCLC Staging Guideline on Primary Tumor 
Sizing Criteria................................................................................................135
CCI
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Randomized, Placebo-Controlled Clinical Study to Evaluate the 
Safety and Efficacy of Stereotactic Body Radiotherapy (SBRT) with or without 
Pembrolizumab (MK-3475) in Participants with Unresected Stage I or II Non-Small Cell 
Lung Cancer (NSCLC) (KEYNOTE-867)
Short Title: Phase 3 study of SBRT ± pembrolizumab for participants with unresected
Stage I or II NSCLC
Acronym: MK-3475-867-08
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
NOTE: Based on the data from an interim safety and efficacy analysis for 
KEYNOTE¬867 (data cutoff 11-JUN-2024), the eDMC recommended stopping the 
study since pembrolizumab in combination with SBRT did not demonstrate an 
improvement in EFS (Event-Free Survival) or OS (Overall Survival), the study’s 
primary endpoint and key secondary endpoint, respectively, compared to placebo plus 
SBRT, and the benefit/risk profile of the combination did not support continuing the 
trial. All prespecified interim analyses after IA1 (Interim Analysis 1) and final analysis 
of the study described in the SAP (Statistical Analysis Plan) will not be performed. 
Safety analysis will be performed at the end of the study; there will be no further pre-
planned analyses for efficacy and ePRO (electronic patient-reported outcome) 
endpoints collected from participants beyond the IA1 cutoff date of 11-JUN-2024.
In alignment with the study update memo sent to Investigators on 29-AUG-2024, all 
study participants must stop ongoing treatment with pembrolizumab/placebo. These 
participants must complete EOT (End of Trial) visit followed by Safety Follow-up visit 
per protocol. All remaining study participants who have completed the safety reporting 
windows for AEs and SAEs per protocol must be discontinued from the study. All study 
participants will undergo unblinding at the end of the study. Investigators may apply 
for unblinding participants per protocol in the interim.
As of Amendment 08, information regarding ePRO assessments (EORTC QLQ-C30, 
EORTC QLQ-LC13, and EuroQoL EQ-5D-5L), biomarker samples (blood for genetic 
analysis, blood for ctDNA analysis, optional tumor sample), biopsies, and tumor 
imaging for BICR (blinded independent central review) will no longer be collected. 
Tumor imaging, biopsies, and disease management should be performed per local SOC 
and Investigator’s discretion. Efficacy data collection, including Follow-up and Survival 
Follow-up visits for efficacy will no longer be conducted. Safety reporting for AEs and 
SAEs must adhere to time windows per protocol. Updated analyses are described in 
Section 9.
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All objectives will compare administration of SBRT + pembrolizumab versus SBRT + 
placebo, unless otherwise indicated.
In male and female participants who are at least 18 years of age with unresected Stage I or II 
(limited Stage IIB N0, M0) NSCLC who have received no prior anticancer therapy for the 
present lung cancer:
Primary Objective
Primary Endpoint
Objective: To compare the Event-free 
Survival (EFS).
Hypothesis: SBRT + pembrolizumab 
prolongs EFS compared to SBRT + 
placebo.
EFS: The time from randomization to an 
event defined as local, regional, or distant 
recurrence of the treated NSCLC or death 
from any cause.
Secondary Objectives
Secondary Endpoints
Objective: To compare Overall Survival 
(OS).
Hypothesis: SBRT + pembrolizumab 
prolongs OS compared to SBRT + placebo.
OS: The time from randomization to death 
from any cause.
Objective: To evaluate the time to death or 
distant metastases.
Time to death or distant metastases: The 
time from randomization to the first 
documented distant metastases or death 
from any cause, whichever occurs first.
Objective: To evaluate the safety and 
tolerability of SBRT + pembrolizumab.

Adverse events

Study intervention discontinuations due 
to AEs
Objective: To evaluate the change from 
baseline scores in global health 
status/quality of life (QoL), cough, chest 
pain, dyspnea, and physical functioning 
scale.
Change from baseline scores, calculated for 
the following scales/items at a prespecified 
time point: global health status/QoL 
(EORTC QLQ-C30 Items 29 and 30), 
cough (EORTC QLQ-LC13 Item 1), 
chest pain (EORTC QLQ-LC13 Item 10), 
dyspnea (EORTC QLQ-C30 Item 8), and 
physical functioning (EORTC QLQ-C30 
Items 1-5).
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Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Treatment of Non-Small Cell Lung Cancer
Population
Participants with unresected Stage I or II 
(limited Stage IIB) NSCLC
Study Type
Interventional
Intervention Model
Parallel
This is a multi site study.
Type of Control
Placebo-controlled
Study Blinding
Double-blind
Blinding Roles
Investigator
Participants or Subjects
Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 84 months 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 436 participants will be randomized in this study.
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Intervention Groups and Duration:
Intervention 
Group Name
Drug / 
Treatment
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period
Use
Arm 1
Pembrolizumab 
(MK-3475)
25 mg/mL
200 mg
IV Infusion
Q3W x17 
cycles (~1 
year) x 17 
cycles (~1 
year)
Test 
Product
Arm 1
SBRT
Peripheral Tumors: 
45-60 Gy in 3 
fractions 
(preferred); 48-50 
Gy in 4 fractions 
(acceptable); 50-55 
Gy in 5 fractions 
(acceptable)
Abutting the chest 
wall: 48-50 Gy in 
4 fractions; 50-55 
Gy in 5 fractions
Central Tumors: 50-
55 Gy in 5 fractions; 
60-70 Gy in 
8 fractions
Peripheral 
Tumors: 45-
60 Gy in 3 
fractions 
(preferred); 
48 50 Gy in 4 
fractions 
(acceptable); 
50 55 Gy in 5 
fractions 
(acceptable)
Abutting the 
chest wall: 48 
50 Gy in 4 
fractions; 50 
55 Gy in 5 
fractions
Central 
Tumors: 50-
55 Gy in 5 
fractions; 60 
70 Gy in 8 
fractions
External Beam 
Radiation
~Q3D over 2 
weeks
Backgroun
d 
Treatment
Arm 2
Placebo
N/A
N/A
IV Infusion
Q3W × 17 
cycles (~1 
year)
Placebo
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Intervention 
Group Name
Drug / 
Treatment
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period
Use
Arm 2
SBRT
Peripheral Tumors: 
45-60 Gy in 3 
fractions 
(preferred); 48-50 
Gy in 4 fractions 
(acceptable); 50-55 
Gy in 5 fractions 
(acceptable)
Abutting the chest 
wall: 48-50 Gy in 
4 fractions; 50-55 
Gy in 5 fractions
Central Tumors: 50-
55 Gy in 5 fractions; 
60-70 Gy in 
8 fractions
Peripheral 
Tumors: 45-
60 Gy in 3 
fractions 
(preferred); 
48 50 Gy in 4 
fractions 
(acceptable); 
50 55 Gy in 5 
fractions 
(acceptable)
Abutting the 
chest wall: 48 
50 Gy in 4 
fractions; 50 
55 Gy in 5 
fractions
Central 
Tumors: 50-
55 Gy in 5 
fractions; 60 
70 Gy in 8 
fractions
External Beam 
Radiation
~Q3D over 2 
weeks
Backgroun
d 
Treatment
C=cycle; D=day; IV=intravenous; N/A=not applicable; Q3D=every 3 days; Q3W=every 3 weeks; SBRT=stereotactic body 
radiotherapy
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Total Number of Intervention Groups/Arms
2 arms
Duration of Participation
Each participant will participate in the study 
from the time the participant provides 
documented informed consent form (ICF) 
through the final protocol-specified contact.
After a Screening phase of up to 42 days, 
each participant will be randomized to 
receive study intervention until disease 
recurrence is documented, unacceptable 
adverse events, intercurrent illness that 
prevents further administration of treatment, 
death from any cause, investigator decision, 
participant decision, or withdrawal of 
consent, or until the participant has received 
17 administrations of pembrolizumab or 
placebo (approximately 1 year). 
After the end-of-treatment, each participant 
will be followed for the occurrence of AEs 
and spontaneously reported pregnancy as 
described in Section 8.4.
Participants who discontinue treatment for 
reasons other than documented disease 
recurrence, or recurrence has not been 
verified by Blinded Independent Central 
Review (BICR), will have posttreatment 
follow-up imaging for disease status until 
disease recurrence is documented 
radiographically and verified by BICR, 
withdrawing consent, pregnancy, death, or 
loss to follow-up, whichever occurs first. 
Images will also continue to be obtained 
after initiating the new anticancer therapy if 
recurrence has not been documented or 
verified by BICR. All participants will be 
followed by telephone for OS until death,
withdrawal of consent, or the end of the 
study.
Upon study completion, participants are 
discontinued and may be enrolled in a 
pembrolizumab extension study, if 
available.
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Study Governance Committees:
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Steering Committee
No
Study governance considerations are outlined in Appendix 1.
As of Amendment 08, the Executive Oversight Committee and Data Monitoring Committee 
are no longer applicable as outlined 10.1.4.1 and 10.1.4.2.
Study Accepts Healthy Participants:
No
A list of abbreviations used in this document can be found in Appendix 10.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Schema
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1.3
Schedule of Activities (SoA)
Table 1
Study Schedule of Activities: Pembrolizumab & SBRT Treatment
As of Amendment 08, information regarding ePRO assessments (EORTC QLQ-C30, EORTC QLQ-LC13, and EuroQoL EQ-
5D-5L), biomarker samples (blood for genetic analysis, blood for ctDNA analysis, optional tumor sample), biopsies, and tumor 
imaging for BICR will no longer be collected. Tumor imaging, biopsies, and disease management should be performed per 
local SOC and Investigator’s discretion. Efficacy data collection, including Follow-up and Survival Follow-up visits for 
efficacy will no longer be conducted. Safety reporting for AEs and SAEs must adhere to time windows per protocol. Updated 
analyses are described in Section 9.
Study Period
Screening 
Phase
Treatment/Intervention 
(3-week cycles) 
EOT
Posttreatment
Notes
Visit Number/Title
Screening
Cycle 
1
Cycle 2
Cycle 
3
Cycle 4 onward
DC
Safety FU
FU 
Visits
Survival 
FU
Scheduling window 
(days)
-42 to -1
+3
±3
±3
±3
At time of DC 
+ 7 days
30 days from 
last dose + 14 
days
Q16Wa
(±7 
days)
Q12W 
(±7 
days)
Administrative Procedures
Informed Consent
X
Informed Consent for 
Future Biomedical 
Research
X
FBR consent is optional.
Inclusion/Exclusion 
Criteria
X
Participant 
Identification Card
X
Medical/Surgical 
History
X
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
X
Prior and concomitant 
medications should be 
tracked from Day -42 
forward.
Intervention 
(Randomization)
X
Subsequent 
Antineoplastic 
Therapy Status
X
X
X
X
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Study Period
Screening 
Phase
Treatment/Intervention 
(3-week cycles) 
EOT
Posttreatment
Notes
Visit Number/Title
Screening
Cycle 
1
Cycle 2
Cycle 
3
Cycle 4 onward
DC
Safety FU
FU 
Visits
Survival 
FU
Scheduling window 
(days)
-42 to -1
+3
±3
±3
±3
At time of DC 
+ 7 days
30 days from 
last dose + 14 
days
Q16Wa
(±7 
days)
Q12W 
(±7 
days)
Survival Status
===========================================
X
After investigator-
determined recurrence or 
start of new anticancer 
treatment. In addition, 
upon Sponsor request, 
participants may be 
contacted for survival 
status at any time during 
the course of the study.
Study Drug Administration
Pembrolizumab or 
Placebo 
X
X
X
X
Maximum of 17 total 
cycles.
SBRT
X
Administered over a 
maximum 2-week interval, 
concurrent with Cycle 1. 
Preferably starting on 
C1D1 with a +7-day 
window allowed (up to 
C1D8 inclusive) following 
pembrolizumab/placebo 
administration.
Safety Procedures
Complete physical 
examination 
including height and 
weight
X
X
To be performed within 
7 days before start of study 
intervention.
Directed Physical 
Examination
X
X
X
X
X
X
Conducted at all treatment 
visits.
Vital Signs (pulse 
rate, blood pressure)
X
X
X
X
X
X
X
X
Conducted at all treatment 
visits.
12-lead ECG
X
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Study Period
Screening 
Phase
Treatment/Intervention 
(3-week cycles) 
EOT
Posttreatment
Notes
Visit Number/Title
Screening
Cycle 
1
Cycle 2
Cycle 
3
Cycle 4 onward
DC
Safety FU
FU 
Visits
Survival 
FU
Scheduling window 
(days)
-42 to -1
+3
±3
±3
±3
At time of DC 
+ 7 days
30 days from 
last dose + 14 
days
Q16Wa
(±7 
days)
Q12W 
(±7 
days)
Urine or Serum 
Pregnancy Test 
(WOCBP only)
X
X
X
X
X
X
X
Screening test must be 
performed within 24 hours 
for urine or within 72 
hours for serum prior to 
first dose of study 
intervention.
HIV, hepatitis B and 
C screen 
X
Not required unless 
mandated by the local 
health authority.
Hematology and 
clinical chemistry 
laboratory 
assessment
X
X
X
X
X
X
Screening test must be 
performed within 7 days 
prior to first dose of study 
intervention. For all 
subsequent visits, 
laboratory assessments 
may be performed within 7 
days prior to the visit.
PT/INR aPTT
X
Coagulation factors should 
be monitored closely 
throughout the study if 
participant is on 
anticoagulation therapy.
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Study Period
Screening 
Phase
Treatment/Intervention 
(3-week cycles) 
EOT
Posttreatment
Notes
Visit Number/Title
Screening
Cycle 
1
Cycle 2
Cycle 
3
Cycle 4 onward
DC
Safety FU
FU 
Visits
Survival 
FU
Scheduling window 
(days)
-42 to -1
+3
±3
±3
±3
At time of DC 
+ 7 days
30 days from 
last dose + 14 
days
Q16Wa
(±7 
days)
Q12W 
(±7 
days)
TSH, T3/FT3, 
T4/FT4 
X
X
X
X
X
T3/FT3 and T4/FT4 only 
required if TSH is 
abnormal. Thyroid 
function tests are to be 
repeated at alternate cycles 
after Cycle 4. Beginning 
with Cycle 2, participants 
may receive 
pembrolizumab or placebo 
while thyroid function tests 
are pending. Screening test 
must be performed within 
7 days prior to first dose of 
study intervention. 
Subsequent tests may be 
performed within 7 days 
prior to the visit.
Urinalysis
X
See Note
X
X
Screening test must be 
performed within 7 days 
prior to first dose of study 
intervention. Repeat test 
every 6 cycles during 
treatment phase within 7 
days prior to the visit. 
AE/SAE review
X
=============================
X
X
ECOG performance 
status 
X
X
X
X
X
X
To be assessed within 7 
days prior to first dose of 
study intervention and 
prior to dosing during all 
subsequent scheduled 
visits.
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Study Period
Screening 
Phase
Treatment/Intervention 
(3-week cycles) 
EOT
Posttreatment
Notes
Visit Number/Title
Screening
Cycle 
1
Cycle 2
Cycle 
3
Cycle 4 onward
DC
Safety FU
FU 
Visits
Survival 
FU
Scheduling window 
(days)
-42 to -1
+3
±3
±3
±3
At time of DC 
+ 7 days
30 days from 
last dose + 14 
days
Q16Wa
(±7 
days)
Q12W 
(±7 
days)
Efficacy Measurements
Tumor Imaging 
(CT/MRI)
X
See Note
X
X
Scans performed within the 
Screening period but 
before signing informed 
consent may be used if 
consistent with protocol 
requirements per Site 
Imaging Manual. Scans to 
be performed at Week 12, 
then Q16W from Week 12 
until Week 156, and Q6M 
thereafter. Scans will 
continue to be performed 
after initiating new 
anticancer therapy if 
recurrence has not been 
documented or verified by 
BICR. Confirmation scans 
of recurrence should be 
performed 4 to 6 weeks 
after initial recurrence 
when biopsy is not 
medically appropriate.
Tumor Imaging 
(FDG-PET)
X
Tumor Biopsy
See Note
Where medically 
appropriate, disease 
recurrence should be 
verified by biopsy at the 
first documented instance 
of recurrence by imaging 
or physical examination.
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Study Period
Screening 
Phase
Treatment/Intervention 
(3-week cycles) 
EOT
Posttreatment
Notes
Visit Number/Title
Screening
Cycle 
1
Cycle 2
Cycle 
3
Cycle 4 onward
DC
Safety FU
FU 
Visits
Survival 
FU
Scheduling window 
(days)
-42 to -1
+3
±3
±3
±3
At time of DC 
+ 7 days
30 days from 
last dose + 14 
days
Q16Wa
(±7 
days)
Q12W 
(±7 
days)
Biomarkers
Blood for Genetic 
Analyses
X
Collect predose (see 
Section 8.8.1 for additional 
information).
Blood for ctDNA 
Analysis
X
X
X
See Note
X
X
Collect predose, C1, C2, 
C3, C6, then every 3 cycles 
through C15 and at 
EOT/DC. For the second 
year forward, align with 
imaging visits. During FU 
Visits, if a clinic visit is not 
feasible, blood for ctDNA 
collection will not be 
collected.
Optional Tumor 
Tissue Sample for 
Biomarker Analyses
X
Collection of a biopsy is 
not required for trial, and 
submission is contingent 
on signing Optional Tumor 
Tissue Collection Consent. 
Patient-reported Outcomes (PROs)
EORTC QLQ-C30
X
See Note
X
X
X
Administered prior to 
dosing at C1, C5, C9, C13, 
and C17. Also 
administered at treatment 
discontinuation, safety 
follow-up, and 
concurrently with follow-
up tumor imaging (Q16W 
for the first 3 years, Q6M 
thereafter).
EORTC QLQ-LC13
X
See Note
X
X
X
EuroQol (EQ)-5D-5L
X
See Note
X
X
X
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AE=adverse event; aPTT=activated partial thromboplastin time; C=cycle; CT=computed tomography; ctDNA=circulating tumor DNA; D=day; DC=discontinuation; 
DNA=deoxyribonucleic acid; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EORTC QLQ-C30=European Organization for Research and Treatment 
of Cancer Quality of Life Core 30; EORTC QLQ-LC13=European Organization for Research and Treatment of Cancer Quality of Life Cancer Quality of Life Questionnaire 
Lung Cancer 13; EOT=end-of-treatment; EuroQoL EQ-5D-5L=European Quality of Life Five-dimension Five-level Scale Questionnaire; FBR=future biomedical research; 
FDG-PET=fluorodeoxyglucose-positron emission tomography; FU=follow-up; HIV=human immunodeficiency virus; MRI=magnetic resonance imaging; PT/INR=prothrombin 
time/international normalized ratio; Q6M=every 6 months; Q16W=every 16 weeks; SAE=serious adverse event; SBRT=stereotactic body radiotherapy; SOP=standard operating 
procedure; T3/FT3=(free) triiodothyronine; T4/FT4=(free) thyroxine; TSH=thyroid-stimulating hormone; WOCBP=women of childbearing potential.
Note: Country-specific differences are noted in Appendix 7.
a.
Follow-up visits should be aligned to CT scans as described in the tumor imaging section of Table 1– Schedule of Activities.
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2
INTRODUCTION
Lung cancer is the most common malignancy in the world, with an estimated global 
incidence in 2018 of 2.1 million new cases of lung cancer (comprising 12% of total new 
global cancer cases) and an associated 1.8 million deaths [Bray, F., et al 2018]. Due to 
widespread continued cigarette smoking, lung cancer will remain a significant worldwide 
public health problem for the foreseeable future.
NSCLC represents 80% to 85% of all lung cancers [National Cancer Institute 2016]. At the 
time of diagnosis, approximately 57% of patients with NSCLC had metastatic (Stage IV) 
disease, and 22% have tumors with regional (including nodal) spread (some Stage IIB and 
III) [National Cancer Institute 2018]. Patients with local disease and no nodal involvement 
(Stage I, IIA, and some IIB) constitute 16% of cases at initial diagnosis, with the remaining 
5% not having staging completed [National Cancer Institute 2018]. 
Standard treatment for patients with Stage I or II NSCLC (any T, N0, M0 staging) is surgical 
resection, typically lobectomy [National Comprehensive Cancer Network 2018] [Postmus, P. 
E., et al 2017] [Pisters, K. M. W. and Le Chevalier, T. 2005]. However, in a subset of 
patients (approximately 4% of all lung cancers diagnosed), surgery is not an option due to 
underlying comorbidities. These patients may be deemed medically inoperable due to severe 
single organ impairment, or to moderate or severe multiple organ impairment [Guckenberger, 
M., et al 2017] [Videtic, G. M. M., et al 2017] [Rodrigues, G., et al 2015] [De Ruysscher, D., 
et al 2017] [Charlson, M. E., et al 1987] [Brunelli, A., et al 2013] [Fleisher, L. A., et al 
2014]. There is no accepted definition of the physiologic abnormalities that render a patient 
unable to undergo thoracic surgery. Typically, the decision to pursue non-operative therapy is 
made by the medical oncologist/radiation oncologist in consultation with a thoracic surgeon. 
Institutions with a multidisciplinary tumor board often discuss the management of these 
complicated patients and make recommendations to the treating physician.  
For medically inoperable patients, or patients refusing surgery, with Stage I or II NSCLC, 
SBRT is the recommended course of treatment [Tandberg, D. J., et al 2018]. SBRT consists 
of ablative doses of radiotherapy applied over a short period of time. The local control rate 
with SBRT is similar to that achieved with surgery. Although the 5-year survival is between 
50% and 70% [Garrett, M., et al 2017], SBRT has been reported to have a poorer long-term 
survival rate than lobectomy [Bryant, A. K., et al 2018]. Thus, additional therapy, or a 
combination that would be tolerated by this medically compromised patient cohort, is needed 
to improve treatment results. While surgical resection is the preferred treatment for early-
stage NSCLC, SBRT is currently considered the standard of care for patients with early-stage 
NSCLC who have elected not to have an operation after appropriate multidisciplinary 
consultation [Postmus, P. E., et al 2017] [Guckenberger, M., et al 2017] [Videtic, G. M. M., 
et al 2017] [National Comprehensive Cancer Network 2020]. Multiple prospective and 
retrospective studies have shown that SBRT, when delivered to operable early-stage NSCLC 
patients, achieved 3-year OS rates of 77% to 95%, 5-year OS rates of 45% to 70%, and 5-
year local control rates of 86% to 97%, which are comparable to long-term surgical data 
[Daniels, C. P., et al 2019].
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2.1
Study Rationale
SBRT and immunotherapy, such as pembrolizumab, are synergistic due to the immunogenic 
cell death caused by the former and the mechanism of action, efficacy, and favorable toxicity 
profile of the latter. Animal experiments have documented that tumor necrosis caused by 
high dose hypo-fractionated radiotherapy, such as that used in SBRT, results in increased 
antigen production, increased antitumor T-cells, and a decrease in T-reg cells [Lugade, A. A., 
et al 2005] [Schaue, D., et al 2012]. Radiotherapy has also been shown to favorably affect the 
immune response by facilitating: 1) the translocation of calreticulin to the tumor cell surface, 
which increases the uptake of tumor cells by dendritic cells (DC) [Gameiro, S. R., et al 
2014], 2) the extracellular release of HMGB1, which interacts with the DC surface TLR4 and 
aids in antigen presentation to T-cells [Apetoh, L., et al 2007], 3) release of ATP, which 
stimulates DCs to secrete interleukins necessary for priming T-cells [Aymeric, L., et al 
2010]. 
Published studies have demonstrated the benefit and safety of chemoradiotherapy followed 
by the sequential administration of a checkpoint inhibitor for patients with NSCLC. The 
PACIFIC trial compared maintenance durvalumab to placebo in patients with unresectable 
Stage III NSCLC who had no evidence of disease progression following definitive 
chemoradiotherapy [Antonia, S. J., et al 2017] [Antonia, S. J., et al 2018]. Significant 
improvement in progression-free survival (PFS) and OS was obtained with an acceptable 
small increase in AEs. In a secondary analysis of KEYNOTE-001, PFS and OS were 
significantly longer in patients with NSCLC treated with pembrolizumab who had previously 
received extracranial radiotherapy than in those patients who had not received extracranial 
radiotherapy [Shaverdian, N., et al 2017].
2.2
Background
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the PD-1 receptor, thus inhibiting its interaction 
with PD-L1 and PD-L2. Based on preclinical in vitro data, pembrolizumab has high affinity 
and potent receptor blocking activity for PD-1. Pembrolizumab has an acceptable preclinical 
safety profile and is in clinical development as an IV immunotherapy for advanced 
malignancies. KEYTRUDA® (pembrolizumab) is indicated for the treatment of patients
across a number of indications. For more details on specific indications, refer to the IB.
2.2.1
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved 
prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and 
pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. 
Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable 
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objective tumor responses in cancers such as melanoma [Dudley, M. E., et al 2005] [Hunder, 
N. N., et al 2008].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an 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 PD-L2) 
[Greenwald, R. J., et al 2005] [Okazaki, T., et al 2001].
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an Ig-variable–type (IgV-type) 
domain responsible for ligand binding and a cytoplasmic tail responsible for the binding of 
signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, 
an immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based 
switch motif. Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 
and SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ, and ZAP70, 
which are involved in the CD3 T-cell signaling cascade [Okazaki, T., et al 2001] [Chemnitz, 
J. M., et al 2004] [Sheppard, K-A, et al 2004] [Riley, J. L. 2009]. The mechanism by which 
PD-1 down-modulates T-cell responses is similar to, but distinct from, that of CTLA-4, 
because both molecules regulate an overlapping set of signaling proteins [Parry, R. V., et al 
2005] [Francisco, L. M., et al 2010]. Consequently, the PD-1/PD-L1 pathway is an attractive 
target for therapeutic intervention in unresected early-stage NSCLC.
2.2.2
Preclinical and Clinical Studies
Refer to the IB for preclinical and clinical study data for pembrolizumab.
2.2.3
Ongoing Clinical Studies
There are no other trials currently being conducted by MSD in this patient population.
2.2.4
Information on Other Study-related Therapy: SBRT
SBRT has become the treatment of choice for patients with unresected NSCLC who refuse 
surgery or are medically inoperable [National Comprehensive Cancer Network 2018]
[Guckenberger, M., et al 2017] [Postmus, P. E., et al 2017]. Hypo-fractionation schedules 
place less of a burden on the patient and provide a local control rate similar to that obtained 
with conventional radiotherapy [Chang, J. Y., et al 2014] [Sun, B., et al 2017]. Prescribed 
dose and fractionation ranges are determined by whether the lung tumor location is central, 
peripheral, or abutting the chest wall [Guckenberger, M., et al 2017]. A biologically effective 
dose (BED) ≥100 Gy is accepted as required for efficacy [Guckenberger, M., et al 2017] 
[Postmus, P. E., et al 2017] [Senthi, S., et al 2013]. This BED can be achieved with the 
dosing described in this protocol.
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Though dose and scheduling vary within the above categories, KEYNOTE-867 is designed 
with validated schedules that fall within published guidelines [National Comprehensive 
Cancer Network 2018] [Guckenberger, M., et al 2017]. In this study, peripheral tumors will 
be treated with 3 fractions totaling 45 to 60 Gy (preferred regimen), or 4 fractions totaling 48 
to 50 Gy (acceptable regimen), or 5 fractions totaling 50 to 55 Gy (acceptable regimen) while 
central tumors, defined as within 2 cm of the proximal bronchial tree and/or abutting the 
mediastinal pleural, will receive 5 fractions totaling 50 to 55 Gy or 8 fractions totaling 60 to 
70 Gy, and tumors abutting the chest wall will receive 4 fractions totaling 48 to 50 Gy or 
5 fractions totaling 50 to 55 Gy. Ultra-central tumors, defined as tumors whose PTV directly 
contacts or overlaps the proximal bronchial tree, trachea, mainstem bronchus, esophagus, 
pulmonary vein, or pulmonary artery, are excluded. Details of the required equipment, 
treatment planning, and credentialing of the site are contained within the Radiotherapy QA 
manual.
Recently, results of a Phase 2 randomized (1:1) open-label study evaluating SBRT with or 
without nivolumab in patients with stage IA-IIB (N0) NSCLC per AJCC 8th staging system 
who are medically inoperable or refuse surgery were published [Chang, J. Y., et al 2023]. 
The primary endpoint was 4-year EFS (local, regional, or distant recurrence; second primary 
lung cancer; or death). A total of 156 patients were randomly assigned, and 141 patients 
received assigned therapy (75 SBRT and 66 SBRT + nivolumab). At median 33-month 
follow-up, in the ITT analysis, the 4-year EFS in the SBRT group was 53% (42%–67%) and 
in the SBRT + nivolumab group was 77% (66%–91%) with HR 0.42; 95% CI 0.22–0.80; 
p=0.0080).  
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine. However, pembrolizumab and 
SBRT are independently effective in the treatment of NSCLC. Available evidence 
demonstrates that the 2 modalities can be administered in proximity without increased 
toxicity [Theelen, W. S. M. E., et al 2019] [Campbell, A. M., et al 2018].
Additional details regarding specific benefits and risks for participants in this clinical study 
may be found in the accompanying IB and informed consent documents.
NOTE: Based on the data from an interim safety and efficacy analysis for 
KEYNOTE¬867 (data cutoff 11-JUN-2024), the eDMC recommended stopping the 
study since pembrolizumab in combination with SBRT did not demonstrate an 
improvement in EFS or OS, the study’s primary endpoint and key secondary endpoint, 
respectively, compared to placebo plus SBRT, and the benefit/risk profile of the 
combination did not support continuing the trial. All prespecified interim analyses after 
IA1 and final analysis of the study described in the SAP will not be performed. Safety 
analysis will be performed at the end of the study; there will be no further pre-planned 
analyses for efficacy and ePRO endpoints collected from participants beyond the IA1 
cutoff date of 11-JUN-2024.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
NOTE: Based on the data from an interim safety and efficacy analysis for 
KEYNOTE¬867 (data cutoff 11-JUN-2024), the eDMC recommended stopping the 
study since pembrolizumab in combination with SBRT did not demonstrate an 
improvement in EFS (Event-Free Survival) or OS (Overall Survival), the study’s 
primary endpoint and key secondary endpoint, respectively, compared to placebo plus 
SBRT, and the benefit/risk profile of the combination did not support continuing the 
trial. All prespecified interim analyses after IA1 (Interim Analysis 1) and final analysis 
of the study described in the SAP (Statistical Analysis Plan) will not be performed. 
Safety analysis will be performed at the end of the study; there will be no further pre-
planned analyses for efficacy and ePRO (electronic patient-reported outcome) 
endpoints collected from participants beyond the IA1 cutoff date of 11-JUN-2024.
In alignment with the study update memo sent to Investigators on 29-AUG-2024, all 
study participants must stop ongoing treatment with pembrolizumab/placebo. These
participants must complete EOT (End of Trial) visit followed by Safety Follow-up visit 
per protocol. All remaining study participants who have completed the safety reporting 
windows for AEs and SAEs per protocol must be discontinued from the study. All study 
participants will undergo unblinding at the end of the study. Investigators may apply 
for unblinding participants per protocol in the interim.
As of Amendment 08, information regarding ePRO assessments (EORTC QLQ-C30, 
EORTC QLQ-LC13, and EuroQoL EQ-5D-5L), biomarker samples (blood for genetic 
analysis, blood for ctDNA analysis, optional tumor sample), biopsies, and tumor 
imaging for BICR (blinded independent central review) will no longer be collected. 
Tumor imaging, biopsies, and disease management should be performed per local SOC 
and Investigator’s discretion. Efficacy data collection, including Follow-up and Survival 
Follow-up visits for efficacy will no longer be conducted. Safety reporting for AEs and 
SAEs must adhere to time windows per protocol. Updated analyses are described in 
Section 9.
All objectives will compare administration of SBRT + pembrolizumab versus SBRT + 
placebo, unless otherwise indicated.
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In male and female participants who are at least 18 years of age with unresected Stage I or II 
(limited Stage IIB N0, M0) NSCLC who have received no prior anticancer therapy for the 
present lung cancer:
Primary Objective
Primary Endpoint
Objective: To compare the Event-free 
Survival (EFS).
Hypothesis: SBRT + pembrolizumab 
prolongs EFS compared to SBRT + 
placebo.
EFS: The time from randomization to an 
event defined as local, regional, or distant 
recurrence of the treated NSCLC or death 
from any cause.
The study is considered to have met its primary objective if pembrolizumab plus SBRT is 
superior to placebo plus SBRT in EFS at an interim analysis or final analysis.
Secondary Objectives
Secondary Endpoints
Objective: To compare Overall Survival 
(OS).
Hypothesis: SBRT + pembrolizumab 
prolongs OS compared to SBRT + placebo.
OS: The time from randomization to death 
from any cause.
Objective: To evaluate the time to death or 
distant metastases.
Time to death or distant metastases: The 
time from randomization to the first 
documented distant metastases or death 
from any cause, whichever occurs first.
Objective: To evaluate the safety and 
tolerability of SBRT + pembrolizumab.

Adverse events

Study intervention discontinuations due 
to AEs
Objective: To evaluate the change from 
baseline scores in global health 
status/quality of life (QoL), cough, chest 
pain, dyspnea, and physical functioning 
scale.
Change from baseline scores, calculated for 
the following scales/items at a prespecified 
time point: global health status/QoL 
(EORTC QLQ-C30 Items 29 and 30), 
cough (EORTC QLQ-LC13 Item 1), 
chest pain (EORTC QLQ-LC13 Item 10), 
dyspnea (EORTC QLQ-C30 Item 8), and 
physical functioning (EORTC QLQ-C30 
Items 1-5).
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Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
Objective: To evaluate the time to 
subsequent treatment (TTST).
TTST: The time from randomization to first 
day of next line of therapy or death from 
any cause.
Objective: To evaluate the disease-specific 
survival (DSS).
DSS: The time from randomization to death 
due to disease under study.
Objective: To evaluate the time to 
recurrence/progression on subsequent line 
of therapy (TRSLT).
TRSLT: The time from randomization to 
first day of the recurrence/progression on 
the next line of therapy or death from any 
cause.
Objective: To characterize health utility 
using the 5 level version of the European 
Quality of Life (EuroQoL) 5 dimension 
Questionnaire (EQ-5D-5L) to generate 
utility scores for use in economic models.
Health utilities assessed using the 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 SBRT + 
pembrolizumab.
Molecular (genomic, metabolic, and/or 
proteomic) determinants of response or 
resistance to treatments, using blood and/or 
tumor tissue.
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4
STUDY DESIGN
4.1
Overall Design
NOTE: Based on the data from an interim safety and efficacy analysis for 
KEYNOTE¬867 (data cutoff 11-JUN-2024), the eDMC recommended stopping the 
study since pembrolizumab in combination with SBRT did not demonstrate an 
improvement in EFS or OS, the study’s primary endpoint and key secondary endpoint, 
respectively, compared to placebo plus SBRT, and the benefit/risk profile of the 
combination did not support continuing the trial. All prespecified interim analyses after 
IA1 and final analysis of the study described in the SAP will not be performed. Safety 
analysis will be performed at the end of the study; there will be no further pre-planned 
analyses for efficacy and ePRO endpoints collected from participants beyond the IA1 
cutoff date of 11-JUN-2024.
In alignment with the study update memo sent to Investigators on 29-AUG-2024, all 
study participants must stop ongoing treatment with pembrolizumab/placebo. These 
participants must complete EOT visit followed by Safety Follow-up visit per protocol. 
All remaining study participants who have completed the safety reporting windows for 
AEs and SAEs per protocol must be discontinued from the study. All study participants 
will undergo unblinding at the end of the study. Investigators may apply for unblinding 
participants per protocol in the interim.
As of Amendment 08, information regarding ePRO assessments (EORTC QLQ-C30, 
EORTC QLQ-LC13, and EuroQoL EQ-5D-5L), biomarker samples (blood for genetic 
analysis, blood for ctDNA analysis, optional tumor sample), biopsies, and tumor 
imaging for BICR will no longer be collected. Tumor imaging, biopsies, and disease 
management should be performed per local SOC and Investigator’s discretion. Efficacy 
data collection, including Follow-up and Survival Follow-up visits for efficacy will no 
longer be conducted. Safety reporting for AEs and SAEs must adhere to time windows 
per protocol. Updated analyses are described in Section 9.
This is a multisite, placebo-controlled, randomized, double-blind study designed to compare 
the efficacy and safety of SBRT + pembrolizumab versus SBRT + placebo in participants 
with unresected Stage I or II (N0, M0) NSCLC (AJCC 8th edition, Appendix 9). Eligible 
patients must have histologically or cytologically confirmed Stage I or II (N0, M0) NSCLC 
that has not been previously treated.
The study will be conducted in conformance with Good Clinical Practices (GCP). 
Approximately 436 participants will be randomized. After a Screening phase of up to 
42 days, each eligible participant will be randomized in a 1:1 ratio to receive SBRT + 
pembrolizumab 200 mg Q3W × 17 cycles or SBRT + placebo Q3W × 17 cycles. SBRT will 
be given as outlined in Table 3. The first SBRT administration will preferably start on 
Cycle 1 Day 1 (+7 days allowed up to Cycle 1 Day 8, inclusive) following 
pembrolizumab/placebo administration. All randomized patients will receive either 
pembrolizumab or placebo regardless of if they complete SBRT. Randomization will be 
stratified by stage of disease (Stage I vs Stage II), Eastern Cooperative Oncology Group 
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(ECOG) performance scale (0 or 1 vs 2), geographic region of enrollment site (East Asia vs 
non-East Asia), and reason for not receiving surgery (medically inoperable vs refused 
surgery). Histology was not chosen as a stratification factor because the differentiation 
between squamous and nonsquamous histology is frequently inaccurate when utilizing 
cytology specimens, which is likely to represent the majority of diagnostic specimens in this 
medically compromised population [Nizzoli, R., et al 2011]. In addition, many cytology 
samples cannot be assigned to either histologic category and are merely reported as NSCLC, 
not otherwise specified [Ebrahimi, M., et al 2016].
The primary endpoint of the study is EFS. Participants will be evaluated with radiographic 
imaging to assess response to treatment. The first on-trial imaging assessment will be 
performed at 12 weeks (±7 days) from the date of randomization (at least 10 weeks post 
completion of SBRT). This scan is considered the reference point for monitoring local 
recurrence (see Section 8.2.1.3.1). Subsequent tumor imaging will be performed every 
16 weeks (Q16W ±7 days) until 156 weeks post randomization; and every 6 months 
(Q6M ±14 days) thereafter. All imaging obtained on study will be submitted for BICR. The 
central radiologists will assess the images for determination of EFS. Adverse event (AE) 
monitoring will be ongoing throughout the trial and graded in severity according to the 
guidelines outlined in the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0. The primary endpoint EFS will be assessed 
 
 and the secondary endpoint OS will be assessed at 
 
final analysis.
Treatment with pembrolizumab or placebo control will continue until 17 cycles have been 
administered (approximately one year), or until disease recurrence, unacceptable adverse 
events, intercurrent illness that prevents further administration of treatment, death from any 
cause, investigator decision, or participant decision or withdrawal of consent, whichever 
occurs first.
Participants who discontinue for reasons other than disease recurrence, or where radiographic 
disease recurrence has not been verified by BICR, will have posttreatment follow-up imaging 
until disease recurrence is documented radiographically and verified by BICR, withdrawing 
consent, pregnancy, death, loss to follow-up or early study termination, whichever occurs 
first. Images will continue to be obtained even after initiating the new anticancer therapy if 
recurrence has not been documented or verified by BICR.
After the end-of-treatment, each participant will be followed for the occurrence of AEs and 
spontaneously reported pregnancy as described in Section 8.4.
All participants will be followed by telephone for OS until death, withdrawal of consent, or 
the end of the study.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3, Table 1 of the SoA. Details of each 
procedure are provided in Section 8.
CCI
CCI
CCI
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4.2
Scientific Rationale for Study Design
SBRT and immunotherapy, such as pembrolizumab, are synergistic due to the immunogenic 
cell death caused by the former and the mechanism of action, efficacy, and favorable toxicity 
profile of the latter. Published studies have demonstrated the benefit and safety of 
chemoradiotherapy followed by the sequential administration of a checkpoint inhibitor for 
patients with NSCLC. The PACIFIC trial compared maintenance durvalumab to placebo in 
patients with unresectable Stage III NSCLC who had no evidence of disease progression 
following definitive chemoradiotherapy [Antonia, S. J., et al 2017] [Antonia, S. J., et al 
2018]. Significant improvement in PFS and overall survival (OS) was obtained with an 
acceptable small increase in adverse events. In a secondary analysis of KEYNOTE-001, PFS 
and overall survival (OS) were significantly longer in patients with NSCLC treated with 
pembrolizumab who had previously received extracranial radiotherapy than in those patients 
who had not received extracranial radiotherapy [Shaverdian, N., et al 2017].
Treatment with pembrolizumab/placebo will be administered over a maximum of 17 cycles, 
consistent with other adjuvant trials within the pembrolizumab program. Additionally, as the 
participants in this trial will have significant comorbidities and would typically have minimal 
surveillance following SBRT (ie, “watchful waiting” consisting of 2 to 4 CT scans/year) as 
part of their standard of care, one year of pembrolizumab/placebo was seen as lowering the 
burden to participants as well as encouraging compliance with the visit schedule compared to 
the longer line-treatment plan of 2 years.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
This study will use EFS as assessed by BICR as the primary endpoint. EFS is an acceptable 
measure of clinical benefit for a late-stage study that demonstrates superiority of a new 
antineoplastic therapy, especially if the magnitude of the effect is large and the therapy has 
an acceptable risk/benefit profile. Images will be submitted to an imaging vendor and read by 
an independent central reviewer blinded to treatment assignment to minimize bias in the 
response assessments. In addition, the final determination of radiologic recurrence will be 
based on the central assessment of recurrence, rather than a local site investigator/radiology 
assessment. Expedited verification of radiologic recurrence as determined by central review 
will be communicated to the site. Where a biopsy has been performed locally at site to 
confirm/rule out recurrence of disease, the results of the biopsy will overrule the radiologic 
findings when they conflict. Recurrence will be assessed by (1) BICR, using qualitative 
assessment of recurrence at the primary lesion site and evaluation of possible new lesions 
following RECIST 1.1 principles, (2) pathology by local assessment, or (3) physical 
examination confirmed by local pathology assessment and/or BICR radiographic recurrence. 
The earliest of the 3 possible means of documenting recurrence will be used as the date of 
recurrence. For example, if recurrence is identified by physical examination and 
subsequently confirmed by biopsy or BICR, the date of the abnormal physical finding will be 
utilized to calculate the date of recurrence. Similarly, if a suspected radiographic abnormality 
is biopsy negative, but later enlarges and re-biopsy demonstrates metastatic cancer, the date 
of the first CT scan will be utilized as the date of recurrence.
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EFS is a primary endpoint. The study is considered to have met its primary objective if 
pembrolizumab plus SBRT is superior to placebo plus SBRT in EFS at an interim analysis or 
final analysis. All alpha is allocated to EFS with step down to OS, for more detail see 
Section 9.
4.2.1.2
Safety Endpoints
Safety parameters frequently used for evaluating investigational-systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of AEs/SAEs, and changes in vital signs and laboratory values. AEs 
will be assessed as defined by CTCAE, Version 4.0.
4.2.1.3
Patient-reported Outcomes
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. As part of the 
analyses for this study, health-related quality of life (HRQoL) and disease-related symptoms 
will be investigated among all participants via the following assessment tools: European 
Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC QLQ 
LC13, and EuroQoL EQ-5D-5L 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.
4.2.1.3.1
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 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. TTD and mean change from baseline 
in global health status or QoL scale of the EORTC QLQ-C30, will be evaluated as secondary 
objectives.
4.2.1.3.2
EORTC QLQ-LC13
The EORTC Quality of Life Questionnaire and Lung Cancer Module 13 (QLQ-LC13), a 
supplemental lung cancer-specific module used in combination with QLQ-C30, is comprised 
of multi-item and single item measures of lung cancer associated symptoms (cough, 
hemoptysis, dyspnea, and site-specific pain) and treatment-related symptoms (sore mouth, 
dysphagia, peripheral neuropathy, and alopecia) [Bergman, B., et al 1994]. It is scored on a 
4-point scale (1=not at all, 2=a little, 3=quite a bit, and 4=very much) and has been translated 
and validated into more than 60 languages.
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The EORTC QLQ-C30 and EORTC QLQ-LC13 are the most frequently used and reported 
PRO measures in lung cancer clinical studies. The reliability, validity, and practicality of 
these instruments have been reported [Aaronson, N. K., et al 1993a] [Bergman, B., et al 
1994].
4.2.1.3.3
EuroQoL EQ-5D
The EuroQoL-5D (EQ-5D) 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 include the 
following: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each 
dimension is rated on a 5-point scale from 1 (no problem) to 5 (unable to/extreme problems). 
The EQ-5D also includes a graded (0 to 100) vertical visual analog scale on which the 
participant rates his or her general state of health at the time of the assessment. This 
instrument has been used extensively in cancer studies and published results from these 
studies support its validity and reliability [Pickard, A. S., et al 2007].
4.2.1.4
Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents. 
However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating patients. Thus, to aid future patients, it is important to investigate the determinants 
of response or resistance to cancer immunotherapy and other treatments administered, as well 
as determinants of AEs in the course of our clinical studies. These efforts may identify novel 
predictive/pharmacodynamic biomarkers and generate information that may better guide 
single-agent and combination therapy with immuno-oncology drugs. To identify novel 
biomarkers, biospecimens (ie, blood components, tumor material) will be collected to support 
analyses of cellular components (eg, protein, DNA, RNA, metabolites) and other circulating 
molecules. Investigations may include, but are not limited to:
Germline (blood) genetic analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing)
This research may evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
predict efficacy or AEs, the data might inform optimal use of therapies in the patient 
population. Furthermore, it is important to evaluate germline DNA variation across the 
genome to interpret tumor-specific DNA mutations. Finally, MSI may be evaluated as this is 
an important biomarker for some cancers (ie, colorectal cancer).
Genetic (DNA) analyses from tumor
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (ie, mutations, methylation 
status, microsatellite instability). Key molecular changes of interest to immuno-oncology 
drug development include the mutational burden of tumors and the clonality of T-cells in the 
tumor microenvironment. Increased mutational burden (sometimes called a ‘hyper-mutated’ 
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state) may generate neoantigen presentation in the tumor microenvironment. To conduct this 
type of research, it is important to identify tumor-specific mutations that occur across all 
genes in the tumor genome. Thus, genome-wide approaches may be used for this effort. Note 
that to understand tumor-specific mutations, it is necessary to compare the tumor genome 
with the germline genome. Microsatellite instability may also be evaluated as this is an 
important biomarker for some cancers (ie, colorectal cancer). Circulating tumor DNA and/or 
RNA may also be evaluated from blood samples.
Tumor and/or blood RNA analyses
Both genome-wide and targeted mRNA expression profiling and sequencing in tumor tissue 
and/or in blood may be performed to define gene signatures that correlate to clinical response 
to treatment with pembrolizumab or other immunotherapies. Pembrolizumab induces a 
response in tumors that likely reflects an inflamed/immune phenotype. Specific 
immune-related gene sets (ie, those capturing interferon-gamma transcriptional pathways) 
may be evaluated and new signatures may be identified. Individual genes related to the 
immune system may also be evaluated (eg, IL-10). MicroRNA profiling may also be pursued 
as well as exosomal profiling.
Proteomics and IHC using blood and/or tumor
Tumor and/or blood samples from this study may undergo proteomic analyses (eg, PD-L1 
IHC). PD-L1 protein level in tumor sections, assessed by IHC, has been shown to correlate 
with response to pembrolizumab in patients with NSCLC, and an IVD device has been 
developed for use with pembrolizumab in NSCLC. Preliminary data indicates that this 
association may also be true in additional cancer types (ie, triple negative breast cancer, head 
and neck, and gastric). Additional tumor or blood-derived proteins may also correlate with 
response to pembrolizumab. Therefore, tumor tissue may be subjected to proteomic analyses 
using a variety of platforms that could include, but are not limited to, immunoassays and 
liquid chromatography/mass spectrometry. This approach could identify novel protein 
biomarkers that could aid in patient selection for pembrolizumab (MK-3475) therapy.
Other blood-derived biomarkers
In addition to expression on the tumor tissue, PD-L1 and other tumor derived proteins can be 
shed from tumor and released into the blood. Assays such as ELISA measure such proteins in 
serum. Correlation of expression with response to pembrolizumab therapy may identify new 
approaches for predictive biomarkers in blood, representing a major advance from today’s 
reliance on assessing tumor biomarkers. This research would serve to develop such assays for 
future clinical use.
Other molecular changes of interest include the subtype of T-cells in the tumor 
microenvironment. The T-cell repertoire from tumor tissue and blood components may be 
evaluated.
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4.2.1.5
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics (serum, plasma), 
and/or the measurement of other analytes, depending on which specimens are consented for 
future biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of future biomedical research are presented in Appendix 6.
4.2.2
Rationale for the Use of Comparator/Placebo
The current standard of care (SOC) in this patient population is SBRT followed by regular 
imaging surveillance for recurrence of disease. This SOC can be mimicked using a placebo 
control when adding pembrolizumab to the standard SBRT therapy. A placebo control is 
necessary to minimize confounding factors, such as the more frequent office visits and 
physical exams required for administration of pembrolizumab, as well as control for 
knowledge of treatment effects on patient-reported outcome data.
4.3
Justification for Dose
The planned dose of pembrolizumab for this study is 200 mg Q3W. Based on the totality of 
data generated in the KEYTRUDA® development program, 200 mg Q3W is the appropriate 
dose of pembrolizumab for adults across all indications and regardless of tumor type. As 
outlined below, this dose is justified by:
•
Clinical data from 8 randomized studies in melanoma and NSCLC indications 
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 
10 mg/kg Q2W representing an approximate 5- to 7.5-fold exposure range (refer to IB, 
Section 5.2.2),
•
Clinical data showing meaningful improvement in benefit-risk including OS at 200 mg
Q3W across multiple indications, and
•
Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W.
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease settings 
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(treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy). Five studies compared 2 
mg/kg Q3W versus 10 mg/kg Q3W (KEYNOTE-001 Cohort B2, KEYNOTE-001 Cohort D, 
KEYNOTE-002, KEYNOTE-010, and KEYNOTE-021), and 3 studies compared 10 mg/kg 
Q3W versus 10 mg/kg Q2W (KEYNOTE-001 Cohort B3, KEYNOTE-001 Cohort F2 and 
KEYNOTE-006). All of these studies demonstrated flat dose- and exposure-response 
relationships across the doses studied representing an approximate 5- to 7.5-fold difference in 
exposure. The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to the 
highest doses studied. Subsequently, flat dose-exposure-response relationships were also 
observed in other tumor types including head and neck cancer, bladder cancer, gastric cancer 
and classical Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose 
independent of the tumor type. These findings are consistent with the mechanism of action of 
pembrolizumab, which acts by interaction with immune cells, and not via direct binding to 
cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KEYNOTE-001 evaluating target-mediated drug disposition (TMDD) conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W. Second, a PBPK analysis was conducted to predict tumor PD-1 saturation over a wide 
range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that the fixed-dosing 
provides similar control of PK variability as weight-based dosing, with considerable overlap 
in the distribution of exposures from the 200-mg Q3W fixed-dose and 2-mg/kg Q3W dose. 
Supported by these PK characteristics and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200-mg Q3W fixed-dose was 
selected for evaluation across all pembrolizumab protocols.
Drug administration will continue every 3 weeks for one year (17 cycles), similar to the 
interval chosen for patients enrolled in other Merck lung cancer trials that involve resection 
of the lung tumor (KN-091 and KN-671) as well as Merck trials for other early-stage cancers 
where the intent of treatment is curative. Though the lung cancer is not physically removed, 
the destructive effect of radiotherapy is thought to be comparable to surgery and therefore the 
2-year treatment interval, which has become the SOC for patients with residual/metastatic 
disease, is not thought to be necessary. 
The current trial will use the standard SBRT dosing as outlined in the protocol and aligned 
with standard clinical practices and the current guideline documents.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (Section 
7.3). For purposes of analysis and reporting, the overall study ends when the Sponsor 
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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 EEA is defined as First Site Ready (FSR) in any Member State.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
is unacceptable. In addition, further recruitment in the study or at (a) particular study site(s) 
may be stopped due to insufficient compliance with the protocol, GCP, and/or other 
applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
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5
STUDY POPULATION
Male/female participants who are at least 18 years of age with unresected Stage I or II 
(limited Stage IIB, N0, M0) NSCLC and who have received no prior anticancer therapy for 
the present lung cancer will be randomized in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
1. Has previously untreated NSCLC diagnosed by histology or cytology and confirmed as 
Stage I or II (T1 to limited T3, N0, M0) NSCLC (AJCC 8th edition) by chest CT and 
PET scan. Prospective participants with mediastinal lymph nodes measured on chest CT 
as >1 cm in the short axis or PET avid lymph nodes may be eligible if the lymph node(s) 
in question is biopsied and is histologically benign. Note: participants with pericardium 
invasion, >2 nodules or 2 nodules that cannot be treated in one field (>2 cm apart and/or 
total planned target volume [PTV] >163 cc) and diaphragm elevation suggestive of 
phrenic nerve invasion are excluded.
2. Cannot undergo thoracic surgery due to existing medical illness(es) or anatomically 
unresectable tumor as determined by the site’s multidisciplinary tumor board. Medically 
operable participants who decide to treat with SBRT as definitive therapy rather than 
surgery are also eligible, if patient’s unwillingness to undergo surgical resection is clearly 
documented. If there is no tumor board, then this decision will be made by the 
investigator in consultation with a thoracic surgeon and a radiation oncologist if the 
investigator is not a radiation oncologist.
3. Has an ECOG performance status of 0, 1, or 2.
4. Is able to receive SBRT and does not have an ultra-centrally located tumor as defined in 
the radiation manual.
5. Has adequate organ function as defined in the following table (Table 2). Specimens must 
be collected within 7 days prior to the start of study intervention.
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Table 2
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 calculated creatinine clearance
OR
GFR
≥30 mL/min
≥30 mL/min
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for participants 
with total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN
Coagulation
International normalized ratio (INR) OR 
prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or PTT 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.
aCriteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.
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.
Demographics
6. Is male or female, ≥18 years of age, at the time of signing the informed consent.
Male Participants
7. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 90 days after the last dose of radiotherapy:
•
Refrain from donating sperm.
PLUS either:
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long-term and persistent basis) and agree to remain abstinent.
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OR
•
Must agree to use 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:
-
Agree to use a male condom plus partner use of an additional contraceptive method 
when having penile-vaginal intercourse with a WOCBP (see Section 10.5) who is not 
currently pregnant. Note: Male participants 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.
Female Participants
8. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:
•
Is not a WOCBP.
OR
-
Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year) or be abstinent from heterosexual intercourse as their preferred 
and usual lifestyle (abstinent on a long-term and persistent basis), as described in
Appendix 5 during the intervention period and for at least 120 days after last dose of 
pembrolizumab/placebo and 180 days after the last radiotherapy dose. The 
investigator should evaluate the potential for contraceptive method failure (ie, 
noncompliance, recently initiated) in relationship to the first dose of study 
intervention. 
-
A WOCBP must have 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 8.3.4.2.
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-
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
-
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Informed Consent
9. The participant (or legally acceptable representative) has provided documented informed 
consent/assent for the study. The participant may also provide consent/assent for future 
biomedical research. However, the participant may participate in the study without 
participating in future biomedical research.
10. Has a radiation therapy plan approved by the central radiation therapy quality assurance 
vendor.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Is a WOCBP who has a positive highly sensitive pregnancy test within 24 hours for urine 
or 72 hours for serum prior to randomization or treatment allocation (see Appendix 5). If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required.
Note: If 24 hours for urine or 72 hours for serum have elapsed between the screening 
pregnancy test and the first dose of study intervention, another pregnancy test (urine or 
serum) must be performed and must be negative in order for participant to start receiving 
study medication.
Prior/Concomitant Therapy
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an 
agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, 
OX-40, CD137).
3. Has received prior radiotherapy to the thorax, including radiotherapy to the esophagus, 
mediastinum, or breast. Participants receiving radiotherapy to the contralateral breast at 
least 5 years prior to randomization may still be eligible.
4. Has received a live vaccine within 30 days prior to the first dose of study intervention. 
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 6.5 for 
information on COVID-19 vaccine.
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Prior/Concurrent Clinical Study Experience
5. Has received an investigational agent or has used an investigational device within 4 
weeks prior to the first dose of study intervention administration.
Diagnostic Assessments
6. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of study drug.
7. Has a known additional malignancy that is progressing or has required active treatment 
within the past 3 years. A prior NSCLC that occurred and was treated curatively at least 
2 years prior to the date of the current diagnosis would be considered a separate primary 
lung cancer, and therefore an additional malignancy.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded.
8. Has a known hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. 
9. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis. 
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 an active autoimmune disease that has required systemic treatment in past 2 years 
except replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid).
12. Has an active infection requiring systemic therapy.
13. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing 
is required unless mandated by local health authority.
14. Has a known history of active tuberculosis (TB; Bacillus tuberculosis). No TB testing is 
required unless mandated by local health authority.
15. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant’s participation 
for the full duration of the study, or is not in the best interest of the participant to 
participate, in the opinion of the treating investigator.
16. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
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Other Exclusions
17. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with the Screening Visit through 120 days after 
last dose of pembrolizumab/placebo and 180 days after the last radiotherapy dose.
18. Has had an allogeneic tissue/solid organ transplant.
19. Participants who have not adequately recovered from major surgery or have ongoing 
surgical complications.
Note: Country-specific differences are noted in Appendix 7.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
Participants should maintain a normal lifestyle; however, may be encouraged to restrict 
tobacco use on the study.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen-failure information is 
required to ensure transparent reporting of screen-failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen-failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention or withdraws from the study will not 
be replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
6.1
Study Intervention(s) Administered
In alignment with the study update memo sent to Investigators on 29-AUG-2024, all 
study participants must stop ongoing treatment with pembrolizumab/placebo. These 
participants must complete EOT visit followed by Safety Follow-up visit per protocol. 
All remaining study participants who have completed the safety reporting windows for 
AEs and SAEs per protocol must be discontinued from the study. All study participants 
will undergo unblinding at the end of the study. Investigators may apply for unblinding 
participants per protocol in the interim.
The study interventions to be used in this study are outlined in Table 3.
Country-specific differences are noted in Appendix 7.
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Table 3
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formula-
tion
Unit Dose 
Strength(s)
Dosage Level(s) Route of 
Administ
ration
Regimen/
Treatment 
Period
Use
IMP or
NIMP/A
xMP
Sour-
cing
Arm 1
Experimental
Pembrolizumab 
(MK-3475)
Drug
Injection, 
Solution
25 mg/mL
200 mg
IV 
Infusion
Q3W x17 
cycles (~1 
year)
Test Product
IMP
Central
Arm 1
Experimental
SBRT
Radiation
Not 
Applicable
Peripheral 
Tumors: 45-60 
Gy in 3 
fractions 
(preferred); 
48-50 Gy in 
4 fractions 
(acceptable); 
50-55 Gy in 
5 fractions 
(acceptable)
Abutting the 
chest wall: 
48-50 Gy in 
4 fractions; 
50-55 Gy in 
5 fractions
Central 
Tumors: 50-55 
Gy in 5 
fractions; 
60-70 Gy in 
8 fractions
Peripheral 
Tumors: 45-60 
Gy in 3 fractions 
(preferred); 48 
50 Gy in 4 
fractions 
(acceptable); 50 
55 Gy in 5 
fractions 
(acceptable)
Abutting the 
chest wall: 48 50 
Gy in 4 
fractions; 50 55 
Gy in 5 fractions
Central Tumors: 
50-55 Gy in 5 
fractions; 60 70 
Gy in 8 fractions
External 
Beam 
Radiation
~Q3D over 2 
weeks
Background 
Treatment
NIMP/A
xMP
Local
Arm 2
Placebo 
Comparator
Placebo
Drug
Injection, 
Solution
N/A
N/A
IV 
Infusion
Q3W × 17 
cycles (~1 
year)
Placebo
IMP
Local
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Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formula-
tion
Unit Dose 
Strength(s)
Dosage Level(s) Route of 
Administ
ration
Regimen/
Treatment 
Period
Use
IMP or
NIMP/A
xMP
Sour-
cing
Arm 2
Active 
Comparator
SBRT
Radiation
Not 
Applicable
Peripheral 
Tumors: 45-60 
Gy in 3 
fractions 
(preferred); 
48-50 Gy in 
4 fractions 
(acceptable); 
50-55 Gy in 
5 fractions 
(acceptable)
Abutting the 
chest wall: 
48-50 Gy in 
4 fractions; 
50-55 Gy in 
5 fractions
Central 
Tumors: 50-55 
Gy in 
5 fractions; 
60-70 Gy in 
8 fractions
Peripheral 
Tumors: 45-60 
Gy in 3 fractions 
(preferred); 48 
50 Gy in 4 
fractions 
(acceptable); 50 
55 Gy in 5 
fractions 
(acceptable)
Abutting the 
chest wall: 48 50 
Gy in 4 
fractions; 50 55 
Gy in 5 fractions
Central Tumors: 
50-55 Gy in 5 
fractions; 60 70 
Gy in 8 fractions
External 
Beam 
Radiation
~Q3D over 2 
weeks
Background 
Treatment
NIMP/A
xMP
Local
EEA=European Economic Area; IMP=investigational medicinal product; IV=intravenous, N/A=not applicable; NIMP/AxMP=noninvestigational/auxiliary medicinal 
product.Q3W=every 3 weeks; SBRT=stereotactic body radiotherapy
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with 
respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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All study interventions will be administered on an outpatient basis.
All products indicated in Table 3 will be provided centrally by the Sponsor or locally by the 
study site, subsidiary, or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the study site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number. 
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of pembrolizumab and placebo are provided in the 
Pharmacy Manual.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions 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 intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
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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 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention allocation/randomization will occur centrally using an IRT system. There are 2
study intervention arms. Participants will be assigned randomly in a 1:1 ratio to 
pembrolizumab with SBRT or placebo with SBRT, respectively.
6.3.2
Stratification
Intervention allocation/randomization will be stratified according to the following factors:
•
Disease stage: Stage I versus Stage II
•
ECOG performance status: 0 or 1 versus 2
•
Geographic region of enrollment site: East Asia versus non-East Asia
•
Reason for not receiving surgery: medically inoperable versus refused surgery
6.3.3
Blinding
In alignment with the study update memo sent to Investigators on 29-AUG-2024, all 
study participants must stop ongoing treatment with pembrolizumab/placebo. These 
participants must complete EOT visit followed by Safety Follow-up visit per protocol. 
All remaining study participants who have completed the safety reporting windows for 
AEs and SAEs per protocol must be discontinued from the study. All study participants 
will undergo unblinding at the end of the study. Investigators may apply for unblinding 
participants per protocol in the interim.
The subsection below is retained for reference. 
A double-blinding technique will be used. Pembrolizumab and placebo (normal saline) will 
be prepared and/or dispensed in a blinded fashion by an unblinded pharmacist or qualified 
study-site personnel. The participant, the investigator, and Sponsor personnel or delegate(s) 
who are involved in the study intervention administration or clinical evaluation of the 
participants are unaware of the intervention assignments.
6.4
Study Intervention Compliance
If there are interruptions in the study intervention schedule or infusion/injection was stopped, 
the details of and reason for any interruption or infusion/injection cessation of study 
intervention will be documented in the participant’s medical record.
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Interruptions from the protocol-specified treatment >12 weeks require consultation between 
the investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study. If there is a clinical indication for any medication or vaccination 
specifically prohibited, discontinuation from study therapy or vaccination may be required. 
the investigator should discuss any questions regarding this with the Sponsor's Clinical 
Director. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician. However, the decision to continue the 
participant on study intervention requires the mutual agreement of the investigator, the 
Sponsor, and the participant.
Participants are prohibited from receiving the following concomitant therapy or vaccination 
during the course of the study:
•
Antineoplastic systemic chemotherapy or biological therapy
•
Immunotherapy not specified in this protocol
•
Investigational agents other than pembrolizumab
•
Radiation therapy not specified in this protocol
•
Live or liveattenuated vaccines within 30 days prior to the first dose of study intervention 
and while participating in the study. 
Examples of live vaccines include, but are not limited to, the following: measles, mumps, 
rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. Seasonal 
influenza vaccines for injection are generally killed virus vaccines and are allowed; 
however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and 
are not allowed.
•
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, replication-
incompetent adenoviral vaccines, or inactivated vaccines. These vaccines will be treated 
just as any other concomitant therapy.
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not 
allowed.
•
Systemic glucocorticoids except when used for the following purposes:
-
To modulate symptoms of an AE that is suspected to have an immunologic etiology
-
For the prevention of emesis
-
To premedicate for IV contrast allergies
-
To treat asthma or chronic obstructive pulmonary disease (COPD) exacerbations 
(only short-term oral or IV use in doses >10 mg/day prednisone equivalent)
-
For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent
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-
Treatment of radiation pneumonitis. Refer to Table 4 to follow the same management 
guidelines for irAE pneumonitis
•
Other glucocorticoid use except when used for the following purposes:
-
For topical use or ocular use
-
Intraarticular joint use
-
For inhalation in the management of asthma or COPD
Participants who, in the assessment of the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the eCRF including all 
prescription, over-the-counter (OTC) products, herbal supplements, and IV medications and 
fluids. If changes occur during the study period, documentation of drug dosage, frequency, 
route, and date should also be included on the eCRF.
All concomitant medications received within 42 days prior to the first dose of study 
intervention and up to 30 days after the last dose of study intervention should be recorded. 
Concomitant medications administered 30 days after the last dose of study intervention 
should be recorded for SAEs and events of clinical interest (ECIs) as defined in 
Section 8.4.7.
6.5.1
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 6.6, Table 4. Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids. Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be 
related to pembrolizumab.
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. Refer to Table 4 in 
Section 6.6 for guidelines regarding dose modification and supportive care.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
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6.6
Dose Modification (Escalation/Titration/Other)
Pembrolizumab dose reductions are not permitted. Pembrolizumab treatment may be 
interrupted or discontinued due to toxicity. Pembrolizumab may be interrupted for a 
maximum of 12 weeks. An interruption of study intervention for more than 12 weeks will 
require Sponsor approval before treatment can be resumed (see Section 6.4). See Appendix 7 
for country-specific dose modification requirements.
If radiotherapy is not completed for any reason, the participant may continue with 
pembrolizumab/placebo for up to 17 total treatment cycles (1 year). If SBRT is interrupted 
due to toxicity, all fractions of radiotherapy must be completed prior to Cycle 2 Day 1 of 
pembrolizumab/placebo (day second dose is administered) or SBRT must be discontinued 
early. Should the participant develop radiation pneumonitis, refer to Table 4 to follow the 
same management guidelines for irAE pneumonitis, specifically with action taken for study 
intervention, and treat as per local SOC.
Dose Modification and Toxicity Management for Immune-related AEs Associated With 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids, and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation.
Based on the severity of irAEs, withhold or permanently discontinue pembrolizumab and 
administer corticosteroids.
Dose Modification and Toxicity Management Guidelines for irAEs Associated With 
Pembrolizumab Monotherapy, Coformulations, or IO Combinations are provided in Table 4.
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Table 4
Dose Modification and Toxicity Management Guidelines for Immune-related 
Adverse Events Associated with Pembrolizumab Monotherapy, Coformulations or IO 
Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. 
Other immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if 
the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of the last 
treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment 
may resume after the irAE decreased to ≤Grade 1 after corticosteroid taper.
irAEs
Toxicity 
Grade 
(CTCAE
v4.0)
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
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irAEs
Toxicity 
Grade 
(CTCAE
v4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations 
or IO 
Combinations
Corticosteroid and/or 
Other Therapies
Monitoring and 
Follow-up
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
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
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irAEs
Toxicity 
Grade 
(CTCAE
v4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations 
or IO 
Combinations
Corticosteroid and/or 
Other Therapies
Monitoring and 
Follow-up
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
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
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irAEs
Toxicity 
Grade 
(CTCAE
v4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations 
or IO 
Combinations
Corticosteroid and/or 
Other Therapies
Monitoring and 
Follow-up
All Other irAEs
Persistent 
Grade 2
Withhold
• Based on severity 
of AE administer 
corticosteroids
• Ensure adequate 
evaluation to confirm 
etiology or exclude 
other causes
Grade 3
Withhold or 
discontinue 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).
Dose Modification and Toxicity Management of Infusion Reactions Related to 
Pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 5.
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Table 5
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator.
None
Grade 2
Requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment (eg, 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hours
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator.
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (eg, from 
100 mL/hr to 50 mL/hr). Otherwise, dosing will 
be held until symptoms resolve and the 
participant should be premedicated for the next 
scheduled dose.
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further study 
drug intervention.
Participant may be 
premedicated 1.5 h 
(± 30 minutes) prior to 
infusion of study intervention 
with:
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic).
Grades 3 or 4
Grade 3:
Prolonged (ie, not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization 
indicated for other 
clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Participant is permanently discontinued from 
further study drug intervention.
No subsequent dosing
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
CTCAE = Common Terminology Criteria for Adverse Event; IV = intravenous; NCI = National Cancer Institute; 
NSAID = nonsteroidal anti-inflammatory drug; po = orally.
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. Participants should 
be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the Sponsor. The reason for interruption should be documented in 
the participant’s study record.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
The pembrolizumab treatment in the study is blinded but supplies are provided open label; 
therefore, unblinded pharmacist or qualified trial site personnel will be used to blind supplies. 
Study intervention identity (name, strength, or potency) is included in the label text; random 
code/disclosure envelopes or lists are not provided.
6.9
Standard Policies
Study site personnel will have access to a central electronic treatment 
allocation/randomization system (IVRS/IWRS system) to allocate participants, to assign 
study intervention to participants, and to manage the distribution of clinical supplies. Each 
person accessing the IVRS system must be assigned an individual unique PIN. They must 
use only their assigned PIN to access the system, and they must not share their assigned PIN 
with anyone.
6.9.1
Study Site Retention Samples
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to the participants, and the amount 
remaining at the conclusion of the study. For all study sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate. Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Clinical supplies must be stored in a secure, limited access location under the storage 
conditions specified on the label. 
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Receipt and dispensing of study medication must be recorded by an authorized person at the 
study site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
NOTE: Based on the data from an interim safety and efficacy analysis for 
KEYNOTE¬867 (data cutoff 11-JUN-2024), the eDMC recommended stopping the 
study since pembrolizumab in combination with SBRT did not demonstrate an 
improvement in EFS or OS, the study’s primary endpoint and key secondary endpoint, 
respectively, compared to placebo plus SBRT, and the benefit/risk profile of the 
combination did not support continuing the trial. All prespecified interim analyses after 
IA1 and final analysis of the study described in the SAP will not be performed. Safety 
analysis will be performed at the end of the study; there will be no further pre-planned 
analyses for efficacy and ePRO endpoints collected from participants beyond the IA1 
cutoff date of 11-JUN-2024. The subsections below are retained for reference. 
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention 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 intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period regimen will still continue to participate in the study as specified in Section 1.3 and 
Section 8.11.3.
Participants may discontinue study intervention at any time for any reason or be dropped
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9.
A participant must be discontinued from study intervention, 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 intervention.
•
The participant interrupts study intervention administration for more than 12 weeks 
without Sponsor Approval.
•
The participant does not start SBRT for any reason.
•
The participant’s treatment assignment has been intentionally unblinded by the 
investigator, MSD subsidiary, or through the emergency unblinding call center. Note: if a 
participant’s treatment is unintentionally unblinded, the participant is not required to 
discontinue treatment.
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•
Any prolonged interruption of study intervention beyond the permitted periods, for irAE 
management or other allowed dose interruptions, as noted in Section 6.6, require Sponsor 
consultation prior to restarting treatment. If treatment will not be restarted, the participant 
will continue to be monitored in the study and the reason for discontinuation of study 
intervention will be recorded in the medical record.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, places the participant at unnecessary risk from continued 
administration of study intervention.
•
Pathological recurrence of disease or radiographic recurrence of disease outlined in 
Section 8.2.1.3. If the radiographic recurrence is biopsied and the pathology is negative, 
the patient may continue treatment until pathological or radiographic confirmation of 
recurrence by repeat imaging or biopsy.
•
The participant has a confirmed positive serum pregnancy test.
•
Completion of 17 doses (approximately 1 year) of pembrolizumab/placebo.
•
Prohibited concomitant therapy or vaccinations as defined in Section 6.5 are administered 
during the study.
•
Recurrent Grade 2, Grade 3, or Grade 4 pneumonitis of any cause and Grade 3 colitis.
•
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active 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 6.6.
For participants who are discontinued from study intervention but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed. 
Participants who discontinue treatment for reasons other than pathologically confirmed 
recurrence of disease (ie, by biopsy), should continue to be monitored by tumor imaging until 
BICR-verified disease recurrence as described in Section 8.2.1.4, withdrawing consent, 
pregnancy, death, or loss to follow-up, whichever occurs first. Participants assigned to 
placebo will not have an opportunity to crossover to pembrolizumab at the time of recurrence 
within the scope of this clinical trial; however, pembrolizumab may be administered as a 
subsequent therapy off-study based on the current pembrolizumab product labeling if 
indicated for that participant’s disease state at the time of recurrence or at any point in the 
course of the disease.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
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Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in 
Section 8.1.9. The procedures to be performed should a participant repeatedly fail to return 
for scheduled visits and/or if the study site is unable to contact the participant are outlined in 
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
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 providing documented informed consent may be used 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), 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 is described in operations/laboratory manual.
•
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
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8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used 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 intervention 
allocation/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
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The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed within the prior 
10 years that the investigator considers to be clinically important. Details regarding the 
disease for which the participant has enrolled in this study will be recorded separately and 
not listed as medical history.
The medical history must include documentation of the reason(s) the participant is 
undergoing definitive SBRT instead of surgery, as determined by the site’s multidisciplinary 
tumor board. If there is no tumor board, then this decision will be made by the investigator in 
consultation with a thoracic surgeon and a radiation oncologist if the investigator is not a 
radiation oncologist. This documentation will be kept with the participant’s study records. 
If the participant is considered medically inoperable due to one or more comorbidities, these 
comorbidity(ies) should be included in the participant’s study records. Reasons a participant 
may be considered medically inoperable include, but are not limited to, a history of poor 
pulmonary function, heart disease, diabetes, vascular disease, or a combination of several 
unrelated comorbidities that, taken together, contribute to the decision that the participant is 
not suitable for surgery.
If the participant’s tumor is in an anatomically unresectable location, this should be 
documented in the medical history as the reason the participant is considered inoperable. If 
the participant has refused surgery, this must also be documented clearly at site as part of the 
participant’s medical history.
To ensure the ethical inclusion of prospective participants with medically operable NSCLC 
without any undue coercion, these participants will be clearly informed of the advantages of 
surgery and be sufficiently aware that surgical resection is the preferred treatment for 
early-stage NSCLC. This discussion occurs prior to providing the participant with any 
information regarding the KEYNOTE-867 study and in advance of any offer to be screened 
for enrollment in the study. Thus, the participant’s election to forego surgery will be a 
well-informed decision, made in advance of and with no specific knowledge of the 
KEYNOTE-867 study, so that inclusion in the study would not impact the opportunity for 
decision to undergo surgery.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 42 days before starting the study. Treatment for the disease for which the participant 
has enrolled in this study will be recorded separately and not listed as a prior medication.
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8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the Safety Follow-up Visit.
8.1.6
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 before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused 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/rescreening visit 
requirements are provided in Section 8.11.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a randomization number. 
The randomization number identifies the participant for all procedures occurring after 
randomization. Once a randomization number is assigned to a participant, it can never be 
reassigned to another participant.
A single participant cannot be assigned more than 1 randomization number.
Trial treatment should begin on the day of randomization or as close as possible to the date 
on which the participant is allocated/assigned.
8.1.8
Study Intervention Administration
Administration of study medication will be witnessed by the investigator and/or study staff.
8.1.8.1
Timing of Dose Administration
8.1.8.1.1
Pembrolizumab or Matching Placebo
Pembrolizumab will be administered as a dose of 200 mg using a 30-minute IV infusion 
Q3W. Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window 
of -5 minutes and +10 minutes is permitted (ie, infusion time is 30 minutes -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for pembrolizumab reconstitution, 
preparation of the infusion fluid, and administration 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 
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qualified trial site personnel in the same manner as the investigational product 
(pembrolizumab).
The first dose of pembrolizumab or placebo should be administered prior to start of SBRT.
8.1.8.1.2
Stereotactic Body Radiotherapy
Radiotherapy will be administered in 3 fractions totaling 45-60 Gy (preferred regimen), 
4 fractions totaling 48-50 Gy, or 5 fractions totaling 50-55 Gy (acceptable regimens) for 
peripheral tumors, 4 fractions totaling 48-50 Gy or 5 fractions totaling 50-55 Gy for tumors 
abutting the chest wall, and 5 fractions totaling 50-55 Gy or 8 fractions totaling 60-70 Gy for 
central tumors, defined as within 2 cm of the proximal bronchial tree and/or abutting the 
mediastinal pleural. Ultra-centrally located tumors, defined as tumors whose PTV directly 
contacts or overlaps the proximal bronchial tree, trachea, mainstem bronchus, esophagus, 
pulmonary vein, or pulmonary artery are not appropriate for SBRT and are excluded from 
enrollment in this study.
SBRT will be administered preferably starting on C1D1, following administration of 
pembrolizumab/placebo. There is an allowed window of +7 days to begin SBRT treatment 
(SBRT treatment must begin between C1D1 and C1D8, inclusive). SBRT will be 
administered over no more than 2 weeks.
Center credentialing for radiotherapy will be performed according to criteria defined in the 
Radiotherapy QA manual. Participating institutions must comply with the radiation therapy 
quality assurance (RT QA) requirements and procedures described in the Radiotherapy QA 
manual. Sites that do not conform to the requirements of the credentialing will not be allowed 
to participate.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA and Section 8.11.2.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the final study visit should be performed at the time of withdrawal. 
Any AEs that are present at the time of withdrawal should be followed in accordance with 
the safety requirements outlined in Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
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already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.10
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to
him/her promptly and report unblinding to the Sponsor. Before contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
toxicity grade of the AEs observed, the relation to study intervention, the reason thereof, etc, 
in the medical record. If it is not possible to record this assessment in the medical record 
before the unblinding, the unblinding should not be delayed.
If 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.
For studies that require nonemergency unblinding as part of the study design (eg, disease 
progression) to support treatment decisions, instructions in the Procedures Manual should be 
followed. The emergency unblinding center should not be used for this purpose.
Once an emergency unblinding or a nonemergency unblinding that is part of the study design 
has taken place, the investigator, site personnel, and Sponsor personnel may be unblinded so 
that the appropriate follow-up medical care can be provided to the participant.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
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8.2
Efficacy Assessments
8.2.1
Tumor Imaging and Assessment of Disease
As of Amendment 08: Central tumor response assessments will be discontinued. 
Imaging scans will no longer be submitted to iCRO nor read by BICR. Tumor imaging, 
biopsies, and disease management should be performed per local SOC and 
Investigator’s discretion. The subsections below are retained for reference. 
The process for image collection and transmission to the central imaging vendor can be 
found in the Site Imaging Manual. Screening imaging must also be submitted to the radiation 
therapy quality assurance vendor as part of the radiation treatment plan approval process; 
details of this process are found in the RT QA manual. The same imaging technique 
regarding modality and use of contrast should be used consistently throughout the study. The 
imaging schedule should follow calendar days and should not be adjusted for cycle delays.
Screening imaging:
•
CT with IV and oral contrast (preferred) of the chest and abdomen for all participants, or 
non-contrast CT of the chest and magnetic resonance imaging (MRI) of the abdomen 
with IV gadolinium for participants in whom iodinated contrast is contraindicated. 
Additional anatomy (eg, pelvis/brain) should be captured as clinically indicated. A 
whole-body fluorodeoxyglucose-positron emission tomography (FDG-PET) scan should 
also be performed. 
Post allocation imaging:
•
CT of the chest and abdomen, consistent with the method used at screening. Additional 
anatomy (pelvis/brain/extremity/etc.) should be captured as clinically indicated.
Local site investigator/radiology assessment of PET imaging to confirm staging (T1 or 2, N0, 
M0) will be used to determine participant eligibility. All scheduled images for all study 
participants from the sites will be submitted to the central imaging vendor. In addition, all 
other imaging (including all modalities and anatomies) obtained at an unscheduled time point 
to determine disease recurrence, as well as supplemental imaging obtained for other reasons 
that captures radiologic recurrence, must be submitted to the central imaging vendor.
8.2.1.1
Initial Tumor Scans
Initial tumor imaging (whole-body FDG-PET and CT of chest and abdomen) at screening 
must be performed within 42 days prior to the date of randomization. The site 
investigator/local radiology reviewer must review screening images to confirm the 
participant has no nodal or metastatic involvement. The screening images must be submitted 
to the central imaging vendor for retrospective review. This scan is considered the reference 
point for regional or distant recurrence on study.
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Tumor imaging via PET/CT performed as part of routine clinical management (prior to 
documented informed consent signature) is acceptable for use as screening tumor imaging if 
the CT portion is of diagnostic quality, is performed within 42 days prior to the date of 
randomization and can be assessed by the central imaging vendor retrospectively.
8.2.1.2
Tumor Scans During the Study
The first scheduled post randomization imaging assessment (chest and abdomen CT) should 
be performed at 12 weeks (±7 days) from the date of randomization (at least 10 weeks post 
completion of SBRT). This scan is considered the reference point for monitoring local 
recurrence (see Section 8.2.1.3), however, unscheduled imaging due to new clinical 
symptoms can occur at any time, including prior to the Week 12 assessment, to identify 
either new metastatic/regional disease or recurrence of local treated disease. Subsequent 
tumor imaging should be performed every 16 weeks (Q16W ± 7 days) until 156 weeks 
post-randomization; and every 6 months (Q6M ± 14 days) thereafter [Schneider, B. J., et al 
2019]. Images will continue to be obtained (Q6M ± 14 days) even after initiating the new 
anticancer therapy if recurrence has not been document or verified by BICR.
Timing of tumor imaging should follow calendar days and should not be adjusted for delays 
in cycle starts. (Note: the date imaging is performed is the date of assessment, not the date 
the images are reviewed.) Imaging should continue to be performed until disease recurrence 
as assessed by local investigator/radiologist, withdrawal of consent, pregnancy, loss to 
follow-up, or death, whichever occurs first. Supplemental imaging must be submitted to the 
central imaging vendor if it shows evidence of recurrence.
8.2.1.3
Assessment of Disease Recurrence 
As of Amendment 08: Disease recurrence assessments will be discontinued. The 
subsections below are retained for reference. 
Following randomization, the site investigator/radiologist will assess all study imaging for 
local, regional, or distant disease recurrence as defined in this protocol. The CT imaging 
captured at 12 weeks post randomization will be considered the reference scan for qualitative 
assessment of local recurrence. Recurrence must be verified by biopsy where medically 
appropriate, and by sequential imaging (at least 4 weeks after initial recurrence) where 
biopsy is not medically appropriate.
8.2.1.3.1
Local Disease Recurrence 
Local disease recurrence is radiographically defined as the regrowth of the primary lesion as 
compared to the reference imaging acquired at 12 weeks post randomization or the 
appearance of new disease (per the principles of RECIST 1.1) elsewhere within the same 
lobe. For the assessment conducted at 12 weeks, the site radiological review must consider 
the potential for local tissue effects due to SBRT, which may make disease assessment 
challenging. If there are changes that are questionable, scanning should continue at least 
4 weeks later or at the next scheduled scan, and if later imaging shows that the local growth 
continues, the time of recurrence will be assigned to the scan where the changes were first 
observed. Local recurrence must be confirmed with a biopsy unless a biopsy is not medically 
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appropriate per investigator decision. Due to the effects of SBRT, PET-positivity is not
sufficient to determine local recurrence in the absence of other factors (eg, unequivocal 
regrowth, positive biopsy).
8.2.1.3.2
Regional or Distant Disease Recurrence 
Regional disease recurrence is radiographically defined as the appearance of new lesions in a 
different lobe of the lung ipsilateral to where the primary tumor originated, or malignant 
thoracic lymph nodes (thoracic nodes as defined in AJCC v8 staging guideline, Figure 3 and 
Figure 4) as compared to the screening PET/CT. Distant disease recurrence is 
radiographically defined as the appearance of new lesions in lobes of the lung contralateral to 
where the primary tumor originated, malignant pleural/pericardial nodules or effusions, 
organs other than the lungs, or the appearance of malignant non-thoracic lymph nodes as 
compared to the screening PET/CT. Palpable lesions should be confirmed by biopsy and 
captured by imaging for central review. New lesions should be identified following the 
principles of RECIST 1.1 and should be unequivocal. If new lesions are equivocal, the 
participant should continue on study (either on treatment or in follow-up if treatment was 
completed/discontinued) to the next scheduled imaging assessment. This follow-up 
evaluation will be used to clarify if the equivocal lesion represents recurrent disease; if it 
does, the recurrence should be dated to the first appearance of the lesion or malignant node. 
This imaging assessment can be performed early if clinically indicated. Recurrence must be 
confirmed with a biopsy unless a biopsy is not medically appropriate per investigator 
decision. PET avidity is typically considered sufficient to identify a new lesion or support of 
malignancy for an equivocal lesion, according to RECIST 1.1; however, in this study, 
caution should be used when PET avidity is assessed, particularly in the anatomical areas 
within the radiotherapy window for SBRT. SBRT is known to cause changes in tissue that 
can cause PET avidity that can continue beyond the treatment dates for SBRT. When 
medically appropriate, new lesions noted on PET or PET/CT must be confirmed with a 
biopsy.
Regional and distant disease recurrence can be determined at the 12-week reference scan or 
any point thereafter.
If a biopsy is obtained to confirm disease, a solitary new lung cancer with histology identical 
to the primary lung cancer, as determined by investigator, will be considered as disease 
recurrence. A solitary lung cancer with a different histology from the primary tumor, as 
determined by investigator, will be considered as a separate new lung cancer and must be 
documented as a SAE per Section 10.3.3.
8.2.1.4
Central Verification of Disease Recurrence 
Initial tumor imaging showing site assessed disease recurrence should be submitted 
immediately for central imaging vendor verification of recurrence. The site and Sponsor will 
be notified whether the central imaging vendor verifies disease recurrence. If the central 
imaging vendor does not verify site-identified recurrence, the participant should remain on 
study (in treatment or in follow-up if treatment was completed/discontinued) until the next 
scheduled imaging assessment, which would again be submitted for verification of 
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recurrence. This repeat imaging may be performed earlier than the next scheduled imaging 
assessment if clinically indicated. If the recurrent disease was confirmed by biopsy, repeat 
imaging and repeat verification of recurrence is not required.
8.2.1.5
End-of-treatment and Follow-up Tumor Scans
If participants discontinue study intervention, tumor scans should be performed at the time of 
discontinuation (±4-week window) unless previous scans were obtained within 4 weeks of 
discontinuation. If participants discontinue study intervention due to documented disease 
recurrence, this is the final required tumor scan.
If participants discontinue study intervention without documented disease progression, every 
effort is to be made to monitor disease status by acquiring tumor scans using the same 
schedule calculated from the date of [randomization/allocation], refer to Section 8.2.1.2.
Scans are to be continued until one of the following conditions are met:
•
Disease progression as defined by RECIST 1.1 verified by BICR
•
Pregnancy
•
Death
•
Withdrawal of consent
•
The end of the study
8.2.2
Patient-reported Outcomes
The EORTC QLQ-C30, EORTC QLQ-LC13, and EuroQoL EQ-5D-5L questionnaires will 
be administered by trained site personnel and completed electronically by participants in the 
following order: EORTC QLQ-C30 first, then EORTC QLQ-LC13, then EuroQoL 
EQ-5D-5L. 
The questionnaires should be administered prior to dosing at Cycle 1, Cycle 5, Cycle 9, 
Cycle 13, and Cycle 17 during treatment, at the treatment Discontinuation Visit and at the 
Safety Follow-up Visit. Posttreatment, the questionnaires will be administered every 
16 weeks for the first 3 years, followed by every 6 months from the fourth year onwards, and 
should be performed concurrently with the follow-up tumor imaging.
It is best practice and strongly recommended that ePROs are administered to randomized 
participants before drug administration, AE evaluation, and disease status notification. If the 
participant does not complete the ePROs at a scheduled time point, the MISS_MODE form 
must be completed to capture the reason the assessment was not performed.
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8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy 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.
8.3.1
Physical Examinations
8.3.1.1
Full Physical Examination
The investigator or qualified designee will perform a complete physical examination during 
the Screening period (consistent with local requirements) as per institutional standard. Height 
and weight will also be measured and recorded. Investigators should pay special attention to 
clinical signs related to previous serious illnesses. Clinically significant abnormal findings
should be recorded as medical history. The time points for full physical exams are described 
in the SoA in Section 1.3. After the first dose of study intervention, new clinically significant 
abnormal findings should be recorded as AEs.
8.3.1.2
Directed Physical Examination
For cycles that do not require a full physical examination as defined in Section 1.3, the 
investigator or qualified designee will perform a directed physical examination as clinically 
indicated prior to study intervention administration. New clinically significant abnormal 
findings should be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
Vital signs will be measured in a semi-supine position after 5 minutes rest and will include 
temperature, systolic and diastolic blood pressure, pulse, and respiration rate. All vital signs 
should be collected prior to administration of pembrolizumab/placebo.
Country-specific differences are noted in Appendix 7.
8.3.3
Electrocardiograms
A 12-lead ECG will be obtained and reviewed by an investigator or medically qualified 
designee (consistent with local requirements) as outlined in the SoA using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals.
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8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the SoA (Section 1.3).
•
If laboratory values from nonprotocol-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 7 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
Details regarding specific laboratory procedures/assessments to be performed in this study 
are provided below. The total amount of blood/tissue to be drawn/collected over the course 
of the study (from pre-study to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant can be found in the Study 
Procedures Manual. Refer to the SoA (Section 1.3) for the timing of laboratory assessments.
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
8.3.4.2
Pregnancy Test
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1. 
WOCBP require negative highly sensitive pregnancy test (urine or serum) within 24 
hours for urine or within 72 hours for serum before first dose of study intervention. 
The definition of WOCBP is provided in Appendix 5. If a urine test is positive or not 
evaluable, a serum test will be required. Participants must be excluded/discontinued 
from the study in the event of a positive test result. Repeated pregnancy tests (such as 
monthly testing) must be performed prior to each study dose, and additional testing 
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. See Appendix 7 for further country-specific details.
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-
Pregnancy testing (serum as required by local regulations) should be conducted every 
treatment cycle (Q3W) during study intervention.
-
Pregnancy testing (serum or urine as required by local regulations) should be 
conducted for the time required to eliminate systemic exposure after cessation of 
study intervention as described in Section 5.1.
-
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 subject's participation in the study.
8.3.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (see Appendix 8) at 
screening, before the administration of each dose of study intervention and during the 
follow-up period as specified in the SoA (Section 1.3).
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. The investigator, who is a qualified physician, 
will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity/toxicity, and causality. Disease recurrence of the 
cancer under study is not considered an AE, as described in Section 8.4.6.
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8.4.1
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 intervention allocation/randomization, must be 
reported by the investigator if the participant is receiving placebo run-in or other run-in 
treatment, if the event cause the participant to be excluded from the study, or is the result of a 
protocol-specified intervention, including, but not limited to washout or discontinuation of 
usual therapy, diet, or a procedure.
•
All AEs from the time of intervention allocation/randomization through 30 days 
following cessation of study intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of intervention allocation/randomization 
through 90 days following cessation of study intervention or 30 days following cessation 
of study intervention 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 intervention 
allocation/randomization through the time required to eliminate systemic exposure after 
cessation of study intervention as described in Section 5.1, or 30 days following cessation 
of pembrolizumab/placebo 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 related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs 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 he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 6.
Note: Country-specific differences are noted in Appendix 7.
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Table 6
Reporting Periods and Time Frames 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
Time 
Frame 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
Pregnancy/
Lactation Exposure
Report if:
- due to 
intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 
24 hours of 
learning of 
event
Event of Clinical 
Interest (requiring 
regulatory reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- potential drug-
induced liver 
injury (DILI)
- requiring 
regulatory 
reporting
Not required
Within 
24 hours of 
learning of 
event
Event of Clinical 
Interest (does 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
ECI=event of clinical interest.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
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8.4.3
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 AEs, SAEs, and other reportable safety events, 
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities toward the safety of participants and the 
safety of a study intervention 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 intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee), or a pregnancy that occurs during the study in a 
nonparticipant whose sexual partner is a participant capable of producing ejaculate is 
reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
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must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Any event that is disease recurrence of the cancer under study will not be reported as an AE 
or SAE as described in Section 8.4.6.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the study. Any suspected endpoint that upon review is 
not considered recurrence of the cancer under study will be forwarded to Global 
Pharmacovigilance as an SAE within 24 hours of determination that the event is not 
recurrence of the cancer under study.
8.4.7
Events of Clinical Interest
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor.
Events of clinical interest for this study include:
1. An overdose of Sponsor's product, as defined in Section 8.5.
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*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 studysite guidance for assessment 
and follow up of these criteria can be found in the Investigator Study File Binder (or 
equivalent).
8.5
Treatment of Overdose
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater.
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.
Overdose for SBRT is defined as either >20% of the planned total dose, >50% of a planned
single fraction, or any fraction(s) to an incorrect treatment site. In the event of overdose, the 
participant should be observed closely for signs of toxicity. Appropriate supportive treatment 
should be provided if clinically indicated.
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8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
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 as specified in the SoA: As of Amendment 08: 
Biomarker samples (blood for genetic analysis, blood for ctDNA analysis, optional 
tumor sample), biopsies, and tumor imaging for BICR will no longer be collected. The 
subsection below is retained for reference.
•
Blood for genetic analysis
•
Blood for ctDNA analysis
•
An optional tumor tissue sample for biomarker analyses may be collected, including core 
biopsy, bronchoscopic biopsy, or pellet from cytologic examination.
Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be in the operations/laboratory manual.
8.8.1
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.
8.9
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 for future research
•
Leftover main study tumor tissue (including any extracted material from tissue)
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•
Leftover plasma or derivative for ctDNA
8.10
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Documented informed consent must be provided before performing any protocol-specific 
procedure. Results of a test performed before 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 42 days before the first dose of study 
intervention. except for the following:
•
Laboratory tests are to be performed within 7 days prior to the first dose of study 
intervention. 
•
Evaluation of ECOG is to be performed within 7 days prior to the first dose of study 
intervention.
•
For WOCBP, a highly sensitive pregnancy test (urine or serum) within 24 hours for urine 
or within 72 hours for serum prior to the first dose of study intervention. If urine 
pregnancy results cannot be confirmed as negative, a serum pregnancy test will be 
required (performed by the local study site laboratory).
•
Optional tumor tissue sample collection is not required to be obtained within 42 days 
prior to the first dose of study intervention.
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments during the initial screening period are acceptable in lieu of a repeat 
screening test if performed within the specified time frame and the corresponding 
inclusion/exclusion criteria is met. Participants who are rescreened will retain their original 
screening number.
8.11.2
Treatment Period Visit
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.
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8.11.3
Discontinued Participants Continuing to be Monitored in the Study
When a participant discontinues study intervention in the Intervention Phase, procedures for 
discontinuation will be performed.
The Discontinuation Visit should occur at the time study intervention is discontinued for any 
reason. If the Discontinuation Visit occurs 30 days from the last dose of study intervention, at 
the time of the mandatory Safety Follow-up Visit, the Discontinuation Visit procedures and 
any additional safety follow-up procedures should be performed. Visit requirements are 
outlined in Section 1.3. Additional details regarding participant withdrawal and 
discontinuation are presented in Section 7 Discontinuation of Study Intervention and 
Participant Withdrawal.
8.11.4
Posttreatment Visit
8.11.4.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before initiation of a new anticancer treatment, whichever 
comes first.
8.11.4.2
Follow-up Visits
Participants who discontinue study intervention for a reason other than disease recurrence 
will move into the Follow-up Phase and should be assessed every 16 weeks to monitor 
disease status for the first 3 years, and then every 6 months thereafter. Every effort should be 
made to collect information regarding disease status until disease recurrence, death, or the 
end of the study. Information regarding poststudy anticancer treatment will be collected if 
new treatment is initiated. Images will continue to be obtained after the start of the new 
anticancer therapy if recurrence has not been documented or verified by BICR.
8.11.4.3
Survival Follow-up
Participants who experience confirmed disease recurrence will move into the Survival 
Follow-up Phase and should be contacted by telephone approximately every 12 weeks to 
assess for survival status until death, withdrawal of consent, or the end of the study, 
whichever occurs first.
8.11.5
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 period will be 
contacted for their vital status.
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9
STATISTICAL ANALYSIS PLAN
As of Amendment 08: The Statistical Analysis Plan is amended as follows:
NOTE: Based on the data from an interim safety and efficacy analysis for 
KEYNOTE¬867 (data cutoff 11-JUN-2024), the eDMC recommended stopping the 
study since pembrolizumab in combination with SBRT did not demonstrate an 
improvement in event-free survival or overall survival, the study’s primary endpoint 
and key secondary endpoint, respectively, compared to placebo plus SBRT, and the 
benefit/risk profile of the combination did not support continuing the trial. All 
prespecified interim analyses after IA1 and final analysis of the study described in the 
SAP will not be performed. Safety analysis will be performed at the end of the study; 
there will be no further pre-planned analyses for efficacy and ePRO endpoints collected 
from participants beyond the IA1 cutoff date of 11-JUN-2024. 
This section outlines the statistical analysis strategy and procedures for the study. Changes 
made to primary and/or key secondary hypotheses, or the statistical methods related to those 
hypotheses that occurred prior to Amendment 08 were documented in previous protocol 
amendments, (consistent with ICH Guideline E-9). Changes to exploratory or other non-
confirmatory analyses made after the protocol has been finalized, but prior to 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. Other planned analyses (ie, those specific to the analysis of PK data and biomarker 
data) will be documented in separate analysis/operational plans.
9.1
Statistical Analysis Plan Summary 
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 through 9.12. 
As of Amendment 08, all the prespecified interim analyses after IA1 and final analysis 
of the study described in the SAP will not be performed. Safety analysis will be 
performed at the end of the study; there will be no further pre-planned analyses for 
efficacy and ePRO endpoints collected from participants beyond the IA1 cutoff date of 
11-JUN-2024. The SAP summary has been updated accordingly. 
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Study Design Overview
This is a Phase 3, randomized, placebo-controlled clinical study to 
evaluate the safety and efficacy of SBRT with or without pembrolizumab 
in participants with unresected Stage I/II NSCLC.
Treatment Assignment
Approximately 436 eligible participants will be randomized in a 1:1 ratio 
to one of the following 2 treatment arms:
•
Arm 1: SBRT + pembrolizumab 
•
Arm 2: SBRT + placebo
Randomization stratification factors are: 
•
Disease stage: Stage I, Stage II 
•
ECOG performance status: 0 or 1, 2
•
Geographic region of enrollment site: East Asia, non-East Asia
•
Reason for not receiving surgery: medically inoperable vs refused 
surgery
Analysis Populations
Efficacy: Intent to Treat (ITT)
Safety: All Participants as Treated (APaT)
PRO: Full Analysis Set (FAS)
Primary Endpoints
1.
Event-free survival (EFS)
Secondary Endpoints
1.
Overall survival (OS)
2.
Time to death or distant metastases
3.
Safety and tolerability 
4.
PRO outcome
Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
The primary hypothesis will be evaluated by comparing SBRT + 
pembrolizumab arm to SBRT + placebo arm with respect to EFS using a 
stratified log-rank test. The hazard ratio (HR) will be estimated using a Cox 
regression model. Event rates over time will be estimated within each 
treatment group using the Kaplan-Meier method.
Statistical Methods for Key 
Safety Analyses
The analysis of safety results will follow a tiered approach. 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% CIs provided for 
between-group comparison; 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 Miettinen 
and Nurminen method.
Interim Analyses
As of Amendment 08, all the prespecified interim analyses after IA1 and 
final analysis of the study described in the SAP will not be performed.
CCI
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Multiplicity
Details are provided in Section 9.9.
Sample Size and Power 
As of Amendment 08, all the prespecified interim analyses after IA1 and 
final analysis of the study described in the SAP will not be performed.
The planned sample size is approximately 436 participants. 
 
 
 
 
 
9.2
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-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete. In addition, the central radiologist(s) will perform the imaging review without 
knowledge of treatment group assignment.
The Sponsor will generate the randomized allocation schedule(s) for study intervention 
assignment. Randomization will be implemented in IRT.
Blinding issues related to the planned IAs are described in Section 9.7.
9.3
Hypothesis/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
9.4.1
Efficacy Endpoints
9.4.1.1
Primary Endpoints
Event-free Survival (EFS)
EFS is defined as the time from randomization to the first occurrence of the following events:
•
Local, regional, or distant recurrence of disease as assessed by:
-
Radiographic recurrence by BICR
CCI
CCI
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-
Positive pathology by local assessment
-
Physical examination by local assessment confirmed by positive pathology and/or 
radiographic recurrence by BICR
•
Death due to any cause
9.4.1.2
Secondary Endpoint
Overall Survival (OS)
OS is defined as the time from randomization to death due to any cause. 
Time to Death or Distant Metastases
Time to death or distant metastases is defined as the time from randomization to the first 
documented distant metastases or death from any cause, whichever occurs first. 
9.4.1.3
Exploratory Endpoints
Time to Subsequent Treatment (TTST) 
TTST is defined as the time from randomization to first day of next line therapy or death 
from any cause.
Disease-specific Survival (DSS)
DSS is defined as the time from randomization to death due to disease under study.
Time to Recurrence/Progression on Subsequent Line of Therapy (TRSLT)
TRSLT is defined as the time from randomization to the first occurrence of the following 
events:
•
Recurrence/progression of disease by local assessment on the subsequent line of 
treatment
•
Death due to any cause
9.4.2
Safety Endpoints
Safety measurements are described in Section 4.2.1.2.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory values, and vital signs.
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9.4.3
PRO Endpoints
Scores calculated for the following PRO scales/items will be evaluated as described in 
Section 4.2.1.3 as secondary endpoint:
•
Global health status/QoL scale (EORTC QLQ-C30 Items 29, 30)
•
Cough (EORTC QLQ-LC13 Item 1)
•
Chest pain (EORTC QLQ-LC13 Item 10)
•
Dyspnea (EORTC QLQ-C30 Item 8)
•
Physical functioning scale (QLQ-C30 Items 1-5)
•
EQ-5D-5L will be evaluated as an exploratory endpoint
Treatment effect on PRO score change from baseline will primarily be evaluated at 
. 
If the overall PRO completion or compliance rates at 
 are less than 60% or 80%, 
respectively, then the latest analysis time point will be moved to the next earliest time point 
in which the rates are at least 60% for completion and at least 80% for compliance.
9.4.4
Other Exploratory Endpoints
Relationships between molecular (genomic, metabolic, and/or proteomic) biomarkers and 
clinical response/resistance, safety, pharmacodynamic activity, and/or the mechanism of 
action of pembrolizumab and other treatments may be evaluation.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The ITT population will serve as the population for the primary efficacy analyses. All 
randomized participants will be included in this population. Participants will be analyzed in 
the treatment arm to which they are randomized.
9.5.2
Safety Analysis Populations
The 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 1 dose of study 
intervention. Participants will be included in the treatment group corresponding to the study 
intervention they actually received for the analysis of safety data using the APaT population. 
This will be the treatment group to which they are randomized except for participants who 
take incorrect study intervention for the entire treatment period; such participants will be 
included in the treatment group corresponding to the study intervention actually received.
At least 1 laboratory or vital sign obtained after at least 1 dose of study intervention is 
required for inclusion in the analysis of the respective safety parameter. To assess change 
from baseline, a baseline measurement is also required.
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Details on the approach to handling safety analyses are provided in Section 9.6.2.
9.5.3
PRO Analysis Population
The PRO analyses are based on the PRO FAS population, defined as participants who have at 
least 1 PRO assessment available and have received at least 1 dose of study intervention.
9.6
Statistical Methods
NOTE: As of Amendment 08, all the prespecified interim analyses after IA1 and final 
analysis of the study described in the SAP will not be performed. Safety analysis will be 
performed at the end of the study; there will be no further pre-planned analyses for 
efficacy and ePRO endpoints collected from participants beyond the IA1 cutoff date of 
11-JUN-2024. The subsections below are retained for reference.
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the sSAP. Efficacy 
results that will be deemed to be statistically significant after consideration of the Type I 
error control strategy are described in Section 9.8. Nominal p-values will be computed for 
other efficacy analyses but should be interpreted with caution due to potential issues of 
multiplicity. If there are a small number of events in one or more strata, for the purpose of 
analysis, strata will be combined to ensure sufficient number of events in each stratum. 
Details regarding the combining of strata will be specified in the sSAP prior to database lock 
based on a blinded review of response counts by stratum.
9.6.1
Statistical Methods for Efficacy Analyses
9.6.1.1
Event-free Survival (EFS)
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 (ie, HR) between the treatment arms. 
The HR and its 95% CI from the stratified Cox model with Efron’s method of tie handling 
and with a single treatment covariate will be reported. The stratification factors used for 
randomization (see Section 6.3.2) will be applied to both the stratified log-rank test and the 
stratified Cox model.
Since disease recurrence is assessed periodically, recurrence can occur any time in the time 
interval between the last assessment where an event was not documented and the assessment 
when an event is documented. For the primary EFS analysis, the true date of recurrence will 
be approximated by the date of the first assessment at which an event is objectively 
documented, regardless of discontinuation of study medicine or missed study visits. Death is 
always considered as a confirmed EFS event. Participants who do not experience an EFS 
event will be censored at the last disease assessment (Table 7). Sensitivity analyses may be 
conducted using different censoring rules and will be documented in the sSAP as needed.
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Table 7
Censoring Rules for Primary Analysis of EFS
Situation
Primary Analysis
Recurrence, or death documented; ≤1 missed disease 
assessment; and event is before new anti-cancer treatment 
initiation, if any
EFS event at date of documented 
recurrence, or death
Recurrence or death documented; either immediately after 
having ≥2 consecutive missed disease assessments or event is 
after new anti-cancer treatment initiation, if any
EFS event at date of documented 
recurrence, or death
No recurrence and no death; and new anti-cancer treatment is 
not initiated
Censored at last disease assessment 
No recurrence and no death; new anti-cancer treatment is 
initiated
Censored at last disease assessment
If the proportional hazards assumption is not valid, supportive analyses using RMST method 
[Uno, H., et al 2014] may be conducted for EFS to account for the possible non-proportional 
hazards effect.
9.6.1.2
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 (based on the 
stratification factors defined in Section 6.3.2). A stratified Cox proportional hazard model 
with Efron’s method of tie handling will be used to assess the magnitude of the treatment 
difference (ie, the HR). The HR and its 95% CI from the stratified Cox model with a single 
treatment covariate will be reported. The stratification factors used for randomization 
(Section 6.3.2) 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 last 
known alive date. The Restricted Mean Survival Time (RMST) method [Uno, H., et al 2014]
may be conducted for OS to account for the possible non-proportional hazards effect.
9.6.1.3
Time to Death or Distant Metastases (TDDM)
The non-parametric Kaplan-Meier method will be used to estimate the TDDM curve in each 
treatment group. The treatment difference in TDDM 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 (ie, HR) between the 
treatment arms. The HR and its 95% CI from the stratified Cox model with Efron’s method 
of tie handling and with a single treatment covariate will be reported. The stratification 
factors used for randomization (see Section 6.3.2) will be applied to both the stratified log-
rank test and the stratified Cox model.
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Since distant metastasis is assessed periodically, it can occur any time in the time interval 
between the last assessment where an event was not documented and the assessment when an 
event is documented. The true date of distant metastasis will be approximated by the date of 
the first assessment at which an event is objectively documented, regardless of 
discontinuation of study medicine or missed study visits. Death is always considered as a 
confirmed TDDM event. Participants who do not experience a TDDM event will be censored 
at the last disease assessment. 
9.6.1.4
Analysis Strategy for Key Efficacy Endpoints
Table 8 summarizes the primary analysis approach for key efficacy endpoints.
Table 8
Efficacy Analysis Methods for Key Efficacy Endpoints
Endpoint/Variable
Statistical Methoda
Analysis 
Population
Missing Data Approach
Primary Analyses
EFS
Testing: Stratified Log-rank 
Test Estimation: Stratified Cox 
model with Efron’s tie handling 
method
ITT
Censored according to rules in 
Table 7
Key Secondary Analyses
OS 
Testing: Stratified Log-rank Test
Estimation: Stratified Cox model 
with Efron’s tie handling 
method
ITT
Censored at last known alive date
Abbreviations: EFS=event-free survival; ITT=intent to treat; OS=overall survival
a Statistical models are described in further detail in the text. For stratified analyses, the stratification factors used for 
randomization (Section 6.3.2) will be applied to the analysis. Small strata will be combined in a way specified by a 
blinded statistician prior to the analysis.
Analysis strategy for the exploratory efficacy endpoints will be described in the sSAP.
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, and vital signs.
The analysis of safety results will follow a tiered approach as shown in Table 9. The tiers 
differ with respect to the analyses that will be performed. AEs (specific terms as well as 
system organ class terms) and events that meet predefined limits of change (PDLCs) in 
laboratory, and vital signs are either prespecified as “Tier 1” endpoints or will be classified as 
belonging to “Tier 2” or “Tier 3” based on the observed proportions of participants with an 
event.  
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Tier 1 Events
Safety parameters or AEs of interest that are identified a priori constitute “Tier 1” safety 
endpoints that will be subject to inferential testing for statistical significance. There are no 
Tier 1 events for this protocol as SBRT+pembrolizumab does not seem to produce toxicity 
beyond what is expected for these therapies alone based on the early result of the use of 
pembrolizumab and SBRT in the metastatic setting [Theelen, W., et al 2018] [Campbell, A. 
M., et al 2018]. 
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% confidence intervals 
provided for differences in the proportion of participants with events via the Miettinen & 
Nurminen method [Miettinen, O. and Nurminen, M. 1985] and will be presented using forest 
plots.
Membership in Tier 2 requires that at least 1% of participants in any treatment group exhibit 
the event (with the exception of any AE, which requires at least 10%). The threshold of at 
least 1% of participants was chosen because the population randomized in this study is in 
critical condition and usually experiences various AEs of similar types regardless of 
treatment; events reported less frequently than 1% of participants would obscure the 
assessment of the overall safety profile and add little to the interpretation of potentially 
meaningful treatment differences. Grade 3 to 5 AEs (≥1% of participants in one of the 
treatment groups) and SAEs (≥1% of participants in one of the treatment groups) are 
considered as Tier 2 endpoints. Any AE (≥10% of participants in one of the treatment 
groups) is also considered as a Tier 2 endpoint (the cutoff 10% is chosen due to the higher 
incidence of any AE). 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 rather than formal methods for assessing the statistical significance of the between-
group differences. All other AEs and predefined limits of change will belong to Tier 3 
endpoints.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment group are provided for Tier 3 safety parameters.
Continuous Safety Measures 
For continuous measures such as changes from baseline in laboratory and vital signs, 
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 9
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE (≥10% of participants in one of the 
treatment groups)
X
X
Any SAE (≥1% of participants in one of the 
treatment groups)
X
X
Any Grade 3 to 5 AE (≥1% of participants in one 
of the treatment groups)
X
X
Tier 3
Other specific AEs, SOCs or PDLCs
X
Change from baseline results (laboratory test 
results, vital signs)
X
Abbreviations: AE=adverse event; CI=confidence interval; PDLC=predefined limit of change; SAE=serious 
adverse event; SOC=system organ class; X=results will be provided.
9.6.3
Analysis Methods for PRO Endpoints
A constrained longitudinal data analysis (cLDA) model will be applied for each endpoint, 
with the PRO score as the response variable, and treatment, time, treatment by time 
interaction, and clinical study stratification factors as covariates. Least square mean change 
from baseline will be summarized for each outcome. The difference in the least square mean 
change from baseline will be reported at the primary analysis time point.
Descriptive analyses will assess the empirical mean change (with 95% CIs) from baseline 
across all time points for the Global health status/QoL (QLQ-C30 items 29, 30), cough 
(QLQ-LC13 item 1), chest pain (QLQ-LC13 item 10), and dyspnea (QLQ-LC13 item 8) 
scores. 
The number and proportion of patients who “improved”, “remained stable”, or “deteriorated” 
from baseline will be summarized. 
Details of additional PRO analyses will be included in the sSAP.
9.6.4
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis 
tests will be performed on these characteristics. The number and percentage of participants 
screened and randomized and the primary reason for screening failure and discontinuation 
will be displayed. Demographic variables, baseline characteristics, primary and secondary 
diagnoses, and prior and concomitant therapies will be summarized by treatment either by 
descriptive statistics or categorical tables.
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9.7
Interim Analyses
NOTE: As of Amendment 08, all the prespecified interim analyses after IA1 and final 
analysis of the study described in the SAP will not be performed. The subsections below 
are retained for reference.
Blinding to treatment assignment will be maintained at all investigational sites. The results of 
IAs will not be shared with the investigators prior to the completion of the study. Participant-
level unblinding will be restricted to an external unblinded statistician and scientific 
programmer performing the interim analysis, who will have no other responsibilities 
associated with the study.
An eDMC will serve as the primary reviewer of the results of the IAs of the study and will 
make recommendations for discontinuation of the study or protocol modifications to an 
Executive Oversight Committee (EOC) of the Sponsor. If the eDMC recommends 
modifications to the design of the protocol or discontinuation of the study, this EOC may be 
unblinded to results at the treatment-level in order to act on these recommendations. Limited 
additional Sponsor personnel may also be unblinded to the treatment-level results of the 
interim analysis(es), if required, in order to act on the recommendations of the eDMC or 
facilitate regulatory filing. The extent to which individuals are unblinded with respect to 
results of IAs will be documented by the unblinded statistician. Additional logistical details 
will be provided in the DMC charter. 
Treatment-level results from the interim analysis will be provided to the DMC by the 
unblinded statistician. Prior to final study unblinding, the 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 IAs.
9.7.1
Efficacy Interim Analyses
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Table 10
9.8
Multiplicity
NOTE: As of Amendment 08, all the prespecified interim analyses after IA1and final 
analysis of the study described in the SAP will not be performed. This section is 
retained for reference.
The study uses the graphical method of Maurer and Bretz [Maurer, W. and Bretz, F. 2013] to 
strongly control multiplicity 
 Figure 2 shows the initial 
1-sided α allocation for each hypothesis in the ellipse representing the hypothesis. The 
weights for reallocation from each hypothesis to the others are represented in the boxes on 
the lines connecting hypotheses.
 
 The study will be 
considered a success if
 
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Figure 2
9.8.1
Multiplicity Control for Efficacy Interim Analyses
9.8.1.1
Event-free Survival (EFS)
Table 11
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9.8.1.2
Overall Survival
Table 12
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9.9
Sample Size and Power Calculations
NOTE: As of Amendment 08, all the prespecified interim analyses after IA1 and final 
analysis of the study described in the SAP will not be performed. This section is 
retained for reference.
The sample size is estimated based on the secondary endpoint OS. 
A total of approximately 436 participants will be randomized in a 1:1 ratio to the SBRT + 
pembrolizumab arm and the SBRT + placebo arm.
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9.10
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 and key secondary 
endpoint will be estimated and plotted by treatment group within each category of the 
following classification variables:
•
Stage of disease (I, II)
•
ECOG performance status (0 or 1, 2)
•
Geographic region of enrollment site (East Asia, non-East Asia; EU, non-EU)
•
Histology (squamous, nonsquamous)
•
Smoking status (never, ever)
•
Age category (≥65, <65 years)
•
Sex (female, male)
•
Race (white, non-white)
•
Tumor location (peripheral, abutting the chest wall, central) defined as body site location 
of SBRT administration
•
Reason for not receiving surgery (medically inoperable, refused surgery)
The consistency of the treatment effect will be assessed using descriptive statistics for each 
category of the subgroup variables listed above. If the number of participants in a category of 
a subgroup variable is less than 10% of the ITT population, the subgroup analysis will not be 
performed for this category of the subgroup variable, and this subgroup variable will not be 
displayed in the forest plot.
9.11
Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study. Any deviation 
from protocol-directed administration will be reported.
9.12
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.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
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
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD), 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), Regulation (EU) 536/2014, the 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 (eg, contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, 
efficacy, and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. 
Alternatively, MSD may conduct outcomes research trials, trials to assess or validate various endpoint 
measures, or trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
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 to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of 
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 fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
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are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing, in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
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. Unless required by 
law, only the investigator, Sponsor (or representative), 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 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 (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
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, frequently 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.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that their 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 their 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.
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The Sponsor has EU-approved Binding Corporate Rules since 2017, covering all aspects of 
its Global Privacy Program (Corporate Policy 20), and is self-certified pursuant to the EU-US 
Data Privacy Framework.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee, affiliated institution, and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution, and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules, 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
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study results, consider the overall risk and benefit to study participants (Section 9.7) and 
recommend to the EOC whether the study should continue in accordance with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.4.2
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide on any recommendations made by the eDMC regarding the study.
10.1.5
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 ICMJE authorship 
requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trials Regulation 536/2014, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu, https://euclinicaltrials.eu, or other local registries. MSD, as 
Sponsor of this study, will review this protocol and submit the information necessary to 
fulfill these requirements. MSD entries are not limited to FDAAA or the EMA clinical trials 
Regulation 536/2014 mandated trials. Information posted will allow participants to identify 
potentially appropriate studies for their disease conditions and pursue participation by calling 
a central contact number for further information on appropriate study locations and study-site 
contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials Regulation 536/2014, or other locally mandated registries 
are that of the Sponsor and agrees not to submit any information about this study or its results 
to those registries.
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10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol, generally accepted standards of GCP 
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP), and 
all applicable federal, state, and local laws, rules, and regulations relating to the conduct of 
the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority.
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
For investigators located in countries with serious breach reporting requirements, investigator 
will promptly report to the Sponsor any serious breach or suspected serious breach that 
occurs in compliance with those requirements. Unless more specifically defined in the 
applicable requirements, a serious breach is any breach of the applicable clinical trial 
regulation or of the clinical trial protocol which is likely to affect to a significant degree: (i) 
the safety or rights of a trial participant, or (ii) the reliability and robustness of the data 
generated in the clinical trial.
10.1.8
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.
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The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period 
(eg, EU CTR: 25 years after the end of the study). 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.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). 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/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
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10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 13 will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 13
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
White blood cell count with differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUNa
Potassium
AST/SGOT
Total bilirubin (and direct 
bilirubin if total bilirubin is 
>ULN)
Albumin
Bicarbonate or 
CO2b
Chloride
Phosphorous
Creatininec
Sodium
ALT/SGPT
Total protein
Glucose (fasting, 
or nonfasting)
Calcium
Alkaline 
phosphatase
Coagulationd

PT/INR

aPTT
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

T3e, FT4, and TSH

Follicle-stimulating hormone (as needed in women of nonchildbearing potential only)

Serum or urine β-hCG pregnancy test (as needed for WOCBP)

Serology (HIV antibody, HBsAg, and HCV antibody) as per local requirements  
ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; β-
hCG=human chorionic gonadotropin; BUN=blood urea nitrogen; FT4=free thyroxine; HbsAg=hepatitis B surface 
antigen; HCV=hepatitis C virus; HIV=human immunodeficiency virus; INR=international normalized ratio; 
PT=prothrombin time; RBC=red blood cells; SGOT=serum glutamic oxaloacetic transaminase; SGPT=serum glutamic 
pyruvic transaminase; T3=triiodothyronine; TSH=thyroid-stimulating hormone (thyrotropin); ULN=upper limit of 
normal; WOCBP=women of child bearing potential.
a. BUN is preferred; if not available, urea may be tested.
b. If these tests are not performed as part of standard of care in your region then these tests do not need to be performed. 
The carbon dioxide may be either a measurement of CO2 or bicarbonate as an electrolyte.
c. Creatinine: GFR (measured or calculated) or creatinine clearance can be used in place of creatinine. Creatinine 
clearance should be calculated using the Cockcroft-Gault Method: 
d. Coagulation factors (PT/INR and aPTT/PTT) should be tested as part of the screening procedures for all 
participants. Any participant receiving anticoagulant therapy should have coagulation factors monitored closely 
throughout the study. aPTT is preferred. If not available, PTT is acceptable.
e. T3 is preferred. If not available, free T3 (FT3) may be tested.
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The investigator (or medically qualified designee) must document their review of each 
laboratory safety report. Safety laboratory test results (with the exception of thyroid tests) 
must be reviewed by the investigator or qualified designee and found to be acceptable prior 
to administration of each dose of study medication. Unresolved abnormal laboratory test 
results that are drug-related AEs should be followed until resolution. Laboratory tests do not 
need to be repeated after the end-of-treatment if laboratory test results are within normal 
range.
Country-specific differences are noted in Appendix 7.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions 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.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
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 intervention.
•
Note: For purposes of AE definition, study intervention includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
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•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
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 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
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 preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
-
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
-
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
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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) that 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 1 
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.
10.3.4
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
•
Is a new cancer (that is not a condition of the study).
-
Is associated with an overdose.
10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
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•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
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 CTCAE, version 4.0. Any AE that changes 
CTCAE grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
-
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
-
Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.
-
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
-
Grade 4: Life-threatening consequences; urgent intervention indicated.
-
Grade 5: Death related to AE.
Assessment of causality
•
Did the study intervention cause the AE?
•
The determination of the likelihood that the study intervention caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
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•
The following components are to be used to assess the relationship between the 
study intervention and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the study 
intervention caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention 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 study intervention? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with IMP)?
-
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 study intervention 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 study 
intervention; (3) the study is a single-dose drug study; or (4) study intervention (s) 
is/are only used 1 time.)
-
Rechallenge: Was the participant reexposed to the study intervention in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability; (2) the study is a single-dose drug study; or (3) study 
intervention (s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE STUDY INTERVENTION, OR IF REEXPOSURE 
TO THE STUDY INTERVENTION 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 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the study intervention or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
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•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a study intervention relationship).
-
Yes, there is a reasonable possibility of study intervention relationship:
◦
There is evidence of exposure to the study intervention. The temporal sequence of 
the AE onset relative to the administration of the study intervention is reasonable. 
The AE is more likely explained by the study intervention than by another cause.
-
No, there is not a reasonable possibility of study intervention relationship:
◦
Participant did not receive the study intervention OR temporal sequence of the AE 
onset relative to administration of the study intervention is not reasonable OR the 
AE is more likely explained by another cause than the study intervention. (Also 
entered for a participant with overdose without an associated AE.)
•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
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.
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10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
-
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure email 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 Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
10.5.1
Definitions
Women 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 follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with 2 FSH measurements in the 
postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal 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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10.5.2
Contraceptive Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantc,d
•
IUSc,e
•
Nonhormonal 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. 
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.
•
Combined (estrogen- and progestogen- containing) hormonal contraceptionc,d
-
Oral
-
Intravaginal
-
Transdermal
-
Injectable
•
Progestogen-only hormonal contraceptionc,d
-
Oral
-
Injectable
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
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
c
Male condoms must be used in addition to female participant hormonal contraception.
d
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
e 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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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease. A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
-
The biology of how drugs/vaccines work
-
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
-
Other pathways with which drugs/vaccines may interact
-
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease, and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
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A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants’ clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history, and intervention outcomes is 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number that does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third-party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
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(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and 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 before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer 
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not used in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility, which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
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If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Argentina-specific Requirements:
•
Exclusion Criterion 10: Hepatitis B and Hepatitis C testing is mandatory.
•
Exclusion Criterion 13: HIV testing is mandatory.
10.7.2
EU Countries-specific Requirements:
According to the CTFG guideline, monthly pregnancy testing should be performed in 
WOCBP during the same period as contraception is mandatory.
10.7.3
Germany-specific Requirements:
•
Exclusion Criterion 10: Hepatitis B and Hepatitis C testing is mandatory.
•
Exclusion Criterion 13: HIV testing is mandatory.
•
Exclusion Criterion 14: TB testing is mandatory.
•
Section 8.4.1: All AEs meeting serious criteria are to be collected for 120 days after the 
last dose of study intervention.
10.7.4
Japan-specific Requirements:
•
For the assistance to early diagnosis of pneumonitis/ILD in study participants, the 
following items such as pulse oximetry monitoring (SpO2), CRP, KL-6, and SP-D will be 
measured in this study. These items should be measured in the following timing.
-
SpO2: at the timing of vital sign assessment.
-
CRP, KL-6, and SP-D: at screening*, predose of Day 1 of every cycle, end-of-
treatment, and Safety Follow-up Visit (30 days after last dose).
* should be measured at the timing of clinical laboratory tests (such as hematology/ 
chemistry).
•
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 5.2 Exclusion Criteria
•
Exclusion Criterion 14:  Known history of active tuberculosis specifies active, ongoing 
tuberculosis. Tuberculosis documented in medical history that is no longer active or 
ongoing is not exclusionary.
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Section 6.1 Study Intervention(s) Administered
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.
10.7.5
South Korea-specific Requirements:
•
Participants must be 19 years old or older.
10.7.6
Romania-specific Requirements:
•
Exclusion Criterion 10: Hepatitis B and Hepatitis C testing is mandatory.
•
Exclusion Criterion 13: HIV testing is mandatory.
10.7.7
United Kingdom-specific Requirements
•
Live vaccines must not be administered for 90 days after the last dose of study 
intervention. Refer to Section 6.5 for information on COVID-19 vaccines.
10.7.8
Italy-specific Requirements
Section 1.3 Schedule of Activities
HBV, HCV, and HIV testing at screening is mandatory.
Section 5.2 Exclusion Criteria
•
Has a known history of HIV infection.
•
History of hepatitis B (defined as HBsAg reactive) or known active hepatitis C (defined 
as detectable HCV RNA [qualitative]) infection.
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10.8
Appendix 8: Eastern Cooperative Oncology Group
Grade
Performance Status
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 (eg, light 
housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable 
to carry out any work activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair.
5
Dead 
*As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. 
Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group 
Chair.
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10.9
Appendix 9: NSCLC Staging Definitions
The staging allowed in this trial includes NSCLC Stage I and Stage II, per AJCC version 8 
NSCLC staging guideline [Detterbeck, F. C., et al 2017].
Figure 3
Excerpt From AJCC v8 NSCLC Staging Guideline on Appropriate Staging of 
N0 Disease.
Figure 4
Excerpt From AJCC v8 NSCLC Staging Guideline on Primary Tumor Sizing 
Criteria.
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10.10 Appendix 10: Abbreviations
Abbreviation
Expanded Term
ADL
activities of daily living  
AE
adverse event 
AJCC
American Joint Committee on Cancer
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate Aminotransferase
BCG
bacillus Calmette–Guérin
BDS
blood drug screen
BED
biologically effective dose
BICR
blinded independent central review 
CAC
Clinical Adjudication Committee
CD28
cluster of differentiation 28
CD3ζ
CD3 zeta
CI
confidence interval
CNS
central nervous system 
COPD
chronic obstructive pulmonary disease
CRF
Case Report Form 
CRP
C-reactive protein
CRU
clinical research unit
C-SSRS
Columbia-Suicide Severity Rating Scale 
CTCAE
Common Terminology Criteria for Adverse Events
CTFG
Clinical Trial Facilitation Group 
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
DILI
drug-induced liver injury
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
DSS
disease-specific survival
ECG
electrocardiogram 
ECI
event of clinical interest
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Abbreviation
Expanded Term
eCRF
electronic Case Report Form
eCTA
exploratory Clinical Trial Application
EDC
electronic data collection 
EEA
European Economic Area
EFS
event-free survival
ELISA
enzyme-linked immunoassay
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EORTC
European Organization for Research and Treatment of Cancer
EORTC 
QLQ-C13
EORTC Quality of Life Questionnaire C13
EORTC 
QLQ-C30
EORTC Quality of Life Questionnaire C30
EORTC QLQ-
LC13
EORTC Quality of Life Questionnaire and Lung Cancer Module 13
EOT
End of Trial
ePRO
electronic patient-reported outcome(s)
EU
European Union
EuroQoL 
EQ-5D-5L
EuroQoL-5 Dimension Questionnaire
FAS
Full Analysis Set
FBR
Future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle-stimulating hormone 
FSR
first site ready
GCP
Good Clinical Practice 
GFR
glomerular filtration rate
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
hazard ratio
HRQoL
health-related quality of life
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Abbreviation
Expanded Term
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Council on Harmonisation
iCRO
imaging Contract Research Organization
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgG4
immunoglobulin G4
IHC
immunohistochemistry
ILD
interstitial lung disease
IMP
investigational medicinal product
IND
Investigational New Drug 
IO
Immune-oncology
irAE
immune-related adverse events
IRB
Institutional Review Board 
IRT
Interactive Response Technology
ITT
Intent-to-treat
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IVRS
Interactive Voice Response System
KL-6
Krebs von den Lungen-6
MHRA
Medicines and Healthcare products Regulatory Agency
MRI
magnetic resonance imaging
MTD
maximum tolerated dose 
NCI
National Cancer Institute
NDA
New Drug Application 
NOAEL
no observed adverse effect level 
NSCLC
non-small cell lung cancer 
OS
overall survival 
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Abbreviation
Expanded Term
PBPK
physiologically-based PK
PD-1
programmed cell death 1
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PET
positron emission tomography 
PFS
progression-free survival
PK
pharmacokinetic
PKCθ
protein kinase C-theta
PRO
patient-reported outcomes
PS
performance scale
PTV
planned target volume
Q3D
every 3 days
Q3W
every 3 weeks
QA
quality assurance
QoL
quality of life
QP2
department of quantitative pharmacology and pharmacometrics
RNA
ribonucleic acid
RMST
restricted mean survival time
SAE
serious adverse event 
SBRT
stereotactic body radiotherapy
siDMC
Standing Internal Data Monitoring Committee
SoA
schedule of activities
SOC
standard of care
SP-D
surfactant protein D
SpO2
oxygen saturation
sSAP
Supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
TLR4
toll-like receptor 4
TMDD
target-mediated drug disposition
TRSLT
time to recurrence/progression on subsequent line of therapy
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Abbreviation
Expanded Term
TB
Bacillus tuberculosis
TTST
time to subsequent treatment
UDS
urine drug screen
US
United States
WOCBP
woman/women of childbearing potential 
ZAP70
zeta-chain-associated protein kinase
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11
REFERENCES
[Aaronson, N. K., et al 1993]
Aaronson NK, Ahmedzai S, Bergman B, 
Bullinger M, Cull A, Duez NJ, et al. The 
European Organization for Research and 
Treatment of Cancer QLQ-C30: a quality-of-
life instrument for use in international 
clinical trials in oncology. J Natl Cancer Inst 
1993;85(5):365-76.
[03Q3QL]
[Aaronson, N. K., et al 
1993a]
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.
[00TGH7]
[Antonia, S. J., et al 2017]
Antonia SJ, Villegas A, Daniel D, Vicente D, 
Murakami S, Hui R, et al. Durvalumab after 
chemoradiotherapy in stage III non-small-cell 
lung cancer. N Engl J Med. 2017 Nov 
16;377(20):1919-29.
[04V3ZY]
[Antonia, S. J., et al 2018]
Antonia SJ, Villegas A, Daniel D, Vicente D, 
Murakami S, Hui R, et al. Overall survival 
with durvalumab after chemoradiotherapy in 
stage III NSCLC. N Engl J Med. 2018 Dec 
13;379(24):2342-50.
[05540R]
[Apetoh, L., et al 2007]
Apetoh L, Ghiringhelli F, Tesniere A, Obeid 
M, Ortiz C, Criollo A, et al. Toll-like 
receptor 4-dependent contribution of the 
immune system to anticancer chemotherapy 
and radiotherapy. Nat Med. 2007 
Sep;13(9):1050-9.
[04WMHC]
[Aymeric, L., et al 2010]
Aymeric L, Apetoh L, Ghiringhelli F, 
Tesniere A, Martins I, Kroemer G, et al. 
Tumor cell death and ATP release prime 
dendritic cells and efficient anticancer 
immunity. Cancer Res. 2010 Feb 
1;70(3):855-8.
[0532QT]
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[Bergman, B., et al 1994]
Bergman B, Aaronson NK, Ahmedzai S, 
Kaasa S, Sullivan M. The EORTC QLQ-
LC13: a modular supplement to the EORTC 
core quality of life questionnaire (QLQ-C30) 
for use in lung cancer clinical trials. Eur J 
Cancer 1994;30A(5):635-42.
[00VTZB]
[Bray, F., et al 2018]
Bray F, Ferlay J, Soerjomataram I, Siegel 
RL, Torre LA, Jemal A. Global cancer 
statistics 2018: GLOBOCAN estimates of 
incidence and mortality worldwide for 36 
cancers in 185 countries. CA Cancer J Clin. 
In press 2018.
[050XQN]
[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-90S. 
Erratum in: Chest. 2014 Feb;145(2):437.
[052MR7]
[Bryant, A. K., et al 2018]
Bryant AK, Mundt RC, Sandhu AP, Urbanic 
JJ, Sharabi AB, Gupta S, et al. Stereotactic 
body radiation therapy versus surgery for 
early lung cancer among US veterans. Ann 
Thorac Surg. 2018;105:425-31.
[052949]
[Campbell, A. M., et al 2018]
Campbell AM, Herbst RS, Gettinger SN, 
Goldberg SB, Kluger HM, Chiang AC, et al. 
Final results of a phase I prospective trial 
evaluating the combination of stereotactic 
body radiotherapy (SBRT) with concurrent 
pembrolizumab in patients with metastatic 
non-small cell lung cancer (NSCLC) or 
melanoma [abstract]. Presented at: 2018 
American Society of Clinical Oncology 
(ASCO) Annual Meeting; 2018 Jun 1-5; 
Chicago, IL. J Clin Oncol. 2018;36(15 
suppl). Abstract no. 9099.
[053KHB]
08TMTD


PRODUCT: MK-3475
143
PROTOCOL/AMENDMENT NO.: 867-08
MK-3475-867-08 FINAL PROTOCOL
11-OCT-2024
[Chang, J. Y., et al 2014]
Chang JY, Li QQ, Xu QY, Allen PK, 
Rebueno N, Gomez DR, et al. Stereotactic 
ablative radiation therapy for centrally 
located early stage or isolated parenchymal 
recurrences of non-small cell lung cancer: 
how to fly in a "no fly zone". Int J Radiat 
Oncol Biol Phys. 2014;88(5):1120-8.
[05378F]
[Chang, J. Y., et al 2023]
Chang JY, Lin SH, Dong W, Liao Z, Gandhi 
SJ, Gay CM, et al. Stereotactic ablative 
radiotherapy with or without immunotherapy 
for early-stage or isolated lung parenchymal 
recurrent node-negative non-small-cell lung 
cancer: an open-label, randomised, phase 2 
trial. Lancet. 2023 Sep 9;402:871-81.
[08GDZD]
[Charlson, M. E., et al 1987]
Charlson ME, Pompei P, Ales KL, 
MacKenzie CR. A new method of classifying 
prognostic comorbidity in longitudinal 
studies:  development and validation. J Chron 
Dis 1987;40(5):373-83.
[03N0KP]
[Chemnitz, J. M., et al 2004]
Chemnitz JM, Parry RV, Nichols KE, June 
CH, Riley JL. SHP-1 and SHP-2 associate 
with immunoreceptor tyrosine-based switch 
motif of programmed death 1 upon primary 
human T cell stimulation, but only receptor 
ligation prevents T cell activation. J Immunol 
2004;173:945-54.
[00VMPN]
[Daniels, C. P., et al 2019]
Daniels CP, Moghanaki D, Siva S. 
Stereotactic ablative radiation therapy for 
operable early-stage lung cancer-
considerations and controversies. Ther 
Radiol Oncol. 2019 Jan 9;3:3.
[05MG45]
[De Ruysscher, D., et al 
2017]
De Ruysscher D, Faivre-Finn C, Moeller D, 
Nestle U, Hurkmans CW, Le Pechoux C, et 
al. European Organization for Research and 
Treatment of Cancer (EORTC) 
recommendations for planning and delivery 
of high-dose, high precision radiotherapy for 
lung cancer. Radiother Oncol. 2017;124:1-
10.
[052MQN]
08TMTD


PRODUCT: MK-3475
144
PROTOCOL/AMENDMENT NO.: 867-08
MK-3475-867-08 FINAL PROTOCOL
11-OCT-2024
[Detterbeck, F. C., et al 2017]
Detterbeck FC, Boffa DJ, Kim AW, Tanoue 
LT. The Eighth Edition Lung Cancer Stage 
Classification. Chest. 2017 Jan;151(1):193-
203.
[04PX8D]
[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]
[Ebrahimi, M., et al 2016]
Ebrahimi M, Auger M, Jung S, Fraser RS. 
Diagnostic concordance of non-small cell 
lung carcinoma subtypes between biopsy and 
cytology specimens obtained during the same 
procedure. Cancer Cytopathol. 2016 
Oct;124:737-43.
[05540S]
[Fleisher, L. A., et al 2014]
Fleisher LA, Fleischmann KE, Auerbach AD, 
Barnason SA, Beckman JA, Bozkurt B, et al. 
2014 ACC/AHA guideline on perioperative 
cardiovascular evaluation and management 
of patients undergoing noncardiac surgery: 
executive summary: a report of the American 
College of Cardiology/American Heart 
Association task force on practice guidelines. 
Circulation. 2014 Dec 9-16;130:2215-45. 
Supplemental data; 87 p.
[052NH2]
[Francisco, L. M., et al 2010]
Francisco LM, Sage PT, Sharpe AH. The 
PD-1 pathway in tolerance and 
autoimmunity. Immunol Rev 2010;236:219-
42.
[058SQP]
[Gameiro, S. R., et al 2014]
Gameiro SR, Jammeh ML, Wattenberg MM, 
Tsang KY, Ferrone S, Hodge JW. Radiation-
induced immunogenic modulation of tumor 
enhances antigen processing and calreticulin 
exposure, resulting in enhanced T-cell 
killing. Oncotarget. 2014;5(2):403-16.
[0532R6]
08TMTD


PRODUCT: MK-3475
145
PROTOCOL/AMENDMENT NO.: 867-08
MK-3475-867-08 FINAL PROTOCOL
11-OCT-2024
[Garrett, M., et al 2017]
Garrett M, Wang TJC, Cheng SK. Combined 
versus sequential radiation and 
immunotherapy in advanced lung cancer. 
Presented at: American Society for Radiation 
Oncology (ASTRO's) 59th Annual Meeting; 
2017 Sep 24-27; San Diego, CA. Int J Radiat 
Oncol Biol Phys. 2017;99(2 suppl):E455-6.
[0529C2]
[Greenwald, R. J., et al 2005]
Greenwald RJ, Freeman GJ, Sharpe AH. The 
B7 family revisited. Annu Rev Immunol 
2005;23:515-48.
[00VMQL]
[Guckenberger, M., et al 
2017]
Guckenberger M, Andratschke N, 
Dieckmann K, Hoogeman MS, Hoyer M, 
Hurkmans C, et al. ESTRO ACROP 
consensus guideline on implementation and 
practice of stereotactic body radiotherapy for 
peripherally located early stage non-small 
cell lung cancer. Radiother Oncol. 
2017;124:11-7.
[052MR3]
[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]
[Lugade, A. A., et al 2005]
Lugade AA, Moran JP, Gerber SA, Rose RC, 
Frelinger JG, Lord EM. Local radiation 
therapy of B16 melanoma tumors increases 
the generation of tumor antigen-specific 
effector cells that traffic to the tumor. J 
Immunol. 2005;174:7516-23.
[0532DP]
[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]
[Miettinen, O. and Nurminen, 
M. 1985]
Miettinen O and Nurminen M. Comparative 
analysis of two rates. Stat Med 1985;4:213-
26.
[00VMQY]
08TMTD


PRODUCT: MK-3475
146
PROTOCOL/AMENDMENT NO.: 867-08
MK-3475-867-08 FINAL PROTOCOL
11-OCT-2024
[Nagata, Y., et al 2015]
Nagata Y, Hiraoka M, Shibata T, Onishi H, 
Kokubo M, Karasawa K, et al. Prospective 
trial of stereotactic body radiation therapy for 
both operable and inoperable T1N0M0 non-
small cell lung cancer: Japan Clinical 
Oncology Group study JCOG0403. Int J 
Radiat Oncol Biol Phys. 2015;93(5):989-96.
[0559NV]
[National Cancer Institute 
2016]
National Cancer Institute: SEER Cancer 
Statistics Review 1975-2014. Table 15.28: 
Cancer of the lung and bronchus (Invasive) 
[Internet]. Bethesda, MD: National Cancer 
Institute; [2016]. Available from: 
https://seer.cancer.Sogov/csr/1975_2014/resu
lts_single/sect_15_table.28.pdf.
[04V3HX]
[National Cancer Institute 
2018]
SEER*Stat [Internet]. Bethesda (MD): 
National Cancer Institute. 2018. Cancer stat 
facts: lung and bronchus cancer; [about 12 
screens]. Available from: 
https://seer.cancer.gov/statfacts/html/lungb.ht
ml.
[0507C2]
[National Comprehensive 
Cancer Network 2018]
National Comprehensive Cancer Network. 
NCCN clinical practice guidelines in 
oncology: non-small cell lung cancer; version 
6.2018. Fort Washington (PA): National 
Comprehensive Cancer Network (NCCN); 
2018. 214 p.
[050FMG]
[National Comprehensive 
Cancer Network 2020]
National Comprehensive Cancer Network. 
NCCN clinical practice guidelines in 
oncology: non-small cell lung cancer; version 
8.2020. Plymouth Meeting (PA): National 
Comprehensive Cancer Network (NCCN); 
2020. 254 p.
[05MG46]
[Nizzoli, R., et al 2011]
Nizzoli R, Tiseo M, Gelsomino F, Bartolotti 
M, Majori M, Ferrari L, et al. Accuracy of 
fine needle aspiration cytology in the 
pathological typing of non-small cell lung 
cancer. J Thorac Oncol. 2011 Mar;6(3):489-
93.
[05540T]
08TMTD


PRODUCT: MK-3475
147
PROTOCOL/AMENDMENT NO.: 867-08
MK-3475-867-08 FINAL PROTOCOL
11-OCT-2024
[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]
[Parry, R. V., et al 2005]
Parry RV, Chemnitz JM, Frauwirth KA, 
Lanfranco AR, Braunstein I, Kobayashi SV, 
et al. CTLA-4 and PD-1 receptors inhibit T-
cell activation by distinct mechanisms. Mol 
Cell Biol 2005;25(21):9543-53.
[00VMQ7]
[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]
[Pisters, K. M. W. and Le 
Chevalier, T. 2005]
Pisters KMW and Le Chevalier T. Adjuvant 
chemotherapy in completely resected non-
small-cell lung cancer. J Clin Oncol 
2005;23(14):3270-8.
[03PXJ8]
[Postmus, P. E., et al 2017]
Postmus PE, Kerr KM, Oudkerk M, Senan S, 
Waller DA, Vansteenkiste J, et al. Early and 
locally advanced non-small-cell lung cancer 
(NSCLC): ESMO Clinical Practice 
Guidelines for diagnosis, treatment and 
follow-up. Ann Oncol. 2017;28 Suppl 4:iv1-
21.
[04QFNF]
[Rabin, R. and de Charro, F. 
2001]
Rabin R and de Charro F. EQ-5D: a measure 
of health status from the EuroQol group. Ann 
Med 2001;33:337-43.
[03QM46]
[Riley, J. L. 2009]
Riley JL. PD-1 signaling in primary T cells. 
Immunol Rev 2009;229:114-25.
[00VMQ9]
[Rodrigues, G., et al 2015]
Rodrigues G, Choy H, Bradley J, 
Rosenzweig KE, Bogart J, Curran WJ Jr, et 
al. Definitive radiation therapy in locally 
advanced non-small cell lung cancer: 
executive summary of an American Society 
for Radiation Oncology (ASTRO) evidence-
based clinical practice guideline. Pract Radiat 
Oncol. 2015 May-Jun;5:141-8.
[052MR5]
08TMTD


PRODUCT: MK-3475
148
PROTOCOL/AMENDMENT NO.: 867-08
MK-3475-867-08 FINAL PROTOCOL
11-OCT-2024
[Schaue, D., et al 2012]
Schaue D, Ratikan JA, Iwamoto KS, 
McBride WH. Maximizing tumor immunity 
with fractionated radiation. Int J Radiat 
Oncol Biol Phys. 2012;83(4):1306-10.
[0532DT]
[Schneider, B. J., et al 2019]
Schneider BJ, Ismaila N, Aerts J, Chiles C, 
Daly ME, Detterbeck FC, et al. Lung cancer 
surveillance after definitive curative-intent 
therapy: ASCO guideline. J Clin Oncol. 
2019;38(7):753-66.
[05LYT5]
[Senthi, S., et al 2013]
Senthi S, Haasbeek CJA, Slotman BJ, Senan 
S. Outcomes of stereotactic ablative 
radiotherapy for central lung tumours: a 
systematic review. Radiother Oncol. 
2013;106:276-82. Erratum in: Radiother 
Oncol. 2013;109:183.
[05334L]
[Shaverdian, N., et al 2017]
Shaverdian N, Lisberg AE, Bornazyan K, 
Veruttipong D, Goldman JW, Formenti SC, 
et al. Previous radiotherapy and the clinical 
activity and toxicity of pembrolizumab in the 
treatment of non-small-cell lung cancer: a 
secondary analysis of the KEYNOTE-001 
phase 1 trial. Lancet Oncol. 2017 Jul;18:895-
903.
[0532J7]
[Sheppard, K-A, et al 2004]
Sheppard K-A, Fitz LJ, Lee JM, Benander C, 
George JA, Wooters J, et al. PD-1 inhibits T-
cell receptor induced phosphorylation of the 
ZAP70/CD3zeta signalosome and 
downstream signaling to PKCtheta. FEBS 
Lett. 2004;574:37-41.
[00VMQC]
[Sun, B., et al 2017]
Sun B, Brooks ED, Komaki RU, Liao Z, 
Jeter MD, McAleer MF, et al. 7-year follow-
up after stereotactic ablative radiotherapy for 
patients with stage I non-small cell lung 
cancer: results of a phase 2 clinical trial. 
Cancer. 2017 Aug 15;123:3031-9.
[052RXK]
[Tandberg, D. J., et al 2018]
Tandberg DJ, Tong BC, Ackerson BG, 
Kelsey CR. Surgery versus stereotactic body 
radiation therapy for stage I non-small cell 
lung cancer: a comprehensive review. 
Cancer. 2018 Feb 15;124:667-78.
[052987]
08TMTD


PRODUCT: MK-3475
149
PROTOCOL/AMENDMENT NO.: 867-08
MK-3475-867-08 FINAL PROTOCOL
11-OCT-2024
[Theelen, W. S. M. E., et al 
2019]
Theelen WSME, Peulen HMU, Lalezari F, 
van der Noort V, de Vries JF, Aerts JGJV, et 
al. Effect of pembrolizumab after stereotactic 
body radiotherapy vs pembrolizumab alone 
on tumor response in patients with advanced 
non-small cell lung cancer: results of the 
PEMBRO-RT phase 2 randomized clinical 
trial. JAMA Oncol. In press 2019.
[059Q87]
[Theelen, W., et al 2018]
Theelen W, Peulen H, Lalezari F, de Vries J, 
De Langen J, Aerts J, et al. Randomized 
phase II study of pembrolizumab after 
stereotactic body radiotherapy (SBRT) versus 
pembrolizumab alone in patients with 
advanced non-small cell lung cancer: the 
PEMBRO-RT study [abstract]. Presented at: 
2018 American Society of Clinical Oncology 
(ASCO) Annual Meeting; 2018 Jun 1-5; 
Chicago, IL. J Clin Oncol. 2018;36(15 
suppl). Abstract no. 9023.
[053KHG]
[Uno, H., et al 2014]
Uno H, Claggett B, Tian L, Inoue E, Gallo P, 
Miyata T, et al. Moving beyond the hazard 
ratio in quantifying the between-group 
difference in survival analysis. J Clin Oncol. 
2014 Aug 1;32(22):2380-5.
[045X5X]
[Videtic, G. M. M., et al 
2017]
Videtic GMM, Donington J, Giuliani M, 
Heinzerling J, Karas TZ, Kelsey CR, et al. 
Stereotactic body radiation therapy for early-
stage non-small cell lung cancer: executive 
summary of an ASTRO evidence-based 
guideline. Pract Radiat Oncol. 2017 Sep-
Oct;7:295-301.
[052MQ0]
[Zhang, X., et al 2004]
Zhang X, Schwartz J-CD, Guo X, Bhatia S, 
Cao E, Chen L, et al. Structural and 
functional analysis of the costimulatory 
receptor programmed death-1. Immunity 
2004;20:337-47.
[00VMQJ]
08TMTD