Clinical trial NCT03631784
Conditions: Non-small Cell Lung Cancer
Keywords: Programmed Cell Death-1 (PD1, PD-1) Programmed Cell Death 1 Ligand 1 (PDL1, PD-L1) Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)
Sponsor: Merck Sharp & Dohme LLC
Start date: 2018-10-19; Completion date: 2024-03-19
Enrollment: 216 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a trial in adult participants with unresectable, locally advanced, Stage III non-small cell lung cancer (NSCLC) treated with pembrolizumab in combination with platinum doublet chemotherapy and standard thoracic radiotherapy followed by pembrolizumab monotherapy. The primary hypothesis of the trial is that within each platinum doublet chemotherapy cohort, the percentage of participants who develop Grade 3 or higher pneumonitis is ≤10% and estimation of objective response rate (ORR) by blinded independent central review (BICR).

Detailed description:

Arms: arm 1: Participants received 1 cycle of carboplatin area under the curve (AUC) 6 mg/mL/min with paclitaxel 200 mg/m\^2 and pembrolizumab 200 mg on Day 1. Approximately 3 weeks later, participants received carboplatin AUC 2 mg/mL/min with paclitaxel 45 mg/ m\^2 administered weekly for 6 weeks along with 2 cycles of pembrolizumab 200 mg administered every 3 weeks (Q3W) in conjunction with standard thoracic radiotherapy (TRT) (60 Gray \[Gy\] in 2 Gy fractions administered 5 days per week for 6 weeks). Participants then received 14 additional cycles of pembrolizumab 200 mg administered Q3W. 1 cycle=21 days. arm 2: Participants received 3 cycles of cisplatin 75 mg/m\^2 with pemetrexed 500 mg/m\^2 and pembrolizumab 200 mg on Day 1 of each cycle. Treatment was given in conjunction with standard TRT (60 Gy in 2 Gy fractions administered 5 days per week for 6 weeks) in cycles 2 and 3. Participants then received 14 additional cycles of pembrolizumab 200 mg administered Q3W. 1 cycle=21 days.
Interventions: intervention 1: Pembrolizumab 200 mg intervention 2: Paclitaxel 45 mg/m^2 intervention 3: Carboplatin AUC6 intervention 4: Cisplatin 75 mg/m^2 intervention 5: Pemetrexed 500 mg/m^2 intervention 6: Thoracic Radiation Therapy (TRT) intervention 7: Paclitaxel 200 mg/m^2 intervention 8: Carboplatin AUC2
Intervention descriptions: intervention 1: Pembrolizumab 200 mg intravenous (IV) infusion on Days 1 of each 3-week cycle for up to 17 cycles intervention 2: Paclitaxel 45 mg/m\^2 IV infusion on Days 1, 8, 15 of each 3-week cycle for Cycles 2, and 3 during radiation therapy. intervention 3: Carboplatin AUC6 IV infusion on Day 1 of the 21-day cycle for Cycle 1. intervention 4: Cisplatin 75 mg/m\^2 IV infusion on Day 1 of each 21-day cycle for Cycles 1, 2, 3. intervention 5: Pemetrexed 500 mg/m\^2 IV infusion on Day 1 of each 21-day cycle for Cycles 1, 2, and 3. intervention 6: The target total dose of TRT will be 60 Gy in 30 daily fractions of 2 Gy, prescribed to the planning target volume. intervention 7: Paclitaxel 200 mg/m\^2 IV infusion on Day 1 of the 21-day cycle of Cycle 1. intervention 8: Carboplatin AUC2 IV infusion on Day 1, 8, 15 for Cycles 2 and 3 during radiation therapy.

Protocol documents:
Prot_SAP_001.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 2 Trial of Pembrolizumab (MK-3475) in 
Combination with Platinum Doublet Chemotherapy and 
Radiotherapy for Participants with Unresectable, Locally 
Advanced Stage III Non-Small Cell Lung Cancer 
(NSCLC) (KEYNOTE-799).
NCT03631784
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TITLE PAGE
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 2 Trial of Pembrolizumab (MK-3475) in Combination with 
Platinum Doublet Chemotherapy and Radiotherapy for Participants with Unresectable, 
Locally Advanced Stage III Non-Small Cell Lung Cancer (NSCLC) (KEYNOTE-799).
Protocol Number: 799-04
Compound Number: MK-3475
Sponsor Name and Legal Registered Address: 
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND NUMBER: 116,833
EudraCT NUMBER: 2018-000714-37
Approval Date:  05 December 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Trial 
File Binder (or equivalent). 
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 04
05-Dec-2022
Merck Sharp & Dohme Corp. underwent an entity name and address change to 
Merck Sharp & Dohme LLC, Rahway, NJ, USA. This conversion resulted only in an 
entity name change and update to the address. In addition, the amendment provides 
clarity regarding participation in the optional extension study and statement updates 
regarding binomial sequential testing procedure.
Amendment 03
18-Jun-2019
Modified the timing of the first interim analysis to be conducted when at least 36 
participants in one cohort (rather than in each cohort) have completed a minimum of 
15 weeks of follow up due to the large difference in enrollment rates between the 2 
cohorts.
Amendment 02
26-Sep-2018
Revised to include oversight by an external DMC per German and French Health 
Authorities request.
Amendment 01
06-Aug-2018
UK-specific amendment added monitoring for potential side effects related to 
cisplatin treatment and medications to be used with caution during cisplatin treatment 
per UK MHRA request.
Original Protocol
29-May-2018
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment 04
Overall Rationale for the Amendment:
Sponsor underwent an entity name change and update to the address. In addition, the amendment provides clarity regarding 
participation in the optional extension study and statement updates regarding binomial sequential testing procedure.
Summary of Changes Table:
Section # and Name
Description of Change
Brief Rationale
Title Page
10.1.1 Code of Conduct for 
Clinical Trials
Throughout
Sponsor entity name and 
address change.
Merck Sharp & Dohme Corp. underwent an entity name and 
address change to Merck Sharp & Dohme LLC, Rahway, NJ, USA.
This conversion resulted only in an entity name change and update 
to the address.
1.1 Synopsis, Overall 
Design, Estimated 
Duration of Study
Updated the approximate 
duration of the study.
The update reflects alignment with the planned duration of the 
study.
6.7 Treatment After the 
End of the Study
Added a statement regarding 
participant enrollment in a 
pembrolizumab extension 
study.
To provide clarity in giving participants the option to participate in 
an extension study, if available.
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Section # and Name
Description of Change
Brief Rationale
9.6.1 Statistical Methods
for Efficacy Analyses
9.6.2 Statistical Method for 
Safety Analyses
9.7 Interim Analyses
9.9 Sample Size and Power 
Calculations
Updated statements regarding
binomial sequential testing 
procedure.
Update provides clarity.
Throughout document
Minor administrative, 
formatting, grammatical, and/or 
typographical changes were
made throughout the document
To ensure clarity and accurate interpretation of the intent of the 
protocol.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1.
Protocol Summary .....................................................................................................15
Synopsis....................................................................................................................15
Schema .....................................................................................................................18
Schedule of Activities (SoA) ...................................................................................20
1.3.1
Cohort A Schedule: Screening and Treatment Cycle 1 to 3 ................................20
1.3.2
Cohort B Schedule: Screening and Treatment Cycle 1 to 3 ................................24
1.3.3
Cohorts A and B: Pembrolizumab Monotherapy (Cycle 4-17) and Post-
Treatment Follow Up...........................................................................................28
2.
Introduction................................................................................................................32
Study Rationale .......................................................................................................32
Background..............................................................................................................32
2.2.1
Pharmaceutical and Therapeutic Background .....................................................32
2.2.2
Completed Clinical Studies..................................................................................33
2.2.3
Ongoing Clinical Studies .....................................................................................36
2.2.4
Information on Other Study-related Therapy ......................................................37
Benefit/Risk Assessment.........................................................................................38
3.
Objectives/Hypotheses and Endpoints.....................................................................38
4.
Study Design...............................................................................................................40
Overall Design .........................................................................................................40
Scientific Rationale for Study Design....................................................................41
4.2.1
Rationale for Endpoints .......................................................................................43
Efficacy Endpoints........................................................................................43
Safety Endpoints...........................................................................................44
Planned Exploratory Biomarker Research....................................................44
Future Biomedical Research.........................................................................46
Justification for Dose ..............................................................................................46
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4.3.1
Rationale for Dose Interval and Study Design.....................................................46
Beginning and End of Study Definition ................................................................47
4.4.1
Clinical Criteria for Early Study Termination .....................................................47
5.
Study Population........................................................................................................47
Inclusion Criteria....................................................................................................47
Exclusion Criteria ...................................................................................................50
Lifestyle Considerations .........................................................................................52
5.3.1
Meals and Dietary Restrictions............................................................................52
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ......................................................52
5.3.3
Activity Restrictions ............................................................................................53
5.3.4
Contraception.......................................................................................................53
5.3.5
Pregnancy.............................................................................................................53
5.3.6
Use in Nursing Women........................................................................................53
Screen Failures ........................................................................................................53
Participant Replacement Strategy.........................................................................54
6.
Treatments..................................................................................................................54
Treatments Administered.......................................................................................54
Preparation/Handling/Storage/Accountability ....................................................56
6.2.1
Dose Preparation..................................................................................................56
6.2.2
Handling, Storage and Accountability.................................................................56
Measures to Minimize Bias: Randomization and Blinding.................................57
6.3.1
Method of Treatment Assignment .......................................................................57
Stratification..................................................................................................57
6.3.2
Blinding................................................................................................................57
Treatment Compliance...........................................................................................57
Concomitant Therapy.............................................................................................57
6.5.1
Acceptable Concomitant Medications .................................................................57
6.5.2
Prohibited Concomitant Medication....................................................................58
6.5.3
Rescue Medications and Supportive Care ...........................................................58
Pembrolizumab .............................................................................................58
Chemotherapy...............................................................................................59
Radiotherapy.................................................................................................59
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Dose Modification ...................................................................................................61
6.6.1
Pembrolizumab ....................................................................................................62
Dose Modification and Toxicity Management for Immune-Related 
AEs Associated With Pembrolizumab..........................................................62
Dose Modification and Toxicity Management of Infusion-
Reactions Related to Pembrolizumab...........................................................67
Other Allowed Dose Interruption for Pembrolizumab .................................68
6.6.2
Chemotherapy Dose Modifications .....................................................................69
6.6.3
Radiotherapy Dose Modification.........................................................................69
Treatment After the End of the Study ..................................................................69
Clinical Supplies Disclosure...................................................................................69
Standard Policies.....................................................................................................69
7.
Discontinuation of Study Treatment and Participant Withdrawal ......................70
Discontinuation of Study Treatment.....................................................................70
Participant Withdrawal From the Study..............................................................71
Lost to Follow-up ....................................................................................................71
8.
Study Assessments and Procedures..........................................................................71
Administrative and General Procedures ..............................................................72
8.1.1
Informed Consent.................................................................................................72
General Informed Consent............................................................................72
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 ...................................................................................................73
8.1.5
Prior and Concomitant Medications Review .......................................................73
Prior Medications..........................................................................................73
Concomitant Medications.............................................................................74
8.1.6
Post-Treatment Anticancer Therapy....................................................................74
8.1.7
Assignment of Screening Number.......................................................................74
8.1.8
Assignment of Treatment/Randomization Number.............................................74
8.1.9
Treatment Administration....................................................................................74
Timing of Dose Administration....................................................................75
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Timing of Dose Administration of Pembrolizumab ..............................75
Timing of Dose Administration of Chemotherapy: Cohort A...............75
Paclitaxel .........................................................................................75
Carboplatin......................................................................................76
Timing of Dose Administration of Chemotherapy: Cohort B...............76
Pemetrexed......................................................................................76
Cisplatin ..........................................................................................76
Thoracic Radiation Therapy (TRT) ..............................................................77
Dose Specifications................................................................................77
Variations of Dose Prescription.............................................................78
Localization, Simulation, and Immobilization ......................................79
Treatment Planning/Target Volumes.....................................................80
Treatment Planning................................................................................81
Documentation.......................................................................................81
Organs at Risk........................................................................................82
Treatment Quality Assurance and Compliance with Protocol-
Defined Radiation Prescription (Quality Control).................................83
8.1.10 Discontinuation and Withdrawal .........................................................................83
Survival Follow-up .......................................................................................83
Withdrawal From Future Biomedical Research ...........................................83
8.1.11 Participant Blinding/Unblinding..........................................................................84
8.1.12 Calibration of Equipment.....................................................................................84
Efficacy Assessments...............................................................................................84
8.2.1
Tumor Imaging and Assessment of Disease........................................................84
Initial Tumor Imaging...................................................................................85
Tumor Imaging During the Study.................................................................85
End of Treatment and Follow-up Imaging....................................................86
RECIST 1.1 Assessment of Disease.............................................................86
iRECIST Assessment of Disease..................................................................87
Safety Assessments..................................................................................................92
8.3.1
Physical Examinations.........................................................................................92
Full Physical Exam .......................................................................................92
Directed Physical Examination.....................................................................93
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8.3.2
Vital Signs, Weight, and Height ..........................................................................93
8.3.3
Electrocardiograms ..............................................................................................93
8.3.4
Eastern Cooperative Oncology Group (ECOG) Performance Scale ...................93
8.3.5
Pulmonary Function Tests ...................................................................................93
8.3.6
Clinical Safety Laboratory Assessments..............................................................93
Laboratory Safety Evaluations (Hematology, Chemistry, and 
Urinalysis).....................................................................................................94
Pregnancy Test..............................................................................................94
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events .......................................................................................94
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..................................................................95
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events..............96
8.4.3
Follow-up of AE, SAE and Other Reportable Safety Event Information............96
8.4.4
Regulatory Reporting Requirements for SAE .....................................................97
8.4.5
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as AEs or SAEs..................................................................................97
8.4.6
Pregnancy and Exposure During Breastfeeding ..................................................97
8.4.7
Events of Clinical Interest (ECIs)........................................................................98
Treatment of Overdose...........................................................................................98
Pharmacokinetics....................................................................................................98
8.6.1
Blood Collection for Serum Levels of Pembrolizumab.......................................98
8.6.2
Blood Collection of Anti-Pembrolizumab Antibodies (ADA) ............................99
Pharmacodynamics.................................................................................................99
Biomarkers ..............................................................................................................99
Future Biomedical Research Sample Collection..................................................99
Tumor Tissue Collection ......................................................................................100
Planned Genetic Analysis Sample Collection.....................................................100
Visit Requirements................................................................................................100
8.12.1 Screening............................................................................................................100
8.12.2 Treatment Period................................................................................................101
8.12.3 Post-treatment Period.........................................................................................101
30 Day Safety Follow-up Visit ...................................................................101
Follow-up Visits..........................................................................................101
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Survival Follow-up .....................................................................................101
Survival Status.....................................................................................102
9.
Statistical Analysis Plan ..........................................................................................102
Statistical Analysis Plan Summary......................................................................102
Responsibility for Analyses/In-house Blinding...................................................104
Hypotheses/Estimation .........................................................................................105
Analysis Endpoints................................................................................................105
9.4.1
Primary Endpoints .............................................................................................105
9.4.2
Secondary Endpoints .........................................................................................105
9.4.3
Tertiary/Exploratory Endpoints .........................................................................105
Analysis Populations.............................................................................................105
9.5.1
Efficacy Analysis Populations ...........................................................................105
9.5.2
Safety Analysis Populations ..............................................................................105
Statistical Methods................................................................................................106
9.6.1
Statistical Methods for Efficacy Analyses.........................................................106
9.6.2
Statistical Method for Safety Analyses..............................................................108
9.6.3
Summaries of Baseline Characteristics and Demographics...............................110
Interim Analyses ...................................................................................................110
Multiplicity ............................................................................................................114
Sample Size and Power Calculations ..................................................................114
Subgroup Analyses................................................................................................115
Compliance (Medication Adherence)..................................................................116
Extent of Exposure................................................................................................116
10.
Supporting Documentation and Operational Considerations.............................117
Appendix 1:  Regulatory, Ethical and Study Oversight Considerations .........117
10.1.1 Code of Conduct for Clinical Trials...................................................................117
10.1.2 Financial Disclosure...........................................................................................119
10.1.3 Data Protection...................................................................................................119
10.1.4 Confidentiality of Data ......................................................................................119
10.1.5 Confidentiality of Participant Records...............................................................120
10.1.6 Confidentiality of IRB/IEC Information............................................................120
10.1.7 Committees Structure.........................................................................................120
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Executive Oversight Committee.................................................................120
External Data Monitoring Committee ........................................................120
10.1.8 Publication Policy ..............................................................................................121
10.1.9 Compliance with Study Registration and Results Posting Requirements .........121
10.1.10
Compliance with Law, Audit, and Debarment ...........................................121
10.1.11
Data Quality Assurance ..............................................................................122
10.1.12
Source Documents......................................................................................123
10.1.13
Study and Site Closure................................................................................123
Appendix 2:  Collection and Management of Specimens for Future 
Biomedical Research.............................................................................................124
Appendix 3:  Contraceptive Guidance and Pregnancy Testing........................128
Definitions......................................................................................................................128
Contraception Requirements..........................................................................................128
Pregnancy Testing..........................................................................................................131
Appendix 4: Adverse Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting............................................132
Definition of AE ............................................................................................................132
Definition of SAE ..........................................................................................................133
Additional Events Reported in the Same Manner as SAE.............................................134
Recording AE and SAE .................................................................................................134
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor.............138
Appendix 5: ECOG Performance Status............................................................139
Appendix 6:  Clinical Laboratory Tests..............................................................140
Appendix 7:  Country-specific Requirements ....................................................142
France ............................................................................................................................142
Germany.........................................................................................................................142
Poland ............................................................................................................................143
United Kingdom.............................................................................................................143
Appendix 8:  Abbreviations .................................................................................145
11.
References.................................................................................................................149
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LIST OF TABLES
Table 1
Summary of Recent Trials in NSCLC..................................................................42
Table 2
Adequate Organ Function Laboratory Values......................................................49
Table 3
Study Treatment(s) ...............................................................................................55
Table 4
CTCAE Scale: Acute Esophagitis Related to Radiation ......................................60
Table 5
Suggestions for Management of Radiation Esophagitis.......................................61
Table 6
Dose Modification and Toxicity Management Guidelines for Immune-
related AEs Associated with Pembrolizumab.......................................................63
Table 7
Criteria for Grading of Pneumonitis: Common Terminology Criteria for 
Adverse Events, Version 4.0 ................................................................................66
Table 8
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines.............................................................................................................67
Table 9
Summary of Protocol Constraints and Compliance Criteria ................................79
Table 10
Planning Target Volume.......................................................................................81
Table 11
Imaging and Treatment after First Radiologic Evidence of PD ...........................91
Table 12
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events............................................................................96
Table 13
Censoring Rules for Primary and Sensitivity Analyses of Progression-
free Survival........................................................................................................107
Table 14
Efficacy Analysis Methods for Key Efficacy Endpoints....................................108
Table 15
Analysis Strategy for Safety Parameters Excluding Primary Endpoint 
(Percentage of Participants with Grade 3 or Higher Pneumonitis).....................109
Table 16
Decision Rules for Stopping the Trial for Low Percentage of 
Participants with Grade 3 or Higher Pneumonitis..............................................111
Table 17
Decision Rules for Stopping the Trial for High Percentage of 
Participants with Grade 3 or Higher Pneumonitis..............................................111
Table 18
Decision Rules for Stopping the Trial due to a Low ORR.................................112
Table 19
Decision Rules for Stopping the Trial due to a High ORR ................................113
Table 20
Operating Characteristics of the Sequential Monitoring Approach 
(Percentage of Participants with Grade 3 or Higher Pneumonitis).....................114
Table 21
Operating Characteristics of the Sequential Monitoring Approach 
(ORR) .................................................................................................................115
Table 22
Highly Effective Contraception Methods...........................................................130
Table 23
Protocol-required Safety Laboratory Assessments.............................................141
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LIST OF FIGURES
          
Figure 1
Study Diagram......................................................................................................19
Figure 2
Imaging and Treatment for Clinically Stable Participants after First 
Radiologic Evidence of PD Assessed by the Investigator....................................92
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1. Protocol Summary
Synopsis
Protocol Title:
A Phase 2 Trial of Pembrolizumab (MK-3475) in Combination with Platinum Doublet 
Chemotherapy and Radiotherapy for Participants with Unresectable, Locally Advanced 
Stage III Non-Small Cell Lung Cancer (NSCLC) (KEYNOTE-799).
Short Title:
Phase 2 Trial of Pembrolizumab in Combination with Chemotherapy and Radiotherapy 
in Stage III NSCLC (KEYNOTE-799).
Objectives/Hypotheses and Endpoints:

In adult participants with unresectable, locally advanced, Stage III NSCLC treated 
with pembrolizumab in combination with platinum doublet chemotherapy and 
standard thoracic radiotherapy (TRT) followed by pembrolizumab monotherapy.
Objective/Hypothesis
Endpoint
Primary

Objective: Within each platinum 
doublet chemotherapy cohort,
evaluate the percentage of 
participants who develop Grade 3 or 
higher pneumonitis

Hypothesis: Within each platinum 
doublet chemotherapy cohort, the 
percentage of participants who 
develop Grade 3 or higher
pneumonitis is <10%

Objective: Within each platinum 
doublet chemotherapy cohort,
estimate the objective response rate 
as assessed by blinded independent 
central review (BICR) according to 
Response Evaluation Criteria in 
Solid Tumors (RECIST) 1.1

Grade 3 or higher pneumonitis

Confirmed complete response or partial 
response
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Secondary

Objective: Within each platinum 
doublet chemotherapy cohort,
evaluate the progression-free 
survival (PFS) assessed by BICR 
according to RECIST v.1.1, 
modified to follow a maximum of 10 
target lesions and a maximum of 5 
target lesions per organ 

Objective: Within each platinum 
doublet chemotherapy cohort,
evaluate overall survival (OS)

Objective: Within each platinum 
doublet chemotherapy cohort,
evaluate the safety and tolerability of 
each treatment regimen by the 
percentage of participants who 
develop AEs

PFS defined as the time from enrollment 
to the first documented local recurrence 
or distant metastasis or death due to any 
cause, whichever occurs first

OS defined as the time from enrollment
to death due to any cause

Adverse events (AEs)

Discontinuations due to AEs
Overall Design:
Study Phase
Phase 2
Clinical Indication
The treatment of participants with NSCLC
Population
Unresectable, locally advanced, Stage III NSCLC
Study Type
Interventional
Type of Design
Multi-site, multi-cohort, parallel-group
Type of Control
No treatment control
Study Blinding
Unblinded, open-label
Estimated Duration 
of Study
The Sponsor estimates that the study will require 
approximately 60 months from the time the first participant 
signs the informed consent until the last participant’s last 
study-related telephone call or visit. 
Number of Participants:
Approximately 216 participants will be enrolled.
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Treatment Groups and Duration:
Treatment Groups
There are 2 treatment cohorts. Participants with non-
squamous NSCLC are eligible for both cohorts. The choice 
of platinum doublet chemotherapy will be determined by 
the investigator prior to treatment allocation. Participants 
with squamous NSCLC are eligible only for Cohort A.

Cohort A: Participants will receive 1 cycle of 
carboplatin area under the curve (AUC) 6 with
paclitaxel 200 mg/m2 and pembrolizumab 200 mg on 
Day 1. Approximately 3 weeks later, participants will 
receive carboplatin AUC2 with paclitaxel 45 mg/m2
administered weekly for 6 weeks along with 2 cycles of 
pembrolizumab 200 mg administered every 3 weeks 
(Q3W) in conjunction with standard TRT. To conclude 
the study treatments, participants will receive 14
additional cycles of pembrolizumab 200 mg 
administered Q3W.

Cohort B: Participants will receive 3 cycles of
cisplatin 75 mg/m2 with pemetrexed 500 mg/m2 and
pembrolizumab 200 mg on Day 1 of each 3-week 
cycle. Treatment will be given in conjunction with 
standard TRT in Cycles 2 and 3. To conclude the study 
treatments, participants will receive 14 additional 
cycles of pembrolizumab 200 mg administered Q3W.
Duration of 
Participation
Each participant will participate in the study from the time 
the participant signs the informed consent form through the 
final protocol-specified contact.
After a screening phase of approximately 6 weeks, eligible 
participants will receive assigned treatment as described 
above for approximately 1 year or until documented 
disease progression, unacceptable AEs, intercurrent illness 
that prevents further administration of treatment, 
investigator’s decision to withdraw the participant, 
participant withdraws consent, or pregnancy of the 
participant.
At the end of treatment, each participant will be followed 
for a minimum of 30 days for AE monitoring. Serious AEs 
occurring within 90 days following cessation of treatment, 
or 30 days following cessation of treatment if the 
participant initiates new anticancer therapy, will be 
collected, whichever is earlier.
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Participants will have post-treatment follow-up for disease 
status, including radiographic imaging as outlined in the 
protocol, until initiating a non-study anticancer treatment, 
experiencing disease progression, death, withdrawing 
consent, becoming lost to follow-up, or end of study.
All participants will be followed for OS until death, loss to 
follow-up or withdrawal of consent.
Study Governance:
Study Governance 
Committees
Committee
Included in this study?
Steering Committee
No
Executive Oversight 
Committee
Yes
External Data Monitoring 
Committee
Yes
Clinical Adjudication 
Committee
No
Study governance considerations are outlined in Appendix 
1.
A list of abbreviations used in this document can be found in Appendix 8.
Schema
The study design is depicted in Figure 1.
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Abbreviations: AUC = area under the curve; D = day; RT = radiotherapy.
Figure 1
Study Diagram
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Schedule of Activities (SoA)
1.3.1
Cohort A Schedule: Screening and Treatment Cycle 1 to 3 
Cohort A
Screening 
Phase
Treatment Cycles  (3-Week Cycles)
Notes
Pembrolizumab Treatment 
Cycle
Screening 
Visit
1
2
3
Day (in Pembrolizumab Cycle)
1
8
15
1
8
15
Scheduling Window (Days):1
-42 to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
Administrative Procedures
Informed Consent 
X
Informed consent must be obtained prior to any protocol-related 
intervention.
Informed Consent for Future 
Biomedical Research (optional)
X
The future biomedical research consent must be obtained prior to
performing any procedure related to the future biomedical research 
substudy
Inclusion/Exclusion Criteria
X
Participant Identification Card
X
Demographics and Medical 
History
X
Include all active conditions, clinically significant conditions 
diagnosed within the prior 10 years, and any prior cancer other than 
NSCLC even if diagnosed greater than 10 years prior to Visit 1.
Prior and Concomitant 
Medications
Prior medications: Record medications taken within 42 days of first 
dose and medications regularly administered at intervals greater than 
42 days prior to first dose.
Concomitant medications: Record new medications started during 
the study through the post-treatment Follow-up and changes to dose, 
frequency and route occurring during the study period.
NSCLC Disease Details and Prior 
Treatment
X
Log in to IWRS
X
X
X
X
X
X
X
X
Log in to IWRS at Cycle 1 to obtain allocation number and at 
subsequent visits to ensure visits are captured in the IWRS system. 
A window of – 3 days is allowed.
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Cohort A
Screening 
Phase
Treatment Cycles  (3-Week Cycles)
Notes
Pembrolizumab Treatment 
Cycle
Screening 
Visit
1
2
3
Day (in Pembrolizumab Cycle)
1
8
15
1
8
15
Scheduling Window (Days):1
-42 to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
Clinical Procedures / Assessments
Review AEs
All AEs, SAEs, and other reportable safety events that occur after 
the consent form is signed but before treatment must be reported if 
the event causes the participant to be excluded from the study, or is 
the result of a protocol-specified intervention. 
Report all AEs occurring from the start of treatment through 30 days 
following cessation of study treatment. 
Report SAEs occurring from the start of treatment through 90 
following cessation of study treatment, or 30 days following 
cessation of study treatment if a new anticancer therapy is initiated, 
whichever is earlier
Full Physical Examination
X
Refer to Appendix 7 for country-specific requirements.
Directed Physical Examination
X
X
X
Refer to Appendix 7 for country-specific requirements.
Vital Signs, Weight and Height
X
X
X
X
Vital signs include: temperature, pulse, heart rate, respiratory rate, 
blood pressure.  
Height will be measured only at Visit 1.
12-Lead ECG (local)
X
ECOG Performance Status
X
X
X
X
Screening Visit: ECOG PS is to be performed within 10 days prior to 
the first dose of study treatment. 
Treatment Visits: ECOG PS is to be performed prior to the 
administration of study treatment.
Pulmonary Function Test
X
Pulmonary function tests include pulse oximetry, FEV1 (forced 
expiratory volume in the first second of expiration), FVC (forced 
vital capacity), DLCO (diffusing lung capacity for carbon 
monoxide), and TLC (total lung capacity).
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Cohort A
Screening 
Phase
Treatment Cycles  (3-Week Cycles)
Notes
Pembrolizumab Treatment 
Cycle
Screening 
Visit
1
2
3
Day (in Pembrolizumab Cycle)
1
8
15
1
8
15
Scheduling Window (Days):1
-42 to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
Laboratory Procedures / Assessments: Analysis Performed by Local Laboratory
Pregnancy Test - Urine or Serum 
β-HCG
As Clinically Indicated
For women of reproductive potential, a urine pregnancy test must be 
performed within 72 hours prior to first dose of trial treatment. A 
serum test can be considered if urine test is not appropriate. 
Monthly pregnancy testing must be conducted as per local
regulations where applicable. Refer to Appendix 7 for country-
specific details.
PT/INR and aPTT/PTT
X
Laboratory tests for screening are to be performed within 10 days 
prior to the first dose of study treatment. 
After Cycle 1, lab samples can be collected up to 3 days prior to Day 
1 of subsequent cycles. 
Participants may be dosed in subsequent cycles after Cycle 1 Day 1 
while thyroid function tests are pending.
Hematology
X
X
X
X
X
X
X
Comprehensive Chemistry Panel
X
X
X
X
X
X
X
Urinalysis
X
T3 or FT3, FT4 and TSH 
X
X
Analysis Performed by Central Laboratory
Pembrolizumab Pharmacokinetics
(PK)
X
X
Pre-dose trough PK, and ADA samples will be collected at Cycles 1 
and 2 and must be drawn within 24 hours before infusion of 
pembrolizumab.
Post-dose peak PK samples will be collected at Cycle 1 and must be 
drawn within 30 minutes of the completion of the pembrolizumab 
infusion.  
Anti-pembrolizumab Antibodies
(ADA)
X
X
Blood for Genetic Analysis
X
Whole blood samples must be collected pre-dose.
Blood for genetic analysis must be drawn for planned analysis of the 
association between genetic variants in DNA and drug response. 
This sample will not be collected at that 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 future 
biomedical research if the participant signs the FBR consent. If the 
planned genetic analyses are not approved, but FBR is approved and 
consent is given, this sample will be collected for the purpose of 
FBR.
Blood for RNA Analyses
X
X
Blood for Plasma Biomarker 
Analyses
X
Blood for Serum Biomarker 
Analyses
X
Blood for ctDNA
X
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Cohort A
Screening 
Phase
Treatment Cycles  (3-Week Cycles)
Notes
Pembrolizumab Treatment 
Cycle
Screening 
Visit
1
2
3
Day (in Pembrolizumab Cycle)
1
8
15
1
8
15
Scheduling Window (Days):1
-42 to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
Tumor Biopsies/ Archival Tissue Collection
Tumor Tissue Collection
X
A tumor tissue sample  (ie, core, incisional, or excisional biopsy)
must be provided to the central lab within 42 days prior to treatment
allocation. FFPE tissue blocks are preferred to slides. In cases where 
the biopsy is not available or cannot be obtained, a cell block 
obtained through EUS/EBUS may be submitted after consultation 
with the Sponsor Clinical Director and documenting approval via a 
Sponsor Communication Form.
Efficacy Measurements
Tumor Imaging 
X
Baseline tumor imaging must be performed within 42 days of Cycle 
1. 
FDG-PET or FDG-PET/CT
X
If the participant underwent the required FDG-PET or FDG-PET/CT 
imaging prior to signing ICF and within 60 days prior to Cycle 1 
Day 1, repeat imaging is not required.
MRI Brain With Contrast
X
MRI is preferred; however, head CT imaging with contrast may be 
acceptable if MRI is medically contraindicated.
Study Treatment Administration
Carboplatin
X
X
X
X
X
X
X
Study treatment with pembrolizumab and chemotherapy must be 
administered after all procedures/assessments have been completed 
Study treatments must be administered in the following order: 
pembrolizumab (if required on a given day), paclitaxel, carboplatin, 
TRT (if required on a given day). Confirm/qualify RT prescription. 
Delays in the protocol specified pembrolizumab treatment schedule 
due to toxicity or for situations other than treatment-related AEs are 
described in Section 6.6.1 and 6.6.1.3, respectively. 
Delays in chemotherapy treatment are described in Section 6.6.2
Delays in TRT are described in Section 6.6.3
Paclitaxel 
X
X
X
X
X
X
X
Thoracic radiotherapy (TRT)
Pembrolizumab
X
X
X
1. In general, procedures are to be performed on Day 1 and prior to the first dose of the trial treatment for each cycle unless otherwise specified. The window for each visit is ± 3 
days unless otherwise noted. If treatment cycles are adjusted all procedures except imaging will be completed according to the cycle number and not weeks on treatment.
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1.3.2
Cohort B Schedule: Screening and Treatment Cycle 1 to 3 
Cohort B
Screening 
Phase
Treatment Cycles 
(3-Week Cycles)
Notes
Pembrolizumab Treatment Cycle
Screening 
Visit
1
2
3
Scheduling Window (Days):1
-42 to -1
+3
± 3
± 3
Administrative Procedures
Informed Consent 
X
Informed consent must be obtained prior to any protocol-related intervention.
Informed Consent for Future 
Biomedical Research (optional)
X
The future biomedical research consent must be obtained prior to performing any procedure related 
to the future biomedical research substudy
Inclusion/Exclusion Criteria
X
Participant Identification Card
X
Demographics and Medical History
X
Include all active conditions, clinically significant conditions diagnosed within the prior 10 years, 
and any prior cancer other than NSCLC even if diagnosed greater than 10 years prior to Visit 1.
Prior and Concomitant Medications
Prior medications: Record medications taken within 42 days of first dose and medications regularly 
administered at intervals greater than 42 days prior to first dose. 
Concomitant medications: Record new medications started during the study through the post-
treatment Follow-up and changes to dose, frequency and route occurring during the study period.
NSCLC Disease Details and Prior 
Treatment
X
Log in to IWRS
X
X
X
X
Log in to IWRS at Cycle 1 to obtain allocation number and at subsequent visits to ensure visits are 
captured in the IWRS system. A window of – 3 days is allowed.
Clinical Procedures / Assessments
Review AEs
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed but 
before treatment must be reported if the event causes the participant to be excluded from the study, 
or is the result of a protocol-specified intervention. 
Report all AEs occurring from the start of treatment through 30 days following cessation of study
treatment. 
Report SAEs occurring from the start of treatment through 90 following cessation of study 
treatment, or 30 days following cessation of study treatment if a new anticancer therapy is initiated, 
whichever is earlier.
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Cohort B
Screening 
Phase
Treatment Cycles 
(3-Week Cycles)
Notes
Pembrolizumab Treatment Cycle
Screening 
Visit
1
2
3
Scheduling Window (Days):1
-42 to -1
+3
± 3
± 3
Full Physical Examination
X
Refer to Appendix 7 for country-specific requirements.
Directed Physical Examination
X
X
X
Refer to Appendix 7 for country-specific requirements.
Vital Signs, Weight and Height
X
X
X
X
Vital signs include: temperature, pulse, heart rate, respiratory rate, blood pressure.  
Height will be measured only at Visit 1.
12-Lead ECG (local)
X
ECOG Performance Status
X
X
X
X
Screening Visit: ECOG PS is to be performed within 10 days prior to the first dose of study
treatment. 
Treatment Visits: ECOG PS is to be performed prior to the administration of study treatment.
Pulmonary Function Test
X
Pulmonary function tests include pulse oximetry, FEV1 (forced expiratory volume in the first 
second of expiration), FVC (forced vital capacity), DLCO (diffusing lung capacity for carbon 
monoxide), and TLC (total lung capacity).
Laboratory Procedures / Assessments: Analysis Performed by Local Laboratory
Pregnancy Test - Urine or Serum 
β-HCG
As Clinically Indicated
For women of reproductive potential, a urine pregnancy test must be performed within 72 hours 
prior to first dose of trial treatment. A serum test can be considered if urine test is not appropriate. 
Monthly pregnancy testing must be conducted as per local regulations where applicable. Refer to 
Appendix 7 for country-specific details.
PT/INR and aPTT/PTT
X
Laboratory tests for screening are to be performed within 10 days prior to the first dose of study
treatment. 
After Cycle 1, lab samples can be collected up to 3 days prior to Day 1 of subsequent cycles. 
Participants may be dosed in subsequent cycles after Cycle 1 Day 1 while thyroid function tests are 
pending.
Hematology
X
X
X
Comprehensive Chemistry Panel
X
X
X
Urinalysis
X
T3 or FT3, FT4 and TSH 
X
X
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Cohort B
Screening 
Phase
Treatment Cycles 
(3-Week Cycles)
Notes
Pembrolizumab Treatment Cycle
Screening 
Visit
1
2
3
Scheduling Window (Days):1
-42 to -1
+3
± 3
± 3
Analysis Performed by Central Laboratory
Pembrolizumab Pharmacokinetics
X
X
Pre-dose trough PK, and ADA samples will be collected at Cycles 1 and 2 and must be drawn 
within 24 hours before infusion of pembrolizumab.
Post-dose peak PK samples will be collected at Cycle 1 and must be drawn within 30 minutes of 
the completion of the pembrolizumab infusion.  
Anti-pembrolizumab Antibodies
X
X
Blood for Genetic Analysis
X
Whole blood samples must be collected pre-dose.
Blood for genetic analysis must be drawn for planned analysis of the association between genetic 
variants in DNA and drug response. This sample will not be collected at that 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 
future biomedical research if the participant signs the FBR consent. If the planned genetic analyses 
are not approved, but FBR is approved and consent is given, this sample will be collected for the 
purpose of FBR
Blood for RNA Analyses
X
X
Blood for Plasma Biomarker 
Analyses
X
Blood for Serum Biomarker 
Analyses
X
Blood for ctDNA
X
Tumor Biopsy/Archival Tissue Collection
Tumor Tissue Collection 
X
A tumor tissue sample (ie, core, incisional, or excisional biopsy) must be provided to the central 
lab within 42 days prior to treatment allocation. FFPE tissue blocks are preferred to slides. In cases 
where the biopsy is not available or cannot be obtained, a cell block obtained through EUS/EBUS 
may be submitted after consultation with the Sponsor Clinical Director and documenting approval 
via a Sponsor Communication Form.
Efficacy Measurements
Tumor Imaging
X
Baseline tumor imaging must be performed within 42 days of Cycle 1. 
FDG-PET or FDG-PET/CT
X
If the participant underwent the required FDG-PET or FDG-PET/CT imaging prior to signing ICF 
and within 60 days prior to Cycle 1 Day 1, repeat imaging is not required.
MRI Brain With Contrast
X
MRI is preferred; however, head CT imaging with contrast may be acceptable if MRI is medically 
contraindicated.
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Cohort B
Screening 
Phase
Treatment Cycles 
(3-Week Cycles)
Notes
Pembrolizumab Treatment Cycle
Screening 
Visit
1
2
3
Scheduling Window (Days):1
-42 to -1
+3
± 3
± 3
Study Treatment Administration
Cisplatin
X
X
X
Study treatment with pembrolizumab and chemotherapy must be administered after all 
procedures/assessments have been completed. 
Study treatments must be administered in the following order: pembrolizumab, pemetrexed, 
cisplatin, TRT (if required on a given day). Confirm/qualify RT prescription.
Participants must take a folic acid preparation or multivitamin with folic acid and intramuscular 
vitamin B12as described in Section 8.1.9.1.3.1.
Delays in the protocol specified pembrolizumab treatment schedule due to toxicity or for situations
other than treatment-related AEs are described in Section 6.6.1 and 6.6.1.3, respectively. 
Delays in chemotherapy treatment are described in Section 6.6.2
Delays in TRT are described in Section 6.6.3
Pemetrexed 
X
X
X
Folic acid and Vitamin B12
Thoracic radiotherapy (TRT)
Pembrolizumab
X
X
X
1. In general, procedures are to be performed on Day 1 and prior to the first dose of the trial treatment for each cycle unless otherwise specified. The window for each visit is ± 3 
days unless otherwise noted. If treatment cycles are adjusted all procedures except imaging will be completed according to the cycle number and not weeks on treatment.
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1.3.3
Cohorts A and B: Pembrolizumab Monotherapy (Cycle 4-17) and Post-Treatment Follow Up
Cohorts A and B
Treatment Cycles (3-Week Cycles)
End 
of 
Tx
Post-Treatment
Notes
Treatment Cycle
4
5 & 
6
7
8 & 
9
10
11& 
12
13
14& 
15
16
17
DC
Safety
FU
FU3
Survival
FU4
Scheduling 
Window (Days):1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At 
Tx
DC2
30 D
Post 
Dose
± 3
Per 
imaging 
sched5
Every 
12 
Week
s±14 
Administrative Procedures
Concomitant 
Medications
Record new medications started during the study 
through the post-treatment Follow-up and 
changes to dose, frequency and route occurring 
during the study period.
Log in to IWRS
X
X
X
X
X
X
X
X
X
X
X
Log in to ensure visits are captured in the IWRS 
system.
Subsequent Anti-
neoplastic Therapy 
Status
X
X
X
Review all new antineoplastic therapy initiated 
after the last dose of study treatment.
Survival Status
After investigator determined PD 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.
Clinical Procedures / Assessments
Review Adverse 
Events 4
Report all AEs occurring from the start of 
treatment through 30 days following cessation of 
study treatment. 
Report SAEs occurring from the start of 
treatment through 90 following cessation of 
study treatment, or 30 days following cessation
of study treatment if a new anticancer therapy is 
initiated, whichever is earlier.
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Cohorts A and B
Treatment Cycles (3-Week Cycles)
End 
of 
Tx
Post-Treatment
Notes
Treatment Cycle
4
5 & 
6
7
8 & 
9
10
11& 
12
13
14& 
15
16
17
DC
Safety
FU
FU3
Survival
FU4
Scheduling 
Window (Days):1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At 
Tx
DC2
30 D
Post 
Dose
± 3
Per 
imaging 
sched5
Every 
12 
Week
s±14 
Full Physical 
Examination
X
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
X
Vital Signs and 
Weight 
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs include: temperature, pulse, heart 
rate, respiratory rate, blood pressure.  
ECOG 
Performance 
Status
X
X
X
X
X
X
X
X
X
X
X
X
ECOG PS is to be performed prior to the 
administration of study treatment.
Laboratory Procedures / Assessments: Analysis Performed by Local Laboratory
Pregnancy Test -
Urine or Serum β-
HCG 
As Clinically Indicated
For women of reproductive potential, a urine 
pregnancy test must be performed within 72 
hours prior to first dose of trial treatment. A 
serum test can be considered if urine test is not 
appropriate. 
Monthly pregnancy testing must be conducted as 
per local regulations where applicable. Refer to 
Appendix 7 for country-specific details.
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
Lab samples can be collected up to 3 days prior 
to Day 1 of each cycle.
Urinalysis to be repeated every 6 cycles 
beginning with Cycle 6 and at the 30-Day 
Follow-up visit. 
Thyroid function tests to be repeated every other 
cycle and at the 30-day Follow-up visit.
Participants may be dosed while thyroid 
function tests are pending.
Comprehensive 
Chemistry Panel
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
T3 or FT3, FT4 
and TSH
X
X
X
X
X
X
X
X
X
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Cohorts A and B
Treatment Cycles (3-Week Cycles)
End 
of 
Tx
Post-Treatment
Notes
Treatment Cycle
4
5 & 
6
7
8 & 
9
10
11& 
12
13
14& 
15
16
17
DC
Safety
FU
FU3
Survival
FU4
Scheduling 
Window (Days):1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At 
Tx
DC2
30 D
Post 
Dose
± 3
Per 
imaging 
sched5
Every 
12 
Week
s±14 
Analysis Performed by Central Laboratory
Pembrolizumab
Pharmacokinetics
X
X
X
X
Pre-dose trough PK , and ADA samples will be 
collected at Cycles 4, 8, 12 and 16 and must be 
drawn within 24 hours before infusion of 
pembrolizumab. 
Post-dose peak PK samples will be collected at 
Cycle 8 and must be drawn within 30 minutes of 
the completion of the pembrolizumab infusion.
PK and ADA are not collected at Cycles 9 and 
11.
Anti-
pembrolizumab 
Antibodies
X
X
X
X
Blood for RNA 
Analyses
X
Whole blood samples must be collected pre-
dose. Blood for RNA analyses is collected at 
Cycle 6 only.
Blood for ctDNA
X
X
X
X
X
Whole blood samples must be collected pre-
dose.
Efficacy Measurements
Tumor Imaging
X
X
X
X
X
X
Imaging is performed every 9 weeks (± 7 days) 
until Week 54 and then every 12 weeks (± 14
days) until Week 150 and then every 24 weeks
(± 28 days).
Imaging must be performed based on calendar 
days from Cycle 1 Day 1 and not based on 
treatment cycles.  
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Cohorts A and B
Treatment Cycles (3-Week Cycles)
End 
of 
Tx
Post-Treatment
Notes
Treatment Cycle
4
5 & 
6
7
8 & 
9
10
11& 
12
13
14& 
15
16
17
DC
Safety
FU
FU3
Survival
FU4
Scheduling 
Window (Days):1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At 
Tx
DC2
30 D
Post 
Dose
± 3
Per 
imaging 
sched5
Every 
12 
Week
s±14 
Study Treatment Administration
Pembrolizumab
X
X
X
X
X
X
X
X
X
X
Study treatment with pembrolizumab must be 
administered after all procedures/assessments 
have been completed.
Delays in the protocol specified pembrolizumab 
treatment due to toxicity or for situations other 
than treatment-related AEs are described in 
Section 6.6.1 and 6.6.1.3, respectively. 
Treatment delays during Cycle 4 through Cycle 
17 ≥12 weeks will result in discontinuation from 
the Treatment Phase.  
Abbreviations: ctDNA = circulating tumor DNA; D = Days; DC = discontinuation; ECOG = Eastern Cooperative Oncology Group; FU = follow up; PD = progression of disease; 
Tx = treatment.
1. In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of the trial treatment for each cycle unless otherwise specified. The window for each 
visit is ± 3 days unless otherwise noted. If treatment cycles are adjusted all procedures except imaging will be completed according to the cycle number and not weeks on
treatment. Imaging will not be adjusted for delays in treatment cycles and will be performed per calendar schedule and the allowed visit window.
2. The Discontinuation Visit must occur at the time study drug is discontinued for any reason. If the participant has a Discontinuation Visit ≥27 days after the last dose of study 
treatment, the Safety Follow-up visit is not required.
3. Follow-up visits after treatment discontinuation must coincide with imaging schedule until disease progression or death.
4. Survival follow visits commence once a participant experiences disease progression or starts a new anti-cancer therapy. Visits are conducted by telephone to assess survival 
status until death, withdrawal of consent, or the end of the study, whichever occurs first.
5. Follow-up visits after treatment discontinuation must coincide with imaging schedule until disease progression, the start of a new anticancer treatment, or death, whichever 
occurs first.
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2. Introduction
Pembrolizumab (MK-3475) is a potent and highly selective humanized monoclonal antibody 
of the immunoglobulin (Ig) G4/kappa isotype designed to directly block the interaction 
between programmed cell death protein 1 (PD-1) and its ligands, programmed cell death 
ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2).
Study Rationale 
Lung cancer is the most common global cancer and is responsible for the majority of cancer 
deaths [Torre, L. A., et al 2015]. In 2012, the last year for which the World Health 
Organization statistics are available, an estimated 1.8 million new cases of lung cancer 
occurred (comprising 13% of total new global cancer cases) and resulted in ~1.5 million 
deaths. Due to widespread continued cigarette smoking, lung cancer will remain a significant 
worldwide public health problem for the foreseeable future.
Non-small cell lung cancer (NSCLC) represents 80% of lung cancers and one-third of these 
patients will present with Stage III disease at the time of initial diagnosis [Benitez-Majano, 
S., et al 2016]. The standard of care for patients with a good performance status Stage III 
NSCLC is platinum-based doublet chemotherapy concurrent with radiotherapy (cCTRT).
However, the median progression-free survival (PFS) among patients who have received 
cCTRT is poor (approximately 8 months), and only 17.7% of patients are alive at 5 years 
[National Cancer Institute 2016].
The PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and is, thus, an 
attractive target for therapeutic intervention in the treatment of NSCLC. Pembrolizumab has 
demonstrated durable clinical activity in participants with metastatic NSCLC and is currently 
approved as monotherapy in many countries for the first-line treatment of patients with 
metastatic NSCLC whose tumors have high PD-L1 expression (tumor proportion score [TPS] 
≥50%). Pembrolizumab in combination with pemetrexed and carboplatin was also approved 
in the United States (US) on 10-MAY-2017 for the first-line treatment of patients with 
metastatic non-squamous NSCLC, irrespective of PD-L1 expression.
While advances have been made in improving survival from Stage III NSCLC by optimizing 
local control, evidence suggests that cCTRT does not reduce the risk of distant relapse. There 
is still therefore a significant unmet medical need for additional treatment options for use in 
this patient population to improve treatment outcomes. The scientific rationale regarding the 
current study and the rationale behind the endpoints are outlined in Section 4.2 of the 
protocol.
Background
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475.
2.2.1
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
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prognosis in various malignancies [Dong, H., et al 2002] [Sharpe, A. H. and Freeman, G. J. 
2002] [Brown, J. A., et al 2003] [Francisco, L. M., et al 2010] [Thompson, R. H., et al 2007] 
[Hino, R., et al 2010] [Nomi, T., et al 2007] [Gao, Q., et al 2009] [Hamanishi, J., et al 2007] 
[Fourcade, J., et al 2009] [Cai, G., et al 2004] [Blank, C. and Mackensen, A. 2007], [Iwai, Y., 
et al 2002] [Tsushima, F., et al 2006] [Korman, A., et al 2007] [Oble, D. A., et al 2009] 
[Topalian, Suzanne L., et al 2012] [Patnaik, A., et al 2012] [Phase I Study of Single... ] 
[Chapman, P. B., et al 2011] [Robert, C., et al 2011] [Bellati, F., et al 2009] [Ruffell, B., et al 
2010] [Shirabe, K., et al 2010], [Al-Shibli, K., et al 2010] [Clark, C. E., et al 2009] 
[Diederichsen, A. C. P., et al 2003] [Gao, Q., et al 2007] [Hillen, F., et al 2008] [Laghi, L., et 
al 2009] [Li, J. F., et al 2008] [Nemolato, S., et al 2008] [Nobili, C., et al 2008] [Oshikiri, T., 
et al 2003] [Piersma, S. J., et al 2008] [Rao, U. N. M., et al 2010]. In particular, the presence 
of CD8+ T-cells and the ratio of CD8+ effector T-cells/FoxP3+ regulatory T-cells seems to 
correlate with improved prognosis and long-term survival in solid malignancies such as 
ovarian, colorectal, pancreatic, hepatocellular, malignant melanoma, and renal cell 
carcinoma. Tumor-infiltrating lymphocytes can be expanded ex vivo and re-infused, inducing 
durable objective tumor responses in cancers such as melanoma [Sasaki, A., et al 2008] 
[Shen, Z., et al 2010].
The PD-1 receptor-ligand interaction is a major pathway used by tumors to suppress immune 
control. The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. Programmed cell death protein-1 (encoded by the gene Pdcd1) is an 
Ig superfamily member related to cluster of differentiation (CD)28 and cytotoxic T-
lymphocyte-associated protein 4 (CTLA-4) that has been shown to negatively regulate 
antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) [Talmadge, 
J. E., et al 2007] [Usubütün, A., et al 1998]. 
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 domain 
responsible for ligand binding and a cytoplasmic tail responsible for the binding of signaling 
molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based 
switch motif. Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-
1 and SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as CD3 zeta, protein kinase C-
theta, and zeta-chain-associated protein kinase, which are involved in the CD3 T-cell 
signaling cascade [Okazaki, T., et al 2001] [Chemnitz, J. M., et al 2004] [Sheppard, K-A, et 
al 2004] [Riley, J. L. 2009]. The mechanism by which PD-1 down-modulates T-cell 
responses is similar to, but distinct from, that of CTLA-4, because both molecules regulate an 
overlapping set of signaling proteins [Parry, R. V., et al 2005] [Francisco, L. M., et al 2010]. 
As a consequence, the PD-1/PD-L1 pathway is an attractive target for therapeutic 
intervention in NSCLC. 
2.2.2
Completed Clinical Studies
Several clinical studies have been conducted to evaluate the efficacy of pembrolizumab 
monotherapy in the treatment of metastatic NSCLC:  KEYNOTE-001, KEYNOTE-010, and 
KEYNOTE-024.
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KEYNOTE-001:
An open-label Phase 1 trial (KEYNOTE-001) was conducted to evaluate the safety and 
clinical activity of single agent pembrolizumab. The dose escalation portion of this trial 
evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks 
(Q2W), in participants with advanced solid tumors. All 3 dose levels were well tolerated and 
no dose-limiting toxicities were observed. Based on pharmacokinetic (PK) data showing a 
half-life of 21 days, the protocol was amended to change the dosing frequency in the 
expansion cohort to every 3 weeks (Q3W). All cohorts have completed enrollment [Garon, E. 
B., et al 2015].
In KEYNOTE-001, a total of 495NSCLC participants were treated in several dose expansion 
cohorts with at least 1 dose of pembrolizumab. The initial data from 495 NSCLC participants 
were published and reported. The objective response rate (ORR) was 19.4% (18.0% in the 
394 previously treated participants and 24.8% in the 101 previously untreated participants). 
The response rate (RR) was similar regardless of dose, schedule, and histologic analysis. 
Current or former smokers had a RR of 22.5%, as compared with 10.3% among participants 
who had never smoked cigarettes.
Participants were required to submit a newly obtained tumor biopsy prior to initiating therapy 
with pembrolizumab to evaluate the tumors for expression of PD-L1. After evaluation of 
several methods for pathological assessment, in a training set, membranous PD-L1 
expression in at least 50% of tumor cells (TPS ≥ 50%) was selected as the cutoff point 
defining PD-L1 high. In a validation set of 313 participants, the RR was 45.2% in the 73 
participants with a TPS ≥ 50%, including 43.9% in previously treated participants and 50% 
in previously untreated participants, values that numerically exceeded the RR in the training 
group.
Pembrolizumab has been generally well tolerated. The most common treatment-related 
adverse events (AEs) were fatigue (19.4%), pruritus (10.7%), and decreased appetite 
(10.5%). AEs of Grade 3 or higher were reported in 47 of 495 patients (9.5%). The only 
treatment-related AEs of an inflammatory or immune-mediated nature that occurred in more 
than 2% of patients were infusion-related reactions (in 15 patients [3.0%]), hypothyroidism 
(in 34 patients [6.9%]), and pneumonitis (in 18 patients [3.6%]). One infusion reaction led to 
treatment discontinuation. All the patients with hypothyroidism were successfully treated 
with medical therapy.
KEYNOTE-010:
KEYNOTE-010 was a randomized, adaptively designed Phase 2/3 trial of pembrolizumab at 
2 dose levels versus docetaxel in participants with NSCLC with PD-L1 positive tumors (TPS 
≥1%) who had experienced disease progression after platinum containing systemic therapy. 
Participants were stratified according to their TPS (extent of PD-L1 expression) defined as 
follows: a TPS ≥ 50% was considered strongly positive and a TPS = 1% to 49% was 
considered weakly positive. Approximately 920 participants were planned to be enrolled in 
this trial to examine the efficacy of pembrolizumab compared to docetaxel in an enriched 
population [Herbst, R. S., et al 2016].
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In KEYNOTE-010, pembrolizumab was superior to docetaxel in the strongly positive TPS ≥ 
50% stratum with regard to overall survival (OS), with a hazard ratio (HR) of 0.54 (p = 
0.00024) and 0.50 (p = 0.00002) for pembrolizumab 2 mg/kg Q3W versus docetaxel and 10 
mg/kg Q3W versus docetaxel, respectively. Pembrolizumab was superior to docetaxel in the 
overall positive TPS ≥ 1% population with regard to OS, with an HR of 0.71 (p = 0.00076) 
and 0.61 (p<0.00001) for pembrolizumab 2 mg/kg Q3W and 10 mg/kg Q3W, respectively. 
Pembrolizumab was superior to docetaxel in the strongly positive TPS ≥ 50% stratum with 
regard to progression free survival (PFS) by independent review committee based on 
RECIST 1.1, with an HR of 0.58 (p = 0.00009) and 0.59 (p = 0.00007) for pembrolizumab 2 
mg/kg Q3W and 10 mg/kg Q3W, respectively, compared to docetaxel. Pembrolizumab 
provided numerically superior benefit in PFS by independent review committee based on 
RECIST 1.1 compared to docetaxel in the overall positive TPS ≥ 1% population, with an HR 
of 0.88 and 0.79 for pembrolizumab 2 mg/kg Q3W and 10 mg/kg Q3W, respectively; 
however, the differences were not statistically significant at the 0.001 level required per 
protocol.
Overall, the results from KEYNOTE-001 and KEYNOTE-010 demonstrated that 
pembrolizumab provided substantial, clinically meaningful benefits in OS, PFS, and ORR in 
participants with NSCLC who progressed after platinum-containing chemotherapy and 
whose tumor cells expressed PD-L1. The PD-L1 selection employed in KEYNOTE-010 
identified patients more likely to benefit from pembrolizumab and resulted in favorable HRs 
in OS compared to docetaxel.
In previously treated participants with NSCLC with PD-L1 TPS ≥1%, and disease 
progression following platinum-containing chemotherapy, pembrolizumab provides a 
statistically significant and clinically meaningful OS benefit compared to standard docetaxel 
chemotherapy.
KEYNOTE-024:
KEYNOTE-024 was a multicenter, international, randomized, open-label, controlled trial of 
pembrolizumab monotherapy versus the choice of multiple standard of care (SOC) platinum-
based chemotherapies in participants previously untreated for their Stage IV NSCLC and 
whose tumors expressed PD-L1 at ≥ 50% [Reck, M., et al 2016].
First-line treatment with pembrolizumab significantly prolonged PFS (HR 0.50; 95% CI [CI]: 
0.37, 0.68; p<0.001) and OS (HR 0.60; 95% CI:  0.41, 0.89; p = 0.005) compared with SOC 
chemotherapy, inclusive of pemetrexed maintenance for participants with non-squamous 
tumors.
In addition, pembrolizumab was associated with a higher ORR, including a higher complete 
response (CR), as well as a longer duration of response as compared to SOC.
Pembrolizumab was better tolerated than chemotherapy and AEs were easily managed. The 
observed safety profile of the pembrolizumab arm was consistent with the safety profile for 
pembrolizumab established to date. Based on the mechanism of action of pembrolizumab, 
immune-mediated AEs, including pneumonitis occurred at a greater frequency with 
pembrolizumab compared to chemotherapy. Most immune-mediated events were of Grade 1 
or 2 severity, and none led to death.
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These data underscore the substantial benefit of pembrolizumab as initial therapy for 
participants with previously untreated, advanced NSCLC whose tumors express high levels 
of PD-L1 (TPS ≥50%).
2.2.3
Ongoing Clinical Studies
Ongoing clinical studies to evaluate the efficacy of pembrolizumab in the treatment of 
metastatic NSCLC include: KEYNOTE-021, KEYNOTE-042, KEYNOTE-091, KEYNOTE-
189, KEYNOTE 407 and KEYNOTE-671.
KEYNOTE-021:
This Phase 1/2 trial assessed the safety and efficacy of pembrolizumab in combination with 
multiple therapeutic agents including chemotherapy (carboplatin and pemetrexed; and 
carboplatin, paclitaxel, and bevacizumab); epidermal growth factor receptor (EGFR)
inhibitors including erlotinib and gefitinib; and the CTLA-4 inhibitor, ipilimumab. Cohort G 
of the study evaluated the efficacy and safety of pembrolizumab plus carboplatin and 
pemetrexed (CP) versus CP alone as first-line therapy for advanced non-squamous NSCLC
in 123 participants of whom 60 were accrued to the pembrolizumab plus CP arm and 63 to 
the CP arm. As of 08-AUG-2016, median follow-up was 10.6 months (range, 0.8-19.3); 
median exposure was 8.0 months for pembrolizumab plus CP and 4.9 months for CP. 
Pembrolizumab plus CP significantly improved ORR (55% versus 29%; p = 0.0016) and PFS 
(HR 0.53, 95% CI 0.31 to 0.91, p = 0.010; median 13.0 versus 8.9 months). Overall survival 
was similar; 6-month survival rates were 92% in each arm [Langer, C. J., et al 2016]. 
KEYNOTE-042:
This is a multicenter, international, randomized, open-label, controlled trial of 
pembrolizumab versus SOC platinum-based chemotherapy in participants previously 
untreated for their advanced or metastatic NSCLC and whose tumors express PD-L1 ≥ 1%. 
Approximately 1240 participants will be enrolled.
KEYNOTE-091:
This is a worldwide, randomized, placebo-controlled, Phase 3 trial in participants with early 
stage NSCLC to prospectively investigate whether adjuvant treatment with pembrolizumab 
after completion of radical surgery (lobectomy / pneumonectomy) with or without standard 
adjuvant chemotherapy for Stage IB (T ≥ 4 cm) -II-IIIA NSCLC patients improves Disease 
Free Survival (DFS), as assessed locally by the investigator, compared to placebo. 
Approximately 1380 participants will be enrolled.
KEYNOTE-189:
This is a worldwide, randomized, active-controlled, parallel group, multi-site, double-blind 
trial of pembrolizumab combined with platinum-pemetrexed chemotherapy versus saline 
placebo combined with platinum-pemetrexed chemotherapy in participants with advanced or 
metastatic non-squamous NSCLC who had not previously received systemic therapy for 
advanced disease and in whom EGFR or anaplastic lymphoma kinase (ALK)-directed 
therapy was not indicated. After a median follow-up of 10.5 months, the estimated rate of OS
at 12 months was 69.2% (95% CI, 64.1 to 73.8) in the pembrolizumab combination group 
versus 49.4% (95% CI, 42.1 to 56.2) in the placebo combination group (HR for death, 0.49; 
95% CI, 0.38 to 0.64; P<0.001). Improvement in OS was seen across all PD-L1 categories 
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that were evaluated. Median PFS was 8.8 months (95% CI, 7.6 to 9.2) in the pembrolizumab-
combination group and 4.9 months (95% CI, 4.7 to 5.5) in the placebo-combination group 
(HR for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Adverse events 
of Grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination 
group and in 65.8% of those in the placebo-combination group [Gandhi, L., et al 2018].
KEYNOTE-407:
This is a Phase 3 study of carboplatin and paclitaxel or nano particle albumin-bound 
paclitaxel (nab-paclitaxel) with or without pembrolizumab in first line metastatic squamous 
NSCLC. The total planned enrollment is 560 participants.
KEYNOTE-671:
This is a Phase 3, randomized, trial of platinum doublet chemotherapy with or without 
pembrolizumab as neoadjuvant/adjuvant therapy for participants with resectable Stage IIB or 
IIIA NSCLC. The total planned enrollment is 786 participants.
2.2.4
Information on Other Study-related Therapy
For patients with unresectable Stage IIIA, Stage IIIB disease, combined modality therapy
(chemoradiation) is superior to radiation alone and cCTRT is superior to sequential therapy
[Blackstock, A. W. 2007]. cCTRT regimens that may be used for any histology (squamous or 
non-squamous) for initial treatment include cisplatin/etoposide, cisplatin/vinblastine or
carboplatin/paclitaxel. For non-squamous NSCLC, other cCTRT regimens include
cisplatin/pemetrexed [National Comprehensive Cancer Network 2018]. The guidelines for 
the treatment of patients with unresectable Stage IIIA, Stage IIIB NSCLC in Europe
[Vansteenkiste, J., et al 2013] [Eberhardt, W. E., et al 2015] and Japan [Saijo, N., et al 2010]
are in line with those used in the US.
In this study, Cohort A will use carboplatin/paclitaxel backbone with standard TRT and will 
enroll Stage III NSCLC participants with any histology and Cohort B will use 
cisplatin/pemetrexed backbone with standard TRT and enroll only Stage III NSCLC 
participants with non-squamous histology.
For information on carboplatin/paclitaxel and cisplatin/pemetrexed, please refer to their 
respective product inserts.
The standard TRT for patients with Stage III NSCLC is the most commonly accepted 
radiation therapy dose (60–63 gray (Gy) in 1·8–2·0 Gy fraction sizes) and was established by 
the Radiation Therapy Oncology Group (RTOG) 7301 trial. With the idea that increasing
radiation dose would improve both local-regional control and OS, RTOG 0617 trial
randomly assigned (1:1:1:1) patients to receive either 60 Gy (standard dose), 74 Gy (high 
dose), 60 Gy plus cetuximab, or 74 Gy plus cetuximab. Higher dose of radiation (74 Gy 
radiation given in 2 Gy fractions) with concurrent chemotherapy was not better than standard 
TRT (60 Gy in 2 Gy fractions) plus concurrent chemotherapy for patients with Stage III 
NSCLC, and might be potentially harmful. Addition of cetuximab to concurrent 
chemoradiation and consolidation treatment provided no benefit in overall survival for these 
patients [Bradley, J. D., et al 2015].
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The current study will use standard TRT (60 Gy in 2 Gy fractions). The details regarding the 
standard TRT are provided in Section 8.1.9.2 of the protocol.
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 or a treatment regimen.
As described in Section 4.2, there is a very strong scientific rationale to study pembrolizumab 
in combination with chemotherapy and radiotherapy in the treatment of unresectable Stage 
III NSCLC. Considering the high unmet medical need for new and effective systemic 
treatment options in patients with Stage III NSCLC, the current study will evaluate anti-
tumor activity and the safety profiles of a combination of PD-1 blockade with chemotherapy
and radiation as a combined modality treatment. Pembrolizumab has been combined with 
standard chemotherapy in the treatment of patients with Stage IV NSCLC. The combination 
was generally well tolerated despite a slight increase in AE rates. The AEs, including 
immune-related AEs (irAEs), were managed effectively with either dose interruptions or use
of corticosteroids. Pembrolizumab has also been studied in combination with different 
radiotherapy methods. Pembrolizumab in combination with chemotherapy and radiotherapy 
is being explored in the current study. While there is risk associated with this type of 
approach, the protocol includes all appropriate guidelines to manage anticipated side effects. 
Overall, the current protocol is evaluating a very promising therapeutic strategy for treatment 
of patients with Stage III NSCLC and the benefit/risk assessment for patients enrolled in this 
trial is considered to be favorable.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
3. Objectives/Hypotheses and Endpoints
In adult participants with unresectable, locally advanced, Stage III NSCLC treated with 
pembrolizumab in combination with platinum doublet chemotherapy and standard TRT
followed by pembrolizumab monotherapy
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Objective/Hypothesis
Endpoint
Primary

Objective: Within each platinum 
doublet chemotherapy cohort,
evaluate the percentage of participants 
who develop Grade 3 or higher
pneumonitis

Hypothesis: Within each platinum 
doublet chemotherapy cohort, the 
percentage of participants who 
develop Grade 3 or higher 
pneumonitis is <10%

Objective: Within each platinum 
doublet chemotherapy cohort,
estimate the ORR as assessed by 
BICR according to RECIST 1.1

Grade 3 or higher pneumonitis

Confirmed CR or PR
Secondary

Objective: Within each platinum 
doublet chemotherapy cohort, 
evaluate the PFS assessed by BICR 
according to RECIST v.1.1, modified 
to follow a maximum of 10 target 
lesions and a maximum of 5 target 
lesions per organ.

Objective: Within each platinum 
doublet chemotherapy cohort, 
evaluate OS

Objective: Within each platinum 
doublet chemotherapy cohort, 
evaluate the safety and tolerability of 
each treatment regimen by the 
percentage of participants who 
develop AEs

PFS defined as the time from enrollment 
to the first documented local recurrence or 
distant metastasis or death due to any 
cause, whichever occurs first

OS defined as the time from enrollment to 
death due to any cause

AEs

Discontinuations due to AEs
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Tertiary/Exploratory

Objective: Within each platinum 
doublet chemotherapy cohort, 
evaluate time to distant metastases per 
RECIST 1.1 based on BICR

Objective: To identify molecular 
(genomic, metabolic and/or 
proteomic) biomarkers that may be 
indicative of clinical 
response/resistance, safety, 
pharmacodynamic activity, and/or the 
mechanism of action of 
pembrolizumab in combination with 
platinum doublet chemotherapy and 
radiotherapy
Time to distant metastases is defined as 
the time from enrollment to the first
documented distant metastases, or death 
due to any cause, whichever occurs first

Germline genetic variation, genetic 
(DNA) mutations from tumor, tumor and 
blood RNA variation, proteomics and 
immunohistochemistry (IHC), and other 
biomarkers
4. Study Design 
Overall Design 
This is a nonrandomized, multi-site, open-label Phase 2 study of pembrolizumab in 
combination with chemotherapy and standard TRT in participants with Stage III NSCLC 
(KEYNOTE-799). There are 2 treatment cohorts. Participants with non-squamous NSCLC 
are eligible for both cohorts. The choice of chemotherapy will be determined by the 
investigator prior to treatment allocation. Participants with squamous NSCLC are eligible 
only for Cohort A. Approximately 216 participants will be enrolled: 108 participants per 
cohort.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the Schedule of Activities (SoA), Section 1.3. 
Details of each procedure are provided in Section 8.
This study will use a sequential monitoring procedure based on pre-specified criteria to 
monitor safety and efficacy. There will likely be multiple interim analyses for each cohort of 
the study. The first interim analysis will be conducted when at least 36 participants in one 
cohort have completed a minimum of 15 weeks of follow-up. An external Data Monitoring 
Committee (DMC) will serve as an additional reviewer of the treatment-level results and will 
make recommendations for discontinuation of the study or modification to the Executive 
Oversight Committee (EOC) of the Sponsor. The DMC responsibilities and review schedules 
will be outlined in the DMC charter.
Each cohort, as well as the overall study, may be discontinued at interim analysis for safety 
reasons if the incidence of Grade 3 or higher pneumonitis is unacceptably high or the 
observed ORR is very low. The study may also be discontinued early if the percentage of 
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Grade 3 or higher pneumonitis is very low and the observed ORR is high. The final sample 
size of the study will be changed accordingly. Details are described in Section 9.
It is assumed that the 2 cohorts will enroll participants at a reasonably similar pace. If 
enrollment between the cohorts is vastly different, enrollment will not be paused and each 
cohort may be evaluated independently. The similarity of the 2 treatment cohorts will be 
continuously evaluated after at least 36 participants have completed a minimum of 15 weeks 
of follow-up in each cohort. If at an interim analysis the pneumonitis rates in the 2 cohorts 
are considered similar, then the 2 cohorts will be combined for study analysis and the trial 
stops when the stopping rule is met or once 108 participants have been enrolled. If 
combination rule is not met, the analysis will be based on each cohort. Details are described 
in Section 9.7.
Scientific Rationale for Study Design 
For patients with unresectable Stage IIIA or Stage IIIB disease, combined modality therapy 
(chemoradiation) is superior to radiation alone and cCTRT is superior to sequential therapy 
[Blackstock, A. W. 2007]. Though most clinicians use a combination of a platinum-
containing regimen and radiotherapy, no reference regimen for inoperable Stage III NSCLC 
has been established by randomized trials. The median progression-free survival among 
patients who have received cCTRT is poor, and only 17.7% of patients are alive at 5 years
[National Cancer Institute 2016]. While advances have been made in improving survival 
from Stage III NSCLC by optimizing local control, evidence suggests that cCTRT does not 
reduce the risk of distant relapse. 
The immune checkpoint inhibitors, including pembrolizumab, have shown significant and 
durable clinical activity in patients with advanced NSCLC. Tumors that are poorly
immunogenic or that have become immunosuppressive can likely be made immunogenic 
through administration of pro-immunogenic therapies designed to increase antigen release 
from the cancer cell. Potential priming agents for immunotherapy agents include
chemotherapy and radiotherapy. Some cytotoxic therapies, such as anthracyclines or ionizing 
radiation, promote ‘immunogenic cell death’, which includes the release of ‘danger’
molecules from tumor cells such as calreticulin, high mobility group protein B1 and
adenosine triphosphate. These danger molecules polarize dendritic cells towards a pro-
inflammatory phenotype and increase priming towards T helper 1 anti-tumor T-cells and 
away from regulatory T-cells [Vanneman, M. 2012]. 
The results from recent clinical trials in Stage III unresectable NSCLC are outlined in 
Table 1. These trials showed no evidence of survival improvement from further consolidation 
chemotherapy after cCTRT and no evidence of improved survival from increased doses of 
TRT. Newer approaches including incorporating immune checkpoint inhibitors to standard 
cCTRT is needed to improve outcomes for patients with Stage III NSCLC. 
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Table 1
Summary of Recent Trials in NSCLC
Trial Name
Treatment
Cohorts
N
ORR
(%)
PFS
(months)
OS
(months)
Pneumonitis
Any Gr/Gr 3-5 
(%)
PROCLAIM
(non-squam 
NSCLC 
only)
[Senan, S., et 
al 2016]
Cisplatin/pemetrexed 
+TRT followed by 
cisplatin/pemetrexed
301
35.9
11.4
26.8
17/1.8
Cisplatin/etoposide 
+TRT followed by 
cisplatin/etoposide
297
33
9.8
25.0
10.7/2.6
HR 0.86
(0.71 to 
1.04)
HR 0.98
(0.79-1.20)
RTOG0617
(2x2 
factorial)
[Bradley, J. 
D., et al 
2015]
CTRT+ cetuximab
237
10.8
25
9/4
CTRT
228
10.7
24
11/1
HR 0·99
(0.80–1.22)
HR 1·07
(0.84–1.35)
TRT (60Gy
217
11.8
28.7
TRT (74Gy
207
9.8
20.3
HR 1.19
(0.95–1.47)
HR 1.38
(1.09–1.76)
KCSG-LU05
[Ahn, J. S., et 
al 2015]
Cisplatin/docetaxel+RT
211
38.3
8.1
20.6
5.8/1.2
Cisplatin/docetaxel+RT 
followed by cisplatin/docetaxel 
x 3
209
43.1
9.1
21.8
13.3/1.2
HR 0.91
(0.73-1.12)
HR 0.91
(0.72-1.25)
Abbreviations : CTRT = chemotherapy with radiotherapy, Gr = grade; HR = hazard ratio; ORR = objective response rate, 
OS = overall survival; PFS = progression-free survival; RT: radiotherapy; TRT = thoracic radiotherapy.
Recently, a Phase 3 study compared the anti–PD-L1 antibody, durvalumab, as consolidation 
therapy in patients with Stage III NSCLC who did not have disease progression after 2 or 
more cycles of platinum-based cCTRT. In the planned interim analysis of this trial, PFS was
longer among patients who received durvalumab than among those who received placebo 
(HR for disease progression or death, 0.52; p<0.001). OS was immature at the time of the 
analysis. The safety profile of durvalumab was consistent with that of other 
immunotherapies. Although the incidences of some AEs of any cause, including pneumonitis 
or radiation pneumonitis, were increased with both durvalumab and placebo in this study
compared to historical rates from prior studies, the majority of these are Grade 1 or 2 and 
most of these events were as expected after definitive cCTRT. 
The safety and feasibility of consolidation pembrolizumab following cCTRT for unresectable 
Stage III NSCLC was also evaluated in a single arm Phase 2 study by Hoosier Cancer 
Research Network, LUN14-179 study [Durm, G. A., et al 2017]. Ninety-three patients were 
enrolled and received pembrolizumab 200 mg Q3W for 12 months. The preliminary results 
showed that pembrolizumab following cCTRT was generally well tolerated and the incidence 
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of Grade 3 or higher pneumonitis within the first 3 months was low (6 out of 93 patients or 
6.5%). The study is ongoing and the efficacy results have not been presented.
Despite these advances, consolidation therapy with an immune checkpoint inhibitor is only 
available to patients who have completed cCTRT. A significant number of patients with 
unresectable Stage III NSCLC will not complete cCTRT or will progress during or after 
cCTRT, and hence be ineligible for consolidation therapy. Furthermore, the addition of 
immune checkpoint inhibitors to cCTRT in pre-clinical studies was more effective when 
given concurrently compared to sequentially. 
The purpose of the current Phase 2 study is to evaluate safety and efficacy of pembrolizumab 
in combination with cCTRT in patients with unresectable Stage III NSCLC. Addition of 
pembrolizumab to standard chemotherapy has been shown to improve response rates and 
PFS in KEYNOTE-021G trial [Langer, C. J., et al 2016]. An additional cycle of 
pembrolizumab and a platinum-doublet prior to cCTRT will ensure that an effective systemic 
therapy is given while patients are evaluated and planned for TRT. A similar concept is being 
evaluated with nivolumab in an ongoing NICOLAS trial (NCT02434081). Once the safety 
and efficacy is established in the current phase 2 study, this regimen will be compared to 
cCTRT followed by a checkpoint inhibitor in a future Phase 3 trial.
The current study is designed as a single arm study with 2 parallel cohorts. Each cohort will 
evaluate one of the most commonly used chemotherapy (carboplatin and paclitaxel for 
Cohort A and cisplatin and pemetrexed for Cohort B) in combination with standard TRT and 
pembrolizumab. Since pemetrexed-based chemotherapy is usually not recommended for 
subjects with squamous NSCLC, participants with squamous NSCLC are eligible only for 
Cohort A. Participants with non-squamous NSCLC are eligible for both cohorts. The choice 
of chemotherapy will be determined by the investigator prior to treatment allocation. Similar 
to other studies in adjuvant setting, the overall duration of treatment will be 1 year or total of 
17 cycles of pembrolizumab. 
The percentage of participants with Grade 3 or higher pneumonitis will be closely monitored 
by the study team. Please see Section 9 for details regarding the sequential monitoring 
procedure and the rules for early stopping either due to safety or lack of efficacy. The 
rationale for assumptions for percentage of participants with Grade 3 or higher pneumonitis 
is outlined in Section 4.2.1.2.
4.2.1
Rationale for Endpoints
This trial will use ORR by BICR and percent of Grade 3 or higher pneumonitis as the 
primary endpoints. The trial will be considered positive if the percentage of participants with 
Grade 3 or higher pneumonitis is< 10%. 
Efficacy Endpoints
ORR by RECIST 1.1 criteria as assessed by BICR will be one of the primary endpoints for 
this Phase 2 trial. The preliminary efficacy data from this trial will form the basis to further 
evaluate this regimen in a future Phase 3 trial.
In metastatic setting, several studies have shown a correlation between response rate and 
overall survival.
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Safety Endpoints
The percent of Grade 3 or higher pneumonitis will serve as another primary endpoint. One of 
the most common side effects from cCTRT is pneumonitis or radiation pneumonitis. In the 
majority of these cases, it is Grade 1 or 2 and is usually a radiological finding without much 
clinical sequelae. However, some patients can develop clinically significant Grade 3 or 
higher pneumonitis. 
As outlined in Table 1, in prior studies with cCTRT, the percentage of participants who 
develop Grade 3 or higher pneumonitis rate is 1% to 3%. In the PACIFIC trial evaluating 
durvalumab maintenance after cCTRT, the incidence of Grade 3 or higher pneumonitis was 
3.4% in the durvalumab arm and 2.6% in the placebo arm [Antonia, S. J., et al 2017]. We 
proposed that the percentage of participants with Grade 3 or higher in the current study of 
≤3% will be desirable for the proposed treatment regimen and the percentage of participants 
with Grade 3 or higher pneumonitis ≥10% will be considered unacceptable for this treatment 
regimen to move forward in a Phase 3 trial.
Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents. 
However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating patients. Thus, to aid future patients, it is important to investigate the determinants 
of response or resistance to cancer immunotherapy and other treatments administered, as well 
as determinants of AEs in the course of our clinical studies. These efforts may identify novel 
predictive/PD biomarkers and generate information that may better guide single-agent and 
combination therapy with immuno-oncology drugs. To identify novel biomarkers, 
biospecimens (ie, blood components, tumor material) will be collected to support analyses of 
cellular components (eg, protein, DNA, RNA, metabolites) and other circulating molecules. 
Investigations may include but are not limited to:
Germline (blood) genetic analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing)
This research may evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
predict efficacy or adverse events, the data might inform optimal use of therapies in the 
patient population. Furthermore, it is important to evaluate germline DNA variation across 
the genome in order to interpret tumor-specific DNA mutations. Finally, microsatellite 
instability (MSI) may be evaluated as this is an important biomarker for some cancers (ie, 
colorectal cancer).
Genetic (DNA) analyses from tumor
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (ie, mutations, methylation 
status, microsatellite instability). Key molecular changes of interest to immuno-oncology 
drug development include the mutational burden of tumors and the clonality of T-cells in the 
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tumor microenvironment. Increased mutational burden (sometimes referred to as a ‘hyper-
mutated’ state) may generate neo-antigen presentation in the tumor microenvironment. To 
conduct this type of research, it is important to identify tumor-specific mutations that occur 
across all genes in the tumor genome. Thus, genome-wide approaches may be used for this 
effort. Note that in order to understand tumor-specific mutations, it is necessary to compare 
the tumor genome with the germline genome. Microsatellite instability may also be evaluated 
as this is an important biomarker for some cancers (ie, colorectal cancer). Circulating tumor 
DNA and/or RNA may also be evaluated from blood samples.
Tumor and blood RNA analyses
Both genome-wide and targeted messenger RNA (mRNA) expression profiling and 
sequencing in tumor tissue and in blood may be performed to define gene signatures that 
correlate to clinical response to treatment with immunotherapies and/or other treatments 
administered. Immunotherapies induce a response in tumors that likely reflects an 
inflamed/immune phenotype. Specific immune-related gene sets (ie, those capturing 
interferon-gamma transcriptional pathways) may be evaluated and new signatures may be 
identified. Individual genes related to the immune system may also be evaluated (eg, IL-10). 
MicroRNA profiling may also be pursued as well as exosomal profiling.
Proteomics and immunohistochemistry (IHC) using blood or tumor
Tumor and blood samples from this study may undergo proteomic analyses (eg, PD-L1 IHC). 
PD L1 protein level in tumor sections, assessed by IHC, has been shown to correlate with 
response to immunotherapy in patients with NSCLC, and an in vitro diagnostic (IVD) device 
has been developed for use with immunotherapy in NSCLC. Preliminary data indicates that 
this association may also be true in additional cancer types (ie, triple negative breast cancer, 
head and neck, and gastric). Additional tumor or blood-derived proteins may also correlate 
with response to immunotherapy. Therefore, tumor tissue may be subjected to proteomic 
analyses using a variety of platforms that could include but are not limited to immunoassays 
and liquid chromatography/mass spectrometry. This approach could identify novel protein 
biomarkers that could aid in patient selection for immunotherapy and/or treatments.
Other biomarkers
In addition to expression on the tumor tissue, PD-L1 and other tumor derived proteins can be 
shed from tumor and released into the blood. Assays such as enzyme-linked immunoassay 
(ELISA) that measure proteins may also be evaluated from blood samples. Correlation of 
these biomarkers with response to immunotherapy and/or treatments may identify new 
approaches for predictive biomarkers in blood, representing a major advance from today’s 
reliance on assessing tumor biomarkers. This research would serve to develop such assays for 
future clinical use. 
Other molecular changes of interest include the subtype of T-cells in the tumor 
microenvironment. The T-cell repertoire from tumor tissue and blood components may be 
evaluated.
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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 this future biomedical research substudy are presented in Appendix 2.
Justification for Dose 
4.3.1
Rationale for Dose Interval and Study Design
The planned dose of pembrolizumab for this trial is 200 mg Q3W. Based on the totality of 
data generated in the pembrolizumab development program, 200 mg Q3W is the appropriate 
dose of pembrolizumab across all indications and regardless of tumor type. As outlined 
below, this dose is justified by: 

Clinical data from randomized studies demonstrating flat dose- and exposure- efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg Q2W.

Clinical data showing meaningful improvement in benefit-risk including OS at 200 mg 
Q3W across multiple indications.

Pharmacology data showing full target saturation in both systemic circulation (inferred 
from PK data) and tumor (inferred from physiologically based pharmacokinetic [PBPK] 
analysis) at 200 mg Q3W.
Among the randomized dose-comparison studies, a total of 2262 subjects were enrolled with 
melanoma and NSCLC, covering different disease settings (treatment naïve, previously 
treated, PD-L1 enriched and all-comers) and different treatment settings (monotherapy and in 
combination with chemotherapy). Three studies compared 2 mg/kg Q3W versus 10 mg/kg 
Q3W (KEYNOTE-001 B2, KEYNOTE-001 D, KEYNOTE-002, and KEYNOTE-021), and 
three studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KEYNOTE -01 B3, 
KEYNOTE-001 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 
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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 conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W. Secondly, 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 subject 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.
As discussed in Section 2.2.4, based on the results of RTOG 0617 trial, the current study will 
use the standard TRT (60 Gy in 2 Gy fractions) and the doses of chemotherapy as outlined in 
the protocol are aligned with standard clinical practice and the current guidelines.
Beginning and End of Study Definition
The overall study begins when the first participant signs the Informed Consent Form (ICF). 
The overall study ends when the last participant completes the last study-related telephone-
call or visit, withdraws from the study or is lost to follow-up (ie, the participant is unable to 
be contacted by the investigator).      
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 
as a whole 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, Good Clinical 
Practice (GCP) and/or other applicable regulatory requirements, procedure-related problems 
or the number of discontinuations for administrative reasons is too high.
5. Study Population
Male/Female participants with unresectable, locally advanced Stage III NSCLC, who have 
received no prior anticancer therapy for their disease, and are at least 18 years of age will be 
enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
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Type of Participant and Disease Characteristics
1. Male/female participants, who are at least 18 years of age on the day of signing informed 
consent with previously untreated, unresectable, pathologically confirmed NSCLC and 
Stage IIIA, IIIB or IIIC NSCLC by American Joint Committee on Cancer Version 8. 
Note: Sites are encouraged to obtain tissue confirmation of mediastinal nodal 
involvement if this is safely accessible by endobronchial ultrasound (EBUS)/endoscopic 
ultrasound (EUS) or mediastinoscopy. However, mediastinal nodal involvement can be 
declared when the nodes have distinct margins and the size of the shortest axis of at least 
1 node must be ≥2.0 cm (positron emission tomography [PET]/magnetic resonance 
imaging [MRI]/computed tomography [CT] scan). Cases in which the distinct nodes all 
have short axis of <2.0 cm must have pathologic confirmation of disease presence for 
participants to be declared eligible.
Participants are eligible without obtaining the EBUS sample for pathological 
confirmation of mediastinal nodes < 2.0 cm if a Sponsor Communication Form is 
submitted and approved by the Sponsor Clinical Director and the following criteria are 
met: 
1) the primary tumor is considered unresectable and is clinically confirmed IIIA, IIIB, or 
IIIC NSCLC independent of the hilar lymph nodes and 
2) the presence or absence of metastases in the mediastinal lymph nodes would not 
change the radiotherapy plan. 
Participants with supraclavicular nodal involvement may be entered into the study. 
However, participants with cervical nodes are not permitted. The upper border of 
supraclavicular nodes must not extend above the upper border of the lateral end of the 
clavicle, extended medially.
2. No evidence of metastatic disease by whole body PET/ CT scan, diagnostic quality CT 
scan, and brain imaging. The process for image collection and transmission to the central 
imaging vendor can be found in the Site Imaging Manual.
NOTE:  The presence of pleural/pericardial fluid is presumed indicative of metastatic 
disease. Participants with effusions that are not visible on routine chest x-ray or are too 
small to be tapped safely may be entered on this study, provided the remaining 
inclusion/exclusion criteria are met.
3. Have measurable disease per RECIST 1.1 as assessed by the local site investigator/
radiology.
4. Have provided tumor tissue sample (core, incisional, or excisional biopsy). Formalin-
fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. In cases where the 
core, incisional, or excisional biopsy is not available or cannot be obtained due to 
anatomical location of tumor or medical condition of the participant, a cell block obtained 
through EUS/EBUS may be submitted after consultation with the Sponsor Clinical 
Director and documenting approval via a Sponsor Communication Form.
Note: If submitting unstained cut slides, newly cut slides must be submitted to the testing 
laboratory within 14 days from the date slides are cut (details pertaining to tumor tissue 
submission can be found in the Procedures Manual).
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5. Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
6. Have adequate pulmonary function test (PFT) as a forced expiratory volume in 1 second 
(FEV1) >50% of predicted normal volume and the carbon monoxide lung diffusing 
capacity (DLCO) >40% of predicted normal value. Participants for whom DLCO 
measurements are not available will be deemed to have adequate oxygen transfer if their 
resting capillary/arterial blood gas on room air reveals an oxygen pressure (PO2) >60 
mmHg.
7. Have adequate organ function as defined in Table 2. 
Table 2
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
ANC
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/La
Renal
Serum Creatinine OR
Measured or calculatedb CrCl
≤1.5 × ULN OR
≥60 mL/min for participant with creatinine levels 
>1.5 × institutional ULN
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin within normal 
limits for participants with total bilirubin levels 
>1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN
Endocrine
TSH
Within normal limits. Note:  If TSH is not within 
normal limits at baseline, the participant may still 
be eligible if T3 and free T4 are within the normal 
limits
Coagulation
INR OR PT
aPTT
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy  as long as PT or aPTT is 
within therapeutic range of intended use of 
anticoagulants
Abbreviations: ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); 
ANC = absolute neutrophil count; aPTT = activated partial thromboplastin time; AST (SGOT) = aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); CrCl = creatinine clearance; 
GFR = glomerular filtration rate; INR = international normalized ratio; PT = prothrombin time; 
TSH = thyroid stimulating hormones; ULN = upper limit of normal.
a. Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks. 
b. Creatinine clearance (CrCl) should be calculated per institutional standard.
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.
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Male participants:
8. A male participant must agree to use contraception, as detailed in Appendix 3 for at least 
180 days after the last dose of study treatment in Cycles 1 through 3 or for 120 days after 
the last dose of study treatment in Cycle 4 through the end of treatment and refrain from 
donating sperm during this period.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the participant.
Female participants:
9. A female participant is eligible to participate if she is not pregnant (see Appendix 3), not 
breastfeeding, and if participant is a woman of childbearing potential (WOCBP), agrees 
to follow the contraceptive guidance in Appendix 3 during the treatment period and for at 
least 180 days after the last dose of study treatment in Cycles 1 through 3 or for 120 days 
after the last dose of study treatment in Cycle 4 through the end of treatment.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the participant.
Informed Consent
10. The participant (or legally acceptable representative if applicable) provides written 
informed consent for the trial. The participant may also provide consent for Future 
Biomedical Research. However, participant may participate in the main trial without 
participating in Future Biomedical Research.
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to treatment 
allocation (see Appendix 3). If the urine test is positive or cannot be confirmed as 
negative, a serum pregnancy test will be required.
Note: In the event that 72 hours have elapsed between the screening pregnancy test and 
the first dose of study treatment, another pregnancy test (urine or serum) must be 
performed and must be negative in order for participant to start receiving study 
medication.
Note: Pregnancy tests within 24 hours prior to treatment allocation to determine 
eligibility will be required only in those regions where this is required via documented 
regulatory request, subsequently approved by the Sponsor.
2. Has small cell lung cancer. Mixed tumors will be categorized by the predominant cell 
type: if small cell elements are present, the participant is ineligible; if non-small cell 
histology with any squamous element is present (example squamous, adenosquamous), 
the participant is not eligible for Cohort B (pemetrexed based chemotherapy).
3. Has had documented weight loss >10% in the preceding 3 months.
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Prior/Concomitant Therapy
4. Participants whose radiation treatment plans are likely to encompass a volume of whole 
lung receiving >20 Gy in total (V20) of more than 31% of lung volume. 
Note: The participant must have been assessed by a radiation oncologist who anticipates 
the tumor is treatable, as defined in Section 8.1.9.2.4.
5. Has received prior radiotherapy to the thorax, including radiotherapy to the esophagus or
for breast cancer.
6. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an 
agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, 
OX-40, CD137).
7. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples 
of live vaccines include, but are not limited to, the following: measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), 
and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are 
live attenuated vaccines and are not allowed.
8. Has had an allogenic tissue/solid organ transplant.
Prior/Concurrent Clinical Study Experience
9. Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks prior to the first dose of study 
treatment.
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
Diagnostic Assessments
10. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg prednisone daily or equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of study drug.
11. Has a known additional malignancy that is progressing or has required active treatment 
within the past 5 years. 
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, superficial bladder cancer, or carcinoma in situ (e.g., breast carcinoma, cervical 
cancer in situ) that have undergone potentially curative therapy are not excluded.
12. Has severe hypersensitivity (Grade 3 or higher) to pembrolizumab and/or any of its 
excipients (refer to the IB for a list of excipients).
13. Has a known severe hypersensitivity (Grade 3 or higher) to any of the study 
chemotherapy agents and/or to any of their excipients (refer to the approved product 
label(s) for a list of excipients).
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14. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic 
treatment and is allowed.
15. Has a history of (non-infectious) pneumonitis/ interstitial lung disease that required 
steroids or has current pneumonitis / interstitial lung disease that requires steroids.
16. Has an active infection requiring systemic therapy.
17. Has a known history of human immunodeficiency virus (HIV) infection. HIV testing is 
not required unless mandated by local health authority. Refer to Appendix 7 for country-
specific details.
18. 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: Testing for hepatitis B and/or hepatitis C is not required unless mandated by local 
health authority.
19. Has a known history of active tuberculosis (TB; Bacillus tuberculosis)
20. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant's participation 
for the full duration of the study, or is not in the best interest of the participant to 
participate, in the opinion of the treating investigator.
21. Has a known psychiatric or substance abuse disorder that would interfere with 
cooperating with the requirements of the study.
Other Exclusions
22. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 180 days after 
the last dose of study treatment in Cycles 1-3 or for 120 days after the last dose of study 
treatment in Cycle 4 through the end of treatment.
23. Any other specific criterion determined to be required for treatment with standard of care 
therapies, based on documented regional or country-specific regulatory request,
subsequently approved by the Sponsor.
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, vomiting, or esophagitis.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
No caffeine, alcohol or tobacco restrictions are required.
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Investigation site personnel are encouraged to assist participants with activities aimed at 
discontinuing smoking. All participants who smoke should be strongly advised to cease 
smoking during TRTtreatment.
5.3.3
Activity Restrictions
There are no activity restrictions. Participants may participate in light recreational activities 
during the study.
5.3.4
Contraception
Pembrolizumab and chemotherapy may have adverse effects on a fetus in utero. Refer to 
Appendix 3 for approved methods of contraception.
Participants must be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in 
the study, participants of childbearing potential must adhere to the contraception requirement 
(Appendix 3) from the day of study medication initiation (or 14 days prior to the initiation of 
study medication for oral contraception) throughout the study period up to 180 days after the 
last dose of study medication in Cycles 1 to 3 or for 120 days after the last dose of study 
medication in Cycle 4 through the end of treatment. If there is any question that a participant 
of childbearing potential will not reliably comply with the requirements for contraception, 
that participant must not be entered into the study.
5.3.5
Pregnancy
If a participant inadvertently becomes pregnant while on treatment with chemotherapy and/or 
pembrolizumab, the participant will be immediately discontinued from study treatment. The 
site will contact the participant at least monthly and document the participant’s status until 
the pregnancy has been completed or terminated. The outcome of the pregnancy will be 
reported to the Sponsor without delay and within 24 hours if the outcome is a serious adverse 
experience (eg, death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn). The study investigator will make every effort to 
obtain permission to follow the outcome of the pregnancy and report the condition of the 
fetus or newborn to the Sponsor. If a male participant impregnates his female partner, the 
study personnel at the site must be informed immediately and the pregnancy must be reported 
to the Sponsor and followed as described in Section 8.4.6.
5.3.6
Use in Nursing Women
It is unknown whether chemotherapy and/or pembrolizumab are excreted in human milk.
Since many drugs are excreted in human milk, and because of the potential for serious 
adverse reactions in the nursing infant, participants who are breastfeeding are not eligible for 
enrollment.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
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Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any adverse events (AEs) or serious adverse 
events (SAEs) meeting reporting requirements as outlined in the data entry guidelines.
Participant Replacement Strategy
A participant who discontinues from study treatment or withdraws from the study will not be 
replaced.
6. Treatments
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo,
or medical device(s) intended to be administered to a study participant according to the study 
protocol.
Clinical supplies [study treatment(s) provided by the Sponsor] will be packaged to support 
enrollment. Pembrolizumab will be provided centrally by the Sponsor, while carboplatin, 
paclitaxel, cisplatin, and pemetrexed will be provided centrally by the Sponsor or locally by 
the trial site, subsidiary, or designee. Clinical supplies will be affixed with a clinical label in 
accordance with regulatory requirements.
Treatments Administered
The study treatment(s) to be used in this study are outlined below in Table 3.
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Table 3
Study Treatment(s)
Study 
Treatment 
Name
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Use
IMP/NIMP
Sourcing
COHORT A
Pembrolizumab
(MK-3475)
Solution for 
infusion
25 mg/ml
200 mg
IV infusion
Experimental
IMP
Central
Paclitaxel
Solution for 
infusion
6 mg /mL
200 mg/m2
45 mg/m2
IV infusion
Standard of 
care
NIMP
Local or 
Central
Carboplatin
Solution for 
infusion
10 mg /mL 
AUC6
AUC2
IV infusion
Standard of 
care
NIMP
Local or 
Central
Thoracic 
Radiotherapy
2 Gy/fraction
60 Gy
Standard 
Fractionation
Standard of 
care
NIMP
Local 
COHORT B
Pembrolizumab
(MK-3475)
Solution for 
infusion
25 mg/ ml
200 mg
IV infusion
Experimental
IMP
Central
Pemetrexed
Solution for 
infusion
500 mg 
Lyophilized 
Powder/ vial
500 mg/m2
IV infusion
Standard of 
care
NIMP
Local or 
Central
Cisplatin
Solution for 
infusion
1 mg / mL
75 mg/m2
IV infusion
Standard of 
care
NIMP
Local or 
Central
Thoracic 
Radiotherapy
2 Gy/fraction
60 Gy
Standard 
Fractionation
Standard of 
care
NIMP
Local 
Definitions: Investigational Medicinal Product (IMP) and Non- Investigational Medicinal Product (NIMP) is based on guidance issued by the European Commission. Regional 
and/or Country differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed.
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All supplies indicated in Table 3 will be provided per the ‘Sourcing’ row depending upon 
local country operational requirements. Every attempt should be made to source these 
supplies from a single lot/batch number where possible (e.g., not applicable in the case where 
multiple lots or batches may be required due to the length of the study etc.).
Refer to Section 8.1.9 for details regarding administration of the study treatment.
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
The dose amount required to prepare the pembrolizumab infusion solution will be based on a 
fixed dose of 200 mg. Details on dose calculation, preparation and administration of 
pembrolizumab are provided in the Pharmacy Manual. Dosing and preparation of 
pembrolizumab will be performed by authorized staff. 
Standard chemotherapeutic agents (carboplatin, paclitaxel, cisplatin, or pemetrexed) will be 
prepared and administered by authorized staff as per the approved product label(s).
Radiotherapy must be administered by authorized staff following guidelines detailed in 
Radiation Therapy Quality Assurance 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 treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment. All study treatments must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of study 
treatments in accordance with the protocol and any applicable laws and regulations.
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Measures to Minimize Bias: Randomization and Blinding
6.3.1
Method of Treatment Assignment 
Participants participating in this study will be allocated by nonrandom assignment.
Stratification
The study is a nonrandomized, open-label study. There is no stratification in the study.
Treatment allocation will be assigned according to the following factors:
1. Predominant tumor histology (squamous versus non-squamous)
2. Physician choice of treatment in non-squamous participants
6.3.2
Blinding 
This study is an open-label study; therefore, the Sponsor, investigator and participant will 
know the treatments administered.
Treatment Compliance
Interruptions from the protocol specified pembrolizumab treatment schedule due to toxicity 
or for situations other than treatment-related AEs are described in Section 6.6.1 and Section 
6.6.1.3, respectively. Treatment delays during Cycle 4 through Cycle 17 ≥9 weeks (ie, 12
weeks between pembrolizumab doses) will result in discontinuation from the Treatment
Phase. 
Concomitant Therapy
All medications received within 42 days prior to the first dose of study treatment through 
post-treatment follow-up must be recorded as described in Section 1.3. 
All concomitant medication will be recorded on the electronic case report form (eCRF)
including all prescription, over-the-counter (OTC) products, herbal supplements, and 
intravenous (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.
6.5.1
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. Palliative and supportive care is permitted during the course of the trial for 
underlying medical conditions and management of symptoms. 
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6.5.2
Prohibited Concomitant Medication
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. Participants are prohibited from receiving the following concomitant 
therapy or vaccination during the course of the trial:

Antineoplastic systemic chemotherapy or biological therapy not specified in this 
protocol.

Immunotherapy not specified in this protocol.

Chemotherapy not specified in this protocol.

Surgery or radiotherapy for tumor control not specified in the protocol.

Investigational agents other than pembrolizumab.

Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study. Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, 
and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., 
FluMist®) are live attenuated vaccines and are not allowed. 

Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
irAE or for use as a pre-medication for chemotherapeutic agents specified in the 
protocol or as a pre-medication prior to a CT scan for participants with contrast 
allergy or for use for chronic obstructive pulmonary disease exacerbation requiring 
steroid for recovery. Replacement doses of steroids (for example, prednisone 10 mg 
daily or equivalent) are permitted while on study.
If there is a clinical indication for any medication or vaccination specifically prohibited 
during the trial, discontinuation from the trial therapy may be required. The investigator 
should discuss any questions regarding this with the Sponsor Clinical Director. The final 
decision on any supportive therapy or vaccination rests with the investigator and/or 
participant’ primary physician. However, the decision to continue the participant on trial 
therapy requires the mutual agreement of the investigator, the Sponsor, and the participant.
Refer to Appendix 7 for country-specific information regarding concomitant medications to 
be used with caution.
6.5.3
Rescue Medications and Supportive Care
Pembrolizumab
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 
Table 6. 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, 
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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 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.
Chemotherapy
For supportive care measures for the management of AEs that may result from treatment with 
carboplatin/paclitaxel (Cohort A) or cisplatin/pemetrexed (Cohort B) refer to the approved 
product labels for these agents. 
For Cohort A, all participants should be pre-medicated with oral or intravenous steroid and 
anti-histamines according to the approved product label and/or standard practice prior to 
paclitaxel infusion, see Section 8.1.9.1.2.
For Cohort B, all participants should receive the appropriate supplementation of 
intramuscular vitamin B12 1000 mcg and folic acid according to the approved product label
and/or standard practice prior to pemetrexed infusion; see Section 8.1.9.1.3. In addition, all 
participants should receive the appropriate corticosteroid pre-medications as per the local 
approved label. 
Antiemetic therapy should follow Multinational Association of Supportive Care in Cancer 
(MASCC) guidelines (http://www.mascc.org/antiemetic - guidelines/; [Roila, F., et al 2016])
and should, for the first 3 cycles, include a 5-HT3 receptor antagonist, dexamethasone (or 
equivalent) and/or aprepitant as per the MASCC guidelines. 
Additional pre-medications and pre- and post-cisplatin hydration should be administered as 
per standard practice.
Radiotherapy
Reversible or permanent alopecia, bone marrow toxicity, skin pigmentation, and esophagitis 
are expected side effects of radiation therapy (RT). Radiation-induced transverse myelitis 
rarely occurs at doses lower than 50 Gy to the spinal cord and canal. Radiation-induced 
cardiac injury may occur at whole heart doses of greater than 30-40 Gy and it will be 
important to keep a mean heart dose at approximately 20 Gy or less during treatment 
planning. Radiographic evidence of radiation-induced changes and subsequent fibrosis of the 
lung may occur within lung volumes receiving ≥20 Gy. It is essential to spare as much 
normal lung as possible in order to avoid symptomatic lung and other organ injury.
One of the most common side effects of cCTRT is esophagitis. The first symptoms of acute 
esophagitis usually start in the second or third week of cCTRT, commonly at the dose of 18.0 
to 21.0 Gy of standard fractionated RT [Wei, X., et al 2006], and include a sensation of 
difficult swallowing (dysphagia). This may progress to painful swallowing of food and saliva 
(odynophagia) and later to constant pain not necessarily related to swallowing. In severe 
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cases, participants may not be able to swallow at all and may require intravenous hydration, 
feeding through a gastric tube and, in rare cases, parenteral nutrition.
Esophagitis complaints are common with combined modality therapy [Werner-Wasik, M., et 
al 2011]. Esophagitis does not constitute a reason to interrupt or delay RT, provided oral 
intake is sufficient to maintain hydration. Participants should be advised to avoid alcoholic or 
very cold temperature beverages and acidic or spicy foods and beverages. Acute esophagitis 
symptoms may persist for 1 to 3 weeks after completion of RT. If Common Terminology 
Criteria for Adverse Events (CTCAE) Grade 4 esophagitis occurs and treatment is 
interrupted, every effort should be made to limit the interruption to 3 treatment days or less. 
Participants requiring hospitalization, placement of a feeding tube in the stomach, or 
intravenous feedings because of esophagitis may have their treatment interrupted in order to 
optimize supportive care measures and enteral nutrition. See Section 6.4.
Table 4 lists esophagitis grading and clinical states according to the CTCAE.
Table 4
CTCAE Scale: Acute Esophagitis Related to Radiation
Grade
Clinical State
1
asymptomatic pathologic, radiographic, or endoscopic findings only
2
symptomatic; altered eating/swallowing (for example, altered dietary habits, oral 
supplements); IV fluids indicated < 24 hours
3
symptomatic and severely altered eating/swallowing (for example, inadequate oral 
caloric or fluid intake); IV fluids, tube feedings, or TPN indicated > 24 hours
4
life-threatening consequences (for example, obstruction, perforation)
5
death
Abbreviations: CTCAE = Common Terminology Criteria of Adverse Events; IV = intravenous; TPN = total 
parenteral nutrition.
Acute esophageal toxicity, which manifests as dysphagia, odynophagia, reflux symptoms, 
and so forth, should be pharmacologically managed with the recommended treatment 
options, alone or in various combinations (Table 5), or comparable regimen, and should be 
initiated at the first signs or symptoms of esophageal toxicity.
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Table 5
Suggestions for Management of Radiation Esophagitis
Treatment 
Options
Management of Esophagitis 
1
Ketoconazole 200 mg po QD
2
Fluconazole 100 mg po QD until the completion of radiation
3
Mixture of: 60 mL viscous lidocaine + 30 mL Mylanta (or generic equivalent 
antacid), + 10 mL sucralfate (1 gm/mL). Approximately 15-30 mL of the 
mixture po q3-4h PRN
4
Ranitidine 150 mg po BID (or other histamine-2 [H2] receptor blocker or a 
proton pump inhibitor such as omeprazole) until completion of radiation
5
Grade 4 esophagitis: hold cCTRT until Grade 2 or less.
Abbreviations: BID = twice daily; cCTRT = concurrent chemoradiotherapy; h = hour; po =oral; PRN = when 
necessary; q = every; QD = every day.
Dose Modification  
Toxicity events may be attributed to pembrolizumab, individual chemotherapy agents,
radiotherapy, or to the combination of any of these treatments. 
Dose modifications due to toxicity events must be based on the maximum toxicity 
experienced during a treatment cycle. The CTCAE Version 4.0 must be used to grade the 
severity of AEs. All dose modifications must be based on the AE requiring the greatest dose 
modification. Treatment related toxicity must resolve to Grade ≤1 or baseline prior to 
resuming the subsequent cycle, with the exception of alopecia, Grade 2 fatigue, Grade 2 
esophagitis, Grade 2 peripheral neuropathy, Grade 2 anemia, endocrine-related AEs requiring 
treatment or hormone replacement, which may be Grade ≥2. Consultation with the Sponsor 
Clinical Director and documented approval via a Sponsor Communication may be obtained 
to continue a participant on treatment for an AE Grade ≥2 if in the assessment of the 
investigator the particular AE does not pose a significant medical risk to the participant to 
continue the treatment
If a dose reduction for toxicity occurs with any agent, the dose may not be re-escalated. 
Participants can have a maximum of 2 dose modifications (if applicable) to each of the 
components of study therapy throughout the course of the study for toxicities. If a participant
experiences several toxicities and there are conflicting recommendations, the most 
conservative dose adjustment recommended should be followed (dose reduction appropriate 
to the most severe toxicity). Participants who require a third dose modification to any 
particular component will have that agent discontinued.
Dose modifications for pembrolizumab, chemotherapy, and radiotherapy are summarized in 
Section 6.6.1, Section 6.6.2, and Section 6.6.3, respectively.
If toxicity is related to the combination of 3 agents (ie, 2 chemotherapy agents and 
pembrolizumab), all 3 agents must be interrupted or discontinued according to the 
recommended dose modifications. Participants may have chemotherapy discontinued and 
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continue on pembrolizumab alone. Similarly, participants may discontinue pembrolizumab
and continue on chemotherapy alone (for first 3 cycles) if appropriate.
Systemic treatment (chemotherapy and/or pembrolizumab) given with radiation should be 
suspended if continuation of systemic treatment will compromise delivery of full-dose 
radiation in an uninterrupted manner.
6.6.1
Pembrolizumab
Pembrolizumab dose reductions are not permitted. Pembrolizumab treatment may be delayed 
as described below or discontinued due to toxicity. Pembrolizumab treatment delays greater 
than those specified below will result in discontinuation from the Treatment Phase

Pembrolizumab may be delayed for a maximum of 3 weeks during Cycles 1 to 2 (ie, 
6 weeks between pembrolizumab doses) and for a maximum of 3 weeks during 
Cycles 2 to 3 (ie, 6 weeks between pembrolizumab doses).  

Cycle 4 must be administered within 6 weeks after completion of TRT

Pembrolizumab may be delayed for up to 9 weeks during Cycles 4 through 17 (ie, 12
weeks between pembrolizumab doses). However, delays greater than 9 weeks will 
result in discontinuation from the Treatment Phase (see Section 6.4). See Appendix 7 
for country-specific pembrolizumab discontinuation guidance.
Dose Modification and Toxicity Management for Immune-Related AEs 
Associated With Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than 1 body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical trial 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, and/or 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 are provided 
in Table 6. Guidance for determining severity of pneumonitis is in Table 7.
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Table 6
Dose Modification and Toxicity Management Guidelines for Immune-related AEs 
Associated with Pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper 
over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has 
been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be 
permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot 
be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral 
steroid. Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by 
corticosteroids.
Immune-related 
AEs
Toxicity 
grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management 
with corticosteroid 
and/or other 
therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2
Withhold 

Administer 
corticosteroids 
(initial dose of 
1-2mg/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
Grade 3 or 4, 
or recurrent 
grade 2
Permanently 
discontinue
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Immune-related 
AEs
Toxicity 
grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management 
with corticosteroid 
and/or other 
therapies 
Monitor and follow-up 
Diarrhea / colitis 
Grade 2 or 3
Withhold

Administer 
corticosteroids 
(initial dose of 
1-2mg/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.
Grade 4 or 
recurring 
Grade 3 
Permanently 
discontinue
AST / ALT 
elevation or 
Increased 
Bilirubin
Grade 2
Withhold

Administer 
corticosteroids 
(initial dose of 
0.5- 1mg/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 
1-2mg/kg 
prednisone or 
equivalent) 
followed by 
taper
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Immune-related 
AEs
Toxicity 
grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management 
with corticosteroid 
and/or other 
therapies 
Monitor and follow-up 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated 
with evidence 
of -cell 
failure
Withhold

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 
discontinue1
Hyperthyroidism
Grade 2
Continue 

Treat with non-
selective beta-
blockers (eg, 
propranolol) or 
thioamides as 
appropriate 

Monitor for signs and 
symptoms of thyroid 
disorders 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
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 
1-2mg/kg or 
equivalent) 
followed by 
taper

Monitor changes of 
renal function
Grade 3 or 4 
Permanently 
discontinue
Myocarditis
Grade 1 or 2
Withhold

Based on 
severity of AE 
administer 
corticosteroids

Ensure adequate 
evaluation to confirm 
etiology and/or 
exclude other causes
Grade 3 or 4
Permanently 
discontinue
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Immune-related 
AEs
Toxicity 
grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management 
with corticosteroid 
and/or other 
therapies 
Monitor and follow-up 
All Other 
immune-related 
AEs
Intolerable/ 
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 
based on the type 
of event. Events 
that require 
discontinuation 
include and not 
limited to:  
Guillain-Barre 
Syndrome, 
encephalitis
Grade 4 or 
recurrent 
Grade 3 
Permanently 
discontinue
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. 
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, 
pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement 
therapy or achieved metabolic control (in case of T1DM).
Table 7
Criteria for Grading of Pneumonitis: Common Terminology Criteria for Adverse 
Events, Version 4.0
Grade
Clinical State
1
asymptomatic; clinical or diagnostic observations only; intervention not indicated
2
symptomatic; medical intervention indicated; limiting instrumental ADL
3
severe symptoms; limiting self-care ADL; oxygen indicated
4
life-threatening respiratory compromise; urgent intervention indicated (e.g., 
tracheotomy or intubation)
5
death
Definition: A disorder characterized by inflammation focally or diffusely affecting the lung parenchyma.
Abbreviations: ADL = activities of daily living; CTCAE = Common Terminology Criteria of Adverse 
Events; Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc.; Self-care ADL refers to bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden.
Source: [National Cancer Institute 2010]
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Dose Modification and Toxicity Management of Infusion-Reactions Related to 
Pembrolizumab
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 8.
Table 8
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may include 
but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of the 
original infusion rate (eg, from 100 mL/hr to 50 
mL/hr). Otherwise dosing will be held until 
symptoms resolve and the participant should be 
premedicated for the next scheduled dose.
Participants who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further treatment with 
pembrolizumab
Participant may be premedicated 
1.5h (± 30 minutes) prior to infusion 
of pembrolizumab with:
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine).
Acetaminophen 500-1000 mg po (or 
equivalent dose of analgesic).
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 treatment with pembrolizumab.
No subsequent dosing
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NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may include 
but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of the 
original infusion rate (eg, from 100 mL/hr to 50 
mL/hr). Otherwise dosing will be held until 
symptoms resolve and the participant should be 
premedicated for the next scheduled dose.
Participants who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further treatment with 
pembrolizumab
Participant may be premedicated 
1.5h (± 30 minutes) prior to infusion 
of pembrolizumab with:
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine).
Acetaminophen 500-1000 mg po (or 
equivalent dose of analgesic).
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 treatment with pembrolizumab.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the 
period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov
Other Allowed Dose Interruption for Pembrolizumab
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Participants should 
be placed back on therapy within 3 weeks of the scheduled interruption. The reason for 
interruption must be documented on the Sponsor Communication Form.
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6.6.2
Chemotherapy Dose Modifications
Reduction of 1 chemotherapy agent and not the other agent is appropriate if, in the opinion of 
the investigator, the toxicity is clearly related to 1 of the treatments. If, in the opinion of the 
investigator, the toxicity is related to the combination of both chemotherapy agents, both 
drugs should be reduced according to recommended dose modifications. Chemotherapy may 
be delayed for a maximum of 3 weeks between Cycles 1 to 2 and between Cycles 2 to 3.
Refer to approved product labels for dose modifications regarding carboplatin/paclitaxel 
(Cohort A) and cisplatin/pemetrexed (Cohort B).
The second cycle of chemotherapy must commence during the first week of radiotherapy. 
Concurrent phase chemotherapy cycles can only be commenced if there is ongoing 
radiotherapy. In the event of chemotherapy delays, cycles that are scheduled to resume after 
the last fraction of radiotherapy will be omitted and not considered a reason for patients to 
come off of the trial.
6.6.3
Radiotherapy Dose Modification
Radiotherapy may be interrupted or discontinued due to toxicity. Radiotherapy may be 
interrupted for a maximum of 3 weeks during Cycles 2 to 3. 
Every effort must be made to continue the radiotherapy during the concurrent phase in an 
uninterrupted manner. Should a patient develop severe esophagitis necessitating interruption 
of chemotherapy, the radiotherapy may continue, provided the investigator believes 
supportive care will enable the patient to complete this part of the therapy without excess 
risk.
On days when radiotherapy and/or chemotherapy are delayed for administrative reasons (eg,
holidays or weather), this will not be considered a protocol violation, provided the full 
planned dose of radiotherapy is administered.
Treatment After the End of the Study 
There is no study-specified treatment following the end of the study.
Upon study completion, subjects are discontinued and may be enrolled in a pembrolizumab 
extension study, if available.
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor 
and/or designee are not blinded. Study treatment (name, strength or potency) is included in 
the label text; random code/disclosure envelopes or lists are not provided.
Standard Policies
MK-3475 will be provided by the study site as the innovator product pembrolizumab as 
needed. No generic substitution is permitted.
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7. Discontinuation of Study Treatment and Participant Withdrawal
Discontinuation of Study Treatment 
Discontinuation of study treatment does not represent withdrawal from the study.
As certain data on clinical events beyond study treatment discontinuation may be important 
to the study, they must be collected through the participant’s last scheduled follow-up, even 
if the participant has discontinued study treatment. Therefore, all participants who 
discontinue study treatment prior to completion of the protocol-specified treatment period
will still continue to participate in the study as specified in Section 8.12.3.
Participants may discontinue study treatment at any time for any reason or be discontinued
from the study treatment at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study treatment by the investigator 
or the Sponsor if study treatment is inappropriate, the study plan is violated, or for 
administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study treatment discontinuation are provided in Section 1.3.
A participant must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons:
○
The participant or participant’s legally acceptable representative requests to discontinue 
study treatment.
o
Confirmed radiographic disease progression outlined in Section 8.2.
o
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment.
o
Intercurrent illness other than another malignancy as noted above that prevents further 
administration of treatment.
o
Recurrent Grade 2 pneumonitis.
o
A confirmed positive serum pregnancy test.
o
Completion of 17 treatments with pembrolizumab.
o
Investigator’s decision to discontinue the participant.
o
Use of prohibited medications as described in Section 6.5.2.
o
The participant interrupts pembrolizumab administration for more than 12 consecutive 
weeks for an AE/toxicity or for more than 3 weeks for administrative reasons without 
Sponsor consultation.
See Appendix 7 for country-specific treatment discontinuation requirements.
For participants who are discontinued from study treatment but continue to be monitored in 
the study, all visits and procedures, as outlined in the SoA, should be completed.
Discontinuation from study treatment is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study treatment. 
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Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research are 
outlined in Sections 1.3 and 8.1.10.2. The procedures to be performed should a participant 
repeatedly fail to return for scheduled visits and/or if the study site is unable to contact the 
participant are outlined in Section 7.3.
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
●
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
●
The investigator or designee must make every effort to regain contact with the 
participant at each missed visit (eg, telephone calls and/or a certified letter to the 
participant’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the participant’s medical record.
●
Note:  A participant is not considered lost to follow-up until the last scheduled visit 
for the individual participant. The missing data for the participant will be managed 
via the prespecified statistical data handling and analysis guidelines.
8. Study Assessments and Procedures
●
Study procedures and their timing are summarized in the SoA. 
●
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
●
The investigator is responsible for assuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel 
responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
●
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
●
Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.
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●
Additional evaluations/testing may be deemed necessary by the investigator and or 
the Sponsor for reasons related to participant safety. In some cases, such 
evaluation/testing may be potentially sensitive in nature (eg, HIV, Hepatitis C, etc.), 
and thus local regulations may require that additional informed consent be obtained 
from the participant. In these cases, such evaluations/testing will be performed in 
accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, can be found in the Procedures 
Manual.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
participant or each participant’s legally acceptable representative prior to participating in a 
clinical study or future biomedical research. If there are changes to the participant’s status 
during the study (eg, health or age of majority requirements), the investigator or qualified 
designee must ensure the appropriate consent is in place. 
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF and any written information provided to 
the participant must receive the Institutional Review Board/Independent Ethics Committee’s
(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 dated 
signature or by the participant’s legally acceptable representative’s dated signature.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level. 
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations 
and Sponsor requirements.
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Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the future biomedical research consent to 
the participant, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the future biomedical research substudy. A copy of the 
informed consent will be given to the participant
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the study.
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 utilized in the event of an emergency. The 
investigator or qualified designee will provide the participant with a Participant Identification 
Card immediately after the participant provides written informed consent. At the time of 
treatment allocation/randomization, site personnel will add the treatment/randomization 
number to the Participant Identification Card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
treatment in emergency situations where the investigator is not available.
8.1.4
Medical History
Participant demographics and a medical history will be obtained by the investigator or 
qualified designee.
Medical history will include all active conditions, and any condition diagnosed within the 
prior 10 years that are considered to be clinically significant by the Investigator. Medical 
history will also include any prior cancer other than NCSLC even if diagnosed greater than 
10 years prior to Visit 1 as well as an assessment of smoking history. 
NSCLC history will be recorded separately and not listed as medical history as specified in 
the SoA.
8.1.5
Prior and Concomitant Medications Review
Prior Medications
The investigator or qualified designee will review prior medication use and will record prior 
medication taken by the participant within 42 days before the first dose of study medication
as well as medications regularly administered at intervals greater than 42 days prior to first 
dose. 
A complete history of the participant’s treatment of NSCLC (if any) will be recorded 
separately and not listed as prior medication as specified in the SoA.
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Concomitant Medications
The investigator or qualified designee will record all medications, if any, taken by the 
participant during the trial through post-treatment follow-up including all prescription, OTC 
products, herbal supplements, and IV medications and fluids. If changes occur during the 
study period, documentation of drug dosage, frequency, route, and date will also be included 
on the eCRF.
Concomitant medications prohibited in the study are described in Section 6.5.2.
All medications related to reportable SAEs and ECIs must be recorded as defined in Section
8.4.
8.1.6
Post-Treatment Anticancer Therapy
The investigator or qualified designee will review all new antineoplastic therapy initiated 
after the last dose of trial treatment. 
If a participant initiates a new antineoplastic therapy within 30 days after the last dose of trial 
treatment, the 30-day Safety Follow-up Visit must occur before the first dose of the new 
therapy. 
Once new antineoplastic therapy has been initiated the participant will move into Survival 
Follow-up described in Section 8.12.3.3.
8.1.7
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to treatment assignment. Each 
participant will be assigned only one screening number. Screening numbers must not be re-
used for different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 8.12.1.
8.1.8
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.9
Treatment Administration
Administration of pembrolizumab, chemotherapy, and radiotherapy will be witnessed by the 
investigator or qualified designee.
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Dose administrations of pembrolizumab and chemotherapy are described in Section 8.1.9.1.
Thoracic radiotherapy treatment is described in Section 8.1.9.2.
Study Treatment should begin within 3 days of the date on which the participant is allocated 
to a treatment cohort.
Timing of Dose Administration
Study treatment may be administered up to 3 days before or after the scheduled Day 1 of 
each cycle due to administrative reasons except for Cycle 1, Day 1, where the window is 
+3 days from randomization.
Study treatment with pembrolizumab and chemotherapy must be administered after all 
procedures/assessments have been completed as detailed in the SoA. All study treatments 
will be administered on an outpatient basis. 
Pembrolizumab and chemotherapy study treatments will be administered in the following 
order:
Cohort A: pembrolizumab, paclitaxel, and carboplatin
Cohort B: pembrolizumab, pemetrexed, and cisplatin 
During Cycles 2 and 3, it will be preferable to have pembrolizumab and chemotherapy 
administered prior to TRT delivery. Chemotherapy treatment will end after completion of the
TRT regimen.
Timing of Dose Administration of Pembrolizumab
Pembrolizumab will be administered as a dose of 200 mg using a 30-minute IV infusion. 
Sites must 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).
Refer to the Pharmacy Manual for detailed instructions for pembrolizumab reconstitution, 
preparation of the infusion fluid, and administration.
Timing of Dose Administration of Chemotherapy: Cohort A
Paclitaxel
Paclitaxel 200 mg/m2 will be administered as an IV infusion over 3 hours or per local 
practice and labels on Day 1 of the 21-day cycle for Cycle 1 and paclitaxel 45 mg/m2 will be 
administered as an IV infusion over 1 hour or per local practice and label on Day 1, 8 and 
15 of Cycle 2 and Cycle 3 during TRT. Given the variability of infusion pumps from site to 
site, the time window allowed per local practice or label is permitted. Paclitaxel must be 
completely administered before initiating carboplatin dose.
All participants should be pre-medicated with steroids and anti-histamines according to the 
approved product label and/or standard practice. Additional pre-medications should be 
administered as per standard practice. 
Refer to the approved product label for detailed instructions regarding dose calculation, 
reconstitution, preparation of the infusion fluid, and administration.
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Carboplatin
Carboplatin AUC6 will be administered as an IV infusion over 15-60 minutes or per local 
practice or label on Day 1 of the 21-day cycle for Cycle 1 and carboplatin AUC2 will be 
administered as an IV infusion over 30 minutes or per local standard practice on Day 1, 8 and 
15 of Cycle 2 and Cycle 3 during TRT. Given the variability of infusion pumps from site to 
site, the time window allowed per local practice or label is permitted.
The dose of carboplatin will be calculated using either the Calvert Formula or carboplatin 
dose calculator approved at the local institution.
Calvert Formula
Total Dose (mg) = (target AUC) x (CrCl + 25)
The estimated creatinine clearance (CrCl) used in the Calvert formula should not 
exceed 125 mL/min
Maximum carboplatin dose (mg) = target AUC 6 (mg•min/mL) x (125 + 25) = 6 x
150 mL/min = 900 mg
Refer to the approved product label for detailed instructions regarding dose calculation, 
reconstitution, preparation of the infusion fluid, and administration.
Timing of Dose Administration of Chemotherapy: Cohort B
Pemetrexed
Pemetrexed 500 mg/m2 will be administered as an IV infusion over 10 minutes or per local 
practice or label on Day 1 of the 21-day cycle, for Cycle 1, 2 and 3. Given the variability of 
infusion pumps from site to site, the time window allowed per local practice or label is 
permitted. Pemetrexed must be completely administered before initiating cisplatin dose.
All participants should be pre-medicated with steroids as per the approved label and local 
standard practices. In addition, all participants assigned to pemetrexed must take a folic acid 
preparation or multivitamin with folic acid containing between 350 to 1000 mcg daily. At 
least 5 daily doses of folic acid must be taken during the 7-day period preceding the first dose 
of pemetrexed and dosing should continue during the full course of therapy and for 21 days 
after the last dose of pemetrexed. Participants must also receive 1 intramuscular injection of 
vitamin B12 1000 mcg 1 week preceding the first dose of pemetrexed (Cycle 1) and on Cycle 
3. On Cycle 3, vitamin B12 injections may be given the same day as treatment with 
pemetrexed. Intramuscular vitamin B12 cannot be substituted with oral vitamin B12.
Refer to the approved product label for detailed instructions regarding dose calculation, 
reconstitution, preparation of the infusion fluid, and administration.
Cisplatin
Cisplatin 75 mg/m2 will be administered as an IV infusion over 60 minutes or per local 
practice or label on Day 1 of the 21-day cycle, for Cycle 1, 2 and 3. Given the variability of 
infusion pumps from site to site, the time window allowed per local practice or label is 
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permitted. All participants should be pre-medicated with steroids and anti-emetics per the 
approved label and local standard practices.
Refer to the approved product label for detailed instructions regarding dose calculation, 
reconstitution, preparation of the infusion fluid, and administration.
Thoracic Radiation Therapy (TRT)
Prior to inclusion of any participant on this study, the radiation oncologist will evaluate the 
thoracic CT scan in order to ensure that the treatment volumes are unlikely to significantly 
exceed the specified normal tissue constraints, particularly that the V20 meets the threshold 
of ≤31%, as specified in the exclusion criteria.
Participants in both cohorts will receive concurrent TRT using a standardized 3-dimensional 
conformal radiotherapy (3DCRT) technique on a linear accelerator operating at beam energy 
of ≥6 megavolts (MV). 6MV photons are preferred if possible; 10 MV photons may also be 
used. Use of photon energies higher than 10 MV is allowed but discouraged. The target total 
dose of TRT will be 60 Gy in 30 daily fractions of 2 Gy, prescribed to the planning target 
volume (PTV) as described in Section 8.1.9.2.1. Proton treatment is not allowed.
Beam-Shaping: Multi-leaf collimation will be used to spare normal tissues outside of the 
target volume.
Intensity Modulated Radiotherapy (IMRT) will be permitted if the appropriate credentialing 
has been performed. Motion management will be incorporated for an IMRT approach to 
control respiratory motion to a maximum excursion of 1.0 cm. Acceptable approaches 
include abdominal compression, breath hold using the active breathing device (ABC) device 
or other computer-controlled spirometry, gating or other technologies.
Heterogeneity Corrections: All radiation doses will be calculated with heterogeneity 
corrections that take into account the density differences within the irradiated volume (eg,
air, soft tissue, or bone). Dose calculations should be performed on a non-contrast enhanced 
CT. Alternatively, if calculations are performed on a contrast-enhanced scan, areas of 
contrast enhancement adjacent to the target volumes or nearby critical structures must be 
over-ridden with soft tissue density. A list of acceptable dose calculation algorithms that 
most accurately account for tissue heterogeneities can be found on the QARC website 
(www.qarc.org).
Center credentialing will be performed according to criteria defined in the RT Quality 
Assurance (QA) Manual. Participating institutions must comply with the RT QA 
requirements and procedures described in the RT QA manual. Sites that do not conform to 
the requirements of the credentialing will not be allowed to participate.
Dose Specifications
Participants will receive treatment 5 days per week, in once daily fractions, 2 Gy per fraction, 
to a target dose of 60 Gy in 30 fractions. No field reductions will be permitted and the entire 
PTV must be treated daily. Cycle 2 of chemotherapy and pembrolizumab must be given 
during the first week of TRT. When both chemotherapy and radiation are administered at the 
same center/location, it is recommended that radiation should follow within 30 to 60 minutes 
of the completion of chemotherapy, especially on Day 1 of TRT. When the radiotherapy is 
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delivered at a separate location, logistic considerations may result in radiotherapy being 
delivered prior to the administration of chemotherapy. On days where TRT and/or 
chemotherapy are delayed for administrative reasons (eg, holidays or weather), this will not 
be considered a protocol violation, provided the full planned dose of TRT is administered.
The treatment plan shall be normalized such that 95% of the prescription dose covers at least 
99% of the PTV (V57>99%). The minimum PTV dose must not fall below 95% of the 
prescription dose. All radiation doses will be calculated with inhomogeneity corrections that 
take into account the density differences within the irradiated volume (that is, air in the lung 
and bone). The maximum and minimum point doses (within the PTV) will be reported. No 
more than 0.03 cc of the PTV may receive >120% of the prescription dose (maximum dose 
constraint). 
Variations of Dose Prescription
No deviation: The treatment plan will be normalized so that ≥ 95% of the PTV is covered by 
the prescription dose. No more than 0.03 cc of the PTV may receive >120% of the 
prescription dose (maximum dose constraint).
Variation Acceptable: Deviations of this magnitude are not desirable, but are acceptable. 
The prescribed dose can cover <95% of the PTV provided it covers at least 90% of the PTV.
The minimum dose can fall below 93% of the prescribed dose provided it is at least 90% of 
the prescription dose, if the areas of underdosing are confined to regions of overlap with 
critical structures. The maximum dose within the PTV may exceed 120% of the prescribed 
dose provided it is no more than 125% of the prescription dose, and the areas exceeding 
110% of the prescription dose are confined within the GTV and do not overlap with critical 
structures. Standard naming conventions, protocol constraints, and compliance criteria are 
tabulated in Table 9.
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Table 9
Summary of Protocol Constraints and Compliance Criteria
Structure
Metric
Per Protocol
Variation Acceptable
Deviation 
Unacceptable
PTV
V60Gy
≥95%
≥90%
<90%
Min dose 
(D99%)
≥55.8 Gy (93%)
≥57 Gy (95%)
≥54 Gy (90%)
<54 Gy
Max dose 
(0.03 cc)
≤72 Gy (120%)
≤75 Gy (125%)
>75 Gy
Spinal cord
Max dose 
(0.03 cc)
≤50.0 Gy
≤52 Gy
>52 Gy
Lungs 
(minus 
GTV)
V20Gy
≤31%
None
>31
V5Gy
≤60%
≤65%
>65%
Mean dose
≤20 Gy
≤22 Gy
>22 Gy
Heart
Mean dose
≤20 Gy
≤26 Gy
>26 Gy
Esophagus
Max dose 
(0.03 cc)
≤63 Gy
≤66 Gy
>66 Gy
Mean dose
≤34 Gy
≤35 Gy
>35 Gy
V60Gy
Not circumferential
Circumferential for ≤0.5 
cm contiguous length
Circumferential for 
>0.5 cm contiguous 
length
Brachial 
plexus
Max dose 
(0.03cc)
≤63 Gy
≤66 Gy
>66 Gy
Localization, Simulation, and Immobilization
Immobilization: Immobilization is necessary to assure reproducibility of the setup. An 
immobilization device must be used for positioning of each patient. Each participant will be 
positioned in an institutional specific immobilization device in the treatment position on a 
flat table.
If a conventional (non-4-dimensional CT) treatment planning CT study is performed, the 
GTV, clinical target volume (CTV), and PTV will be defined on all slices (see definitions in 
Section 8.1.9.2.4). 
Target volumes (GTV, CTV), PTV, and normal organs will be outlined on all appropriate CT 
slices. All planning CT scans must be performed in the treatment position using the same 
immobilization device for set-up as is used at the linear accelerator. Optimal immobilization 
is critical for this protocol in order to ensure reproducibility of the daily set-up. Conventional 
CT scans will be performed during quiet, uncoached respiration while the participant 
undertakes a normal respiration, using 5-mm or finer slices through the entire target volume. 
The scan volume must include the entire thorax (cricoid to L2) in order to generate dose-
volume histograms for the lungs, spinal cord, heart, and esophagus. Radiotherapy must
commence within 2 weeks (±) 2 working days of the planning CT scan.
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A treatment planning fluorodeoxyglucose (FDG)-PET/CT scan (or FDG-PET alone) with the 
participant in the treatment position is encouraged for treatment planning. Where a PET/CT 
is obtained in the treatment position, the CT from this study may be used as the planning CT 
scan.
Intravenous contrast during the planning CT is optional, provided that a recent diagnostic 
chest CT was done with contrast to delineate the major blood vessels and involved 
mediastinal lymph nodes. If not, intravenous contrast must be given during the planning CT. 
If contrast is used, the densities can be over-ridden or the contrast scan must be registered to 
a noncontrast scan for planning purposes. 
The use of 4-dimensional CT scans and 4-dimensional radiation treatment planning is 
permitted. Acceptable methods of accounting for tumor motion include: design of the PTV to 
cover the excursion of the primary lung cancer and involved nodal CTV during free 
breathing (motion inclusive), or the more limited excursion during a voluntary or automatic 
breath-hold (i.e., Elekta ABC device), or a gating approach (eg, Varian RPM system).
Treatment Planning/Target Volumes
Target Volumes will be defined in accordance with the International Commission on 
Radiation Units and Measurements Report #62 [Wambersie, A. 1999].
Gross Tumor Volume (GTV) encompasses all identified tumor, identified by radiologic 
imaging, PET scan, bronchoscopy, or mediastinoscopy. Mediastinal lymph nodes with a 
short axis ≥1.0 cm or pretreatment PET scan with standardized uptake values >3 will be 
included in the GTV unless metastases have been shown to be absent using cytologic, 
histologic, or PET studies. This volume(s) may be disjointed. In the event of a collapsed lobe 
or lung segment, the use of PET to distinguish tumor from fluid/atelectasis is allowed.
Clinical Target Volume (CTV) is defined to be the GTV plus a 0.5-cm to 1-cm margin, as 
appropriate, to account for microscopic tumor extension. For participants with N2 disease, 
the CTV will include the ipsilateral hilus in the proximity of the tumor if it is felt appropriate 
to include this region, even if this is radiologically normal. When the hilus is normal, the 
lower pole of the ipsilateral hilus will be excluded if the primary tumor is located in the 
upper lobe and vice versa in the case of a tumor in the lower lobe. The CTV may be extended 
to include the entire ipsilateral hilum that is radiologically normal in cases where the location 
of the primary tumor makes this an appropriate consideration; for example, tumor in close 
proximity to the hilum. Inclusion of the hilus is encouraged for centrally located primary 
lung tumors. Elective treatment of the mediastinum and supraclavicular fossae will not be 
done.
Planning Target Volume (PTV): The appropriate clinical target volumes (described above) 
will be enlarged to allow for organ motion and day-to-day set-up variation to define the PTV. 
Typically the CTV is expanded by 1 cm in all directions (and 1.5 cm superiorly or inferiorly 
for tumors of the lower lobe or with significant respiratory excursion) if no motion 
management is used. 
Tighter PTV margins may be allowed based on assessments of CTV motion using 
fluoroscopy and/or 4DCRT. When a 4-dimensional CT scan is performed, a patient-specific
internal target volume (ITV) may be directly derived for planning and appropriate margins 
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added in order to derive a CTV and PTV, respectively. These determinations must be 
documented but are left to the discretion of the treating radiation oncologist. This PTV will 
be used to define the treated volume.
The ITV is defined as the CTV plus an internal margin to account for target/organ motion.
The final PTV is defined to be the ITV plus a setup margin to account for patient positioning 
uncertainty and machine tolerance. Table 10 below provides guidance on margins of ITV and 
PTV.
Table 10
Planning Target Volume
Motion 
management
Internal 
margin (cm) 
(superior-
inferior)
Internal 
margin (cm)
Axial
Setup margin 
(cm, uniform)
Total PTV 
margin 
(superior-
inferior)
Total PTV 
margin 
(axial)
Free breathing
1
0.5
0.5
1.5
1
Breath hold or 
gating
0.5
0.3
0.5
1
0.8
Abdominal 
compression
0.8
0.5
0.5
1.3
1
4D CT
Union of CTVs
Union of CTVs
0.5
Union of 
CTVs+0.5 cm
Union of 
CTVs +0.5 cm
Treatment Planning
Three-Dimensional Conformal Radiotherapy (3DCRT)
The PTV is to be treated with any combination of coplanar or noncoplanar 3D conformal 
fields shaped to deliver the specified dose while restricting the dose to the normal tissues. 
The treatment plan used for each participant will be based on an analysis of the volumetric 
dose, including dose-volume histogram analyses of the PTV and critical normal structures. 
Each field is to be treated daily.
Intensity Modulated Radiation Therapy (IMRT)
The use of IMRT is permitted, provided that the institution has been credentialed by the 
central vendor (QARC) for intrathoracic IMRT treatments. As IMRT results in a greater 
proportion of lung receiving radiation outside the PTV, it is strongly recommended to 
maintain the total lung V5 level at 60% or less.
Documentation
Centers participating in this study will perform heterogeneity corrections for all study 
treatment planning. It is recognized that differences between calculation algorithms in the 
different treatment planning systems may result in dose variations for individual participants. 
A list of acceptable dose calculation algorithms that most accurately account for tissue 
heterogeneities can be found on the QARC website (www.qarc.org).
Portal imaging of each field of 3DCRT or orthogonal images that localize the isocenter 
placement of IMRT must be obtained on the first day of therapy in accordance with standard 
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department protocols but will not be submitted. The films must be compared to localization 
films and discrepancies corrected.
Weekly verification via orthogonal isocenter images are required to be taken. Images may be 
taken more often at the discretion of the treating physician. This verification information can 
be gathered also with a cone-beam CT or other CT devices that are present in the treatment 
room.
Dose volume histograms will be generated for PTV, both lungs, lungs minus PTV, spinal 
cord, esophagus, and heart. 
Organs at Risk
Normal tissue constraints shall be prioritized in the following order for treatment planning:
1 = spinal cord, 2 = lungs, 3 = heart, 4 = esophagus, and 5 = brachial plexus
When there is gross disease in close proximity to the esophagus or brachial plexus, it may not 
be possible to meet this constraint and give full dose to the gross disease. The dose coverage 
of the PTV will take precedence over a non-critical organ at risk (esophagus or brachial 
plexus only) structure in close proximity.
Spinal cord: The spinal canal will be contoured and taken to represent the spinal cord and 
should be contoured from the top of the CT simulation/cricoid to the bottom of the CT 
simulation/L2. The spinal cord dose limit is the highest priority dose constraint and must be 
met irrespective of other constraints. No more than 0.03 cc of the spinal cord may receive 
greater than 50.0 Gy total dose. 
Lungs: The dose-volume constraint to the lungs is the second highest priority and must be 
met, except if it conflicts with spinal cord dose constraints. The volume of both lungs (total 
lung volume minus GTV) that receive more than 20 Gy (V20) must not exceed 31%. V20s 
up to 35% will be permitted and viewed as a minor deviation. Lung V5 must be limited to 
≤60%. A minor deviation will be considered a V5 of up to 65%.
Heart: The heart will be contoured on all slices. The cranial border will include the 
infundibulum of the right ventricle and the apex of both atria and exclude the great vessels as 
much as possible. The caudal border is defined as the lowest part of the left ventricle that is 
distinguishable from the liver. The following limits are recommended: Mean heart dose ≤20 
Gy. A mean heart dose of up to 26 Gy will be considered a minor deviation.
Esophagus: The esophagus contour must include the mucosa, submucosa, and all muscular 
layers out to the fatty adventitia, from the bottom of the cricoid cartilage to the 
gastroesophageal junction. No more than 0.03 cc of the esophagus may receive >63 Gy. The 
mean dose to the esophagus must be ≤34 Gy. The esophagus must not be circumferentially 
irradiated with greater than 60 Gy at any level.
Brachial Plexus: The ipsilateral brachial plexus must be contoured for upper lobe tumors. 
No more than 0.03 cc of the brachial plexus must receive >63 Gy.
If, after participant enrollment, it is discovered the total tumor dose has to be limited to stay 
within normal tissue dose constraints and falls below 60 Gy in 30 fractions, the treated 
participants will be eligible for toxicity evaluation, but additional participants will be 
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recruited to ensure the appropriate number of participants are treated at the prescribed dose of 
radiation.
Toxicities documented during radiation therapy will be recorded using the CTCAE version 
4.0 scale. Toxicities arising more than 90 days since the completion of radiation therapy and
attributed to radiation will be assessed according to CTCAE criteria and counted as late 
radiation toxicities. As both cohorts use pembrolizumab monotherapy, the toxicities 
encountered during pembrolizumab monotherapy and during the 30-day follow-up period 
will not be declared late radiation toxicities unless the events are confined to tissue within the 
radiation treatment volume.
Treatment Quality Assurance and Compliance with Protocol-Defined
Radiation Prescription (Quality Control)
This study will require a pre-treatment review of the treatment plan for each subject. Details 
regarding the submission process and the data to be submitted can be found in the RT QA 
Manual.
QARC will evaluate the treatment plan for each subject within 3 business days of receiving 
complete data. Feedback from this review will be sent via email to the treating Radiation 
Oncologist, Principal Investigator, study staff and clinical research associate. Corrective 
action in response to the QARC pretreatment review must be implemented promptly. A 
modified treatment plan must be resubmitted for review, but treatment with the modified plan 
may begin prior to review unless otherwise specified. If requested changes are not made, an 
immediate response from the radiation oncologist is expected.
8.1.10 Discontinuation and Withdrawal
Participants who discontinue study treatment prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the Discontinuation visit should be performed (at the time of withdrawal). Any 
AEs which are present at the time of withdrawal should be followed in accordance with the 
safety requirements outlined in Section 8.4.
Survival Follow-up
Participants who withdraw consent for treatment and/or imaging are encouraged to remain on 
the non-invasive Survival Follow-up portion of the study. The only procedures associated 
with this phase are telephone contacts to assess survival status and the current state of the 
participant’s NSCLC. The non-invasive nature and societal benefit of Survival Follow-up 
(every 12 weeks ± 14 days) must be explained to the participant by the site staff, particularly 
when discontinuing treatment or imaging. Participants may withdraw their consent at any 
time from any or all portions of the study.
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the principal investigator for the main study. If 
medical records for the main study are still available, the investigator will contact the 
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Sponsor using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's consent for future biomedical research will be withdrawn. A 
letter will be sent from the Sponsor to the investigator confirming the withdrawal. It is the 
responsibility of the investigator to inform the participant of completion of withdrawal. Any 
analyses in progress at the time of request for withdrawal or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
study data and results. No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
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.
8.1.11 Participant Blinding/Unblinding
This is an open label study; there is no blinding for this study.
8.1.12 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 is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
Efficacy Assessments 
8.2.1
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the central imaging vendor can be 
found in the Site Imaging Manual. Tumor imaging is strongly preferred to be acquired by 
CT. MRI may be used when CT with iodinated contrast is contraindicated or when local 
practice mandates it. 
Brain imaging is required for all participants at screening. MRI is preferred; however, CT 
imaging will be acceptable if MRI is medically contraindicated.
The same imaging technique regarding modality, ideally the same scanner, and the use of 
contrast must be used in a participant throughout the study to optimize the reproducibility of 
the assessment of existing and new tumor burden.
Participant eligibility will be determined using local assessment (investigator assessment) 
based on RECIST 1.1 All scheduled images for all study participants from the sites will be 
submitted to the central imaging vendor. In addition, images (including via other modalities) 
that are obtained at an unscheduled time point to determine disease progression, and imaging 
obtained for other reasons that demonstrate radiologic progression, must also be submitted to 
the central imaging vendor.
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When the investigator identifies radiographic progression per RECIST 1.1, the central 
imaging vendor will perform expedited verification of radiologic disease progression and 
communicate the results to the study site and Sponsor. Treatment must continue until 
progressive disease (PD) has been centrally verified if the participant is clinically stable. 
Regardless of whether PD is verified, if the Investigator considers the participant has 
progressed, but elects to implement modified RECIST 1.1 for immune-based therapeutics 
(iRECIST), the investigator will assess for confirmation of progression by iRECIST at 
subsequent time points. Images must continue to be submitted to the central imaging vendor.
Initial Tumor Imaging
Initial tumor imaging must be performed within 42 days prior to the first dose of trial 
treatment.
MRI is strongly preferred for imaging of the brain; head CT imaging with contrast is 
preferred if MRI is medically contraindicated. If the participant is unable to have CT 
contrast, a head CT without contrast is acceptable. Scans performed as part of routine clinical 
management (ie, CT of the chest, abdomen and pelvis, whole body PET/CT and brain MRI) 
are acceptable for use as the baseline scan if they are of diagnostic quality, include all 
required anatomy, and performed within 42 days prior to randomization. These scans will be 
considered the baseline assessments for the study. PET/CT if acquired within 60 days of 
randomization does not need to be repeated. Pelvic CT required at baseline only and does not 
need to be repeated on-study unless clinically indicated.
Tumor Imaging During the Study
The first imaging assessment during treatment must be performed at 9 weeks (63 ± 7 days) 
from Cycle 1 Day 1. Subsequent imaging must be performed every 9 weeks (63 ± 7 days)
until Week 54 or more frequently if clinically indicated. Imaging timing must follow 
calendar days and must not be adjusted for delays in cycle dosing or radiotherapy.
Imaging must continue to be performed until PD is identified by the investigator and verified 
by BICR, the start of new anticancer treatment, withdrawal of consent for imaging, or death, 
whichever occurs first; however, if the investigator elects to continue treatment and follow 
iRECIST after initial radiographic PD, imaging must continue, and images must be submitted
to the central imaging vendor. In addition, images (including via other modalities) that are 
obtained at an unscheduled time point and determine PD, as well as imaging obtained for 
other reasons, but captures radiologic progression, must be submitted to the central imaging 
vendor.
Objective response (PR or CR) must be confirmed by a repeat imaging assessment. The 
imaging for confirmation of response may be performed no earlier than 4 weeks after the first 
indication of a response. Participants will then return to the regular imaging schedule, 
starting with the next scheduled imaging time point. Participants who receive additional 
imaging for confirmation do not need to undergo the next scheduled tumor imaging if the 
confirmatory scans are taken within 4 weeks of the next scheduled tumor scan. Tumor 
imaging may resume at the subsequent scheduled imaging time point. Note: response does 
not need to be verified in real time by the central imaging vendor.
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Per iRECIST (Section 8.2.1.5), PD must be confirmed by the site 4 to 8 weeks after central 
verification of the site-assessed first radiologic evidence of PD in clinically stable 
participants. Participants who have unconfirmed PD may continue on treatment at the 
discretion of the investigator until progression is confirmed by the site, provided they have 
met the conditions detailed in Section 8.2.1.5. Participants who receive confirmatory imaging 
do not need to undergo the next scheduled tumor imaging if the confirmatory scans are taken 
within 4 weeks of the next scheduled tumor scan. Tumor imaging may resume at the 
subsequent scheduled imaging time point if clinically stable. Participants who have 
confirmed PD by iRECIST as assessed by the site will discontinue the treatment, unless
treatment beyond confirmed progression is approved by the Sponsor, as detailed in Section 
8.2.1.5.
End of Treatment and Follow-up Imaging
For participants who discontinue study treatment, tumor imaging must be performed at the 
time of treatment discontinuation (± 4 week window). If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation 
is not mandatory. For participants who discontinue study treatment due to documented PD, 
this is the final required tumor imaging if the Investigator elects not to implement iRECIST.
For participants who discontinue study treatment without documented PD, every effort must
be made to continue monitoring disease status by tumor imaging every 9 weeks (±7 days)
until Week 54, and then every 12 weeks (± 14 days) until Week 150, and then every 24 
weeks (± 28 days) until PD, the start of new anticancer treatment, pregnancy, death, 
withdrawal of consent, or the end of the study, whichever occurs first. The timing of Follow-
up Visits must be scheduled to coincide with the participant’s follow-up imaging. The 
imaging requirements in the study are considered complete once a participant undergoes 
BICR-verified PD, starts new anti-neoplastic therapy, is lost to follow-up or experiences 
death. The participant will then enter the Survival Follow-up.
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be applied by the BICR as the primary measure for assessment of tumor 
response, date of disease progression, and as a basis for all protocol guidelines related to 
disease status (eg, discontinuation of study treatment). 
Although RECIST 1.1 references a maximum of 5 target lesions in total and 2 per organ, this
protocol allows a maximum of 10 target lesions in total and 5 per organ, if clinically relevant 
to enable a broader sampling of tumor burden.
Because the study treatment includes both systemic therapy and focal radiation, RT to a
target lesion selected at baseline will not render that lesion non-evaluable, for the purposes of 
RECIST 1.1 assessment. 
In addition to overall assessment by RECIST 1.1, response assessment will include separate 
evaluation of local progression (ie, growth of existing lesions or appearance of lesions within 
the same lung lobe as the primary lesion) and metastatic disease (appearance of lesions 
anywhere else).
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Initial tumor imaging showing site-assessed PD must be submitted to the central imaging 
vendor immediately for verification of PD by BICR. The site will be notified if the BICR 
verifies PD using RECIST 1.1. The first half of the flowchart in Figure 2 illustrates the 
imaging flow involving verification of PD for clinically stable participants.
iRECIST Assessment of Disease
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor 
response and progression, and make treatment decisions. When clinically stable, participants 
must not be discontinued until progression is confirmed by the Investigator, working with 
local radiology, according to the rules below. This allowance to continue treatment despite 
initial radiologic PD takes into account the observation that some participants can have a 
transient tumor flare in the first few months after the start of immunotherapy, and then 
experience subsequent disease response. These data will be captured in the clinical database.
A description of the adaptations and iRECIST process is provided here, with additional detail 
in [Seymour, L., et al 2017]. A summary of imaging and treatment requirements after first 
radiologic evidence of progression is provided in Table 11 and illustrated as a flowchart in 
Figure 2.
Assessment at Screening and Prior to RECIST 1.1 Progression
Until radiographic progression based on RECIST 1.1, there is no distinct iRECIST 
assessment.
Assessment and Decision at RECIST 1.1 Progression
For participants who show evidence of radiological PD by RECIST 1.1 as determined by the 
Investigator, the Investigator will decide whether to continue a participant on study treatment 
until repeat imaging is obtained using iRECIST for participant management (see Table 11
and Figure 2). This decision by the investigator must be based on the participant’s overall 
clinical stability.
Clinical stability is defined as the following:

Absence of symptoms and signs indicating clinically significant progression of 
disease.

No decline in ECOG performance status.

No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care.
Any participant deemed clinically unstable must be discontinued from study treatment upon 
central verification of site-assessed first radiologic evidence of PD, and is not required to 
repeat tumor imaging for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per Investigator assessment. Images must continue to be sent in to the 
central imaging vendor for potential retrospective BICR.
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Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:

Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir
o
Note: the iRECIST publication uses the terminology “sum of measurements”, 
but “sum of diameters” will be used in this protocol, consistent with the 
original RECIST 1.1 terminology.

Unequivocal progression of non-target lesion(s) identified at baseline

Development of new lesion(s)
iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, 
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression.
At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or non-measurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target. 
The sum of diameters of these lesions will be calculated, and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively 
as New Lesions – Non-target.
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the participant will be classified as progression confirmed 
(with an overall response of iCPD), persistent unconfirmed progression (with an overall 
response of iUPD), or as showing disease stability or response (immune [i]SD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:

Any of the factors that were the basis for the initial iUPD show worsening
o
For target lesions, worsening is a further increase in the sum of diameters of 
≥5 mm, compared to any prior iUPD time point
o
For non-target lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the 
“unequivocal” standard of RECIST 1.1
o
For new lesions, worsening is any of these:

An increase in the new lesion sum of diameters by ≥5 mm from a prior 
iUPD time point 
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
Visible growth of new non-target lesions 

The appearance of additional new lesions

Any new factor appears that would have triggered PD by RECIST 1.1
Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:

None of the progression-confirming factors identified above occurs AND

The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation imaging proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:

None of the progression-confirming factors identified above occurs, AND

The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset”. This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
NOTE: If a participant has radiographic iCPD as defined above, but the participant is 
achieving a clinically meaningful benefit, and there is no further increase in the tumor burden 
at the confirmatory tumor imaging, an exception to continue study treatment may be 
considered following consultation with the Sponsor. In this case, if study treatment is 
continued, tumor imaging must continue to be performed following the intervals as outlined 
in Section 8.2.1.2 and be submitted to the central imaging vendor.
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Detection of Progression at Visits after Pseudo-progression Resolves
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events:

Target lesions
o
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from 
nadir) either for the first time, or after resolution of previous pseudo-
progression. The nadir is always the smallest sum of diameters seen during the 
entire study, either before or after an instance of pseudo-progression.

Non-target lesions
o
If non-target lesions have never shown unequivocal progression, their doing 
so for the first time results in iUPD.
o
If non-target lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth 
of non-target lesions, taken as a whole.

New lesions
o
New lesions appear for the first time
o
Additional new lesions appear
o
Previously identified new target lesions show an increase of ≥5 mm in the 
new lesion sum of diameters, from the nadir value of that sum
o
Previously identified non-target lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process is repeated (see Assessment at the Confirmatory Imaging above). 
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception: if new lesions occurred at a prior instance of iUPD, and at the confirmatory 
scan the burden of new lesions has increased from its smallest value (for new target lesions, 
the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve to iSD or 
iPR. It will remain iUPD until either a decrease in the new lesion burden allows resolution to 
iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in [Seymour, L., et al 2017].
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Table 11
Imaging and Treatment after First Radiologic Evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD by 
RECIST 1.1 that has 
been verified by 
BICR
Repeat imaging at 
4 to 8 weeks to 
confirm PD
May continue study 
treatment at the 
Investigator’s 
discretion while 
awaiting 
confirmatory tumor 
imaging by site by 
iRECIST.
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
Investigator’s 
discretion only
Discontinue 
treatment
Repeat tumor 
imaging confirms 
PD (iCPD) by 
iRECIST per 
Investigator 
assessment
No additional 
imaging required
Discontinue 
treatment 
(exception is 
possible upon 
consultation with 
the Sponsor)
No additional 
imaging required
Not applicable
Repeat tumor 
imaging shows 
iUPD by iRECIST 
per Investigator 
assessment
Repeat imaging at 
4 to 8 weeks to 
confirm PD. May 
occur at next 
regularly scheduled 
imaging visit.
Continue study 
treatment at the 
Investigator’s 
discretion.
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
Investigator’s 
discretion only.
Discontinue 
treatment
Repeat tumor 
imaging shows iSD, 
iPR or iCR by 
iRECIST per 
Investigator 
assessment
Continue regularly 
scheduled imaging 
assessments 
Continue study 
treatment at the 
Investigator’s 
discretion
Continue regularly 
scheduled imaging 
assessments 
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable 
per investigator’s 
discretion. Next 
tumor image 
should occur 
according to the 
regular imaging 
schedule
Note:  If progression has been centrally verified, further management is by the site, based on iRECIST. Any further 
imaging should still be submitted to the central imaging vendor, but no rapid review will occur.
BICR=blinded independent central review; iCPD=iRECIST confirmed progressive disease; iCR=iRECIST complete 
response; iPR=iRECIST partial response; iRECIST=modified RECIST for Immune-based Therapeutics; iSD=iRECIST 
stable disease; iUPD=iRECIST unconfirmed progressive disease; PD=progressive disease; RECIST 1.1=Response 
Evaluation Criteria in Solid Tumors 1.1.
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Figure 2
Imaging and Treatment for Clinically Stable Participants after First Radiologic 
Evidence of PD Assessed by the Investigator
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the 
screening period and treatment discontinuation. 
Clinically significant abnormal findings at screening must be recorded as medical history. 
After the first dose of trial treatment, new clinically significant abnormal findings must be 
recorded as AEs.
Refer to Appendix 7 for country-specific requirements.
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Directed Physical Examination
The investigator or qualified designee will perform a directed physical exam as clinically 
indicated prior to study treatment administration. Cycles that do not require a full physical
exam are defined in the SoA. 
New clinically significant abnormal findings after the first dose of treatment must be
recorded as AEs.
Refer to Appendix 7 for country-specific requirements.
8.3.2
Vital Signs, Weight, and Height
The investigator or qualified designee will measure vital signs and weight at screening, prior 
to the administration of each dose of pembrolizumab, end of treatment, and during the 30-day 
Safety Follow-up visit as specified in the SoA.
Vital signs include temperature, pulse, heart rate, respiratory rate and blood pressure.
Height will be measured at screening only.
8.3.3
Electrocardiograms
A standard 12-lead electrocardiogram (ECG) will be performed using local standard 
procedures once at screening. Additional ECGs at other time points may be performed as 
clinically necessary.
Clinically significant abnormal findings must be recorded as medical history.
8.3.4
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status a screening (within 10 days 
prior to treatment allocation and within the allowed visit windows at subsequent visits), prior 
to the administration of study treatment, and during the 30 Day Safety Follow-up as specified 
in the SoA. 
The ECOG performance scale is outlined in Appendix 5.
8.3.5
Pulmonary Function Tests
The investigator or qualified designee will assess pulmonary function at screening.
Pulmonary function tests include pulse oximetry, FEV1, forced vital capacity, DLCO, and 
total lung capacity.
8.3.6
Clinical Safety Laboratory Assessments
Refer to Appendix 6 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency. 
●
The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
case report form (CRF). The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which are 
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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 6, must be 
conducted in accordance with the laboratory manual and the SoA.
●
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 30 days after the last dose of study 
treatment, every attempt should be made to perform repeat assessments until the 
values return to normal or baseline or if a new baseline is established as determined 
by the investigator. 
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
Laboratory tests for screening are to be performed within 10 days prior to the first dose of 
trial treatment. After Cycle 1, lab samples can be collected up to 3 days prior to Day 1 of 
subsequent cycles. Participants may be dosed in subsequent cycles after Cycle 1 Day 1 while 
thyroid function tests are pending. Refer to the SoA for the timing of laboratory assessments.
Laboratory tests for hematology, chemistry, and urinalysis are specified Appendix 6. 
Pregnancy Test
All women who are being considered for participation in the study, and who are not 
surgically sterilized or postmenopausal (as defined in Appendix 3), must be tested for 
pregnancy during screening and/or within 72 hours of the first dose of study treatment. 
Pregnancy tests within 24 hours prior to treatment allocation to determine eligibility will be 
required only in those regions where this is required via documented regulatory request, 
subsequently approved by the Sponsor.
Pregnancy testing including monthly pregnancy testing must be conducted as per local 
regulations where applicable. A serum test can be considered if urine test is not appropriate. 
Refer to Appendix 7 for country-specific details.
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 or borderline-positive test 
result.
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events 
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 4.
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Progression of the cancer under study is not considered an AE as described in Section 8.4.5 
and Appendix 4.
AE, SAEs, and other reportable safety events will be reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally authorized representative). 
The investigator, who is a qualified physician, and any designees are responsible for 
detecting, assessing, documenting, and reporting events that meet the definition of an AE or 
SAE as well as other reportable safety events. Investigators remain responsible for following 
up AE, SAEs, and other reportable safety events for outcome according to Section 8.4.3.
Adverse events will not be collected for participants during the prescreening period (for 
determination of archival tissue status) as long as that participant has not undergone any 
protocol-specified procedure or intervention. If the participant requires a blood draw, fresh 
tumor biopsy etc., the participant is first required to provide consent to the main study and 
AEs will be captured according to guidelines for standard AE reporting.
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 consent form is signed 
but before treatment allocation/randomization must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event causes the 
participant to be excluded from the study, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, or a procedure. 
●
All AEs from the time of treatment allocation/randomization through 30 days following 
cessation of study treatment must be reported by the investigator. 
●
All AEs meeting serious criteria, from the time of treatment allocation/randomization 
through 90 days following cessation of study treatment, or 30 days following cessation 
of study treatment if the participant initiates new anticancer therapy, whichever is earlier 
must be reported by the investigator. 
●
All pregnancies and exposure during breastfeeding, from the time of treatment 
allocation/randomization through 180 days following cessation of treatment in Cycles 1 
through 3 or for 120 days following cessation of study treatment in Cycles 4 through the 
end of treatment, or 30 days following cessation of study treatment if the participant 
initiates new anticancer therapy must be reported by the investigator. 
●
Additionally, any SAE brought to the attention of an investigator at any time outside of 
the time period specified above must be reported immediately to the Sponsor if the event 
is considered to be drug-related.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 12.
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Table 12
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Time Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to 
SPONSOR:
Consent to 
Randomization/ 
Allocation
Randomization/ 
Allocation 
through Protocol-
Specified Follow-
up Period
After the Protocol 
Specified Follow-up 
Period
Non-Serious Adverse 
Event (NSAE) 
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse 
Event (SAE) 
including Cancer and 
Overdose
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- 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 (require 
regulatory reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- Potential drug-
induced liver 
injury (DILI)
- Require 
regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (Do not 
require regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 
calendar days 
of learning of 
event
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AE and/or SAE and other reportable 
safety events. Open-ended and nonleading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.
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 AE, SAE, and other reportable safety events 
including pregnancy and exposure during breastfeeding, events of clinical interest (ECIs), 
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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 4.
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 towards the safety of 
participants and the safety of a study treatment under clinical investigation are met. 
●
The Sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study treatment under clinical 
investigation. All AEs will be reported to regulatory authorities, IRB/IECs and 
investigators in accordance with all applicable global laws and regulations, ie, per 
ICH Topic E6 (R2) Guidelines for GCP.
●
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy 
and forwarded to investigators as necessary.
●
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file 
it along with the IB and will notify the IRB/IEC, if appropriate according to local 
requirements.
8.4.5
Disease-related Events and/or Disease-related Outcomes Not Qualifying as AEs 
or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 8.4.1. 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the study. Any suspected endpoint which upon review 
is not progression of the cancer under study will be forwarded to Global Pharmacovigilance
as an SAE within 24 hours of determination that the event is not progression of the cancer 
under study.
8.4.6
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), including the pregnancy of a male participant's female 
partner, that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as 
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serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and serious adverse events are also known as ECIs and must be reported 
to the Sponsor.
Events of clinical interest for this study include: 
1. an overdose of Sponsor's product, as defined in Section 8.5, that is not associated with 
clinical symptoms or abnormal laboratory results.
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow-up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent).
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose exceeding the prescribed 
dose for pembrolizumab by ≥5 times the indicated dose (any dose of 1000 mg or greater). No 
specific information is available on the treatment of overdose of pembrolizumab. In the event 
of overdose, pembrolizumab should be discontinued and the participant should be observed 
closely for signs of toxicity. Appropriate supportive treatment should be provided if 
clinically indicated.
Pharmacokinetics
To evaluate the immunogenicity and exposure of pembrolizumab in this indication, sample 
collections for analysis of anti-pembrolizumab antibodies (ADA) and PK are currently 
planned as shown in the SoA. Blood samples for PK and ADA collected may be stored. 
Analysis will be performed only if required. If ongoing PK and/ADA sampling is deemed to 
be unnecessary by the Sponsor, it may be reduced or discontinued.
8.6.1
Blood Collection for Serum Levels of Pembrolizumab
Pre-dose trough PK samples will be collected at Cycles 1 2, 4, 8, 12, and 16. All pre-dose 
trough samples must be drawn within 24 hours before infusion of pembrolizumab. 
Post-dose peak PK samples will be collected at Cycle 1 and 8. All post-dose PK samples
must be drawn within 30 minutes of the completion of the pembrolizumab infusion. 
Sample collection, storage and shipment instructions will be provided in the Laboratory 
Manual.
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8.6.2
Blood Collection of Anti-Pembrolizumab Antibodies (ADA)
Pre-dose ADA samples will be collected at Cycles 1 2, 4, 8, 12, and 16. All pre-dose samples 
must be drawn within 24 hours before infusion of pembrolizumab. 
Sample collection, storage and shipment instructions will be provided in the Laboratory 
Manual.
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study
Biomarkers
To identify novel biomarkers, the following biospecimens to support exploratory analyses of 
cellular components (eg, protein, RNA, DNA, metabolites) and other circulating molecules 
will be collected from all participants in this study as specified in the SoA:

Archival tumor tissue

Blood for genetic analysis

Blood for RNA analyses

Blood for serum biomarker analyses

Blood for plasma biomarker analyses

Blood for circulating tumor DNA (ctDNA)
Sample collection, storage and shipment instructions for the exploratory biomarker 
specimens will be provided in the laboratory manual.
The sample for genetic analysis should be drawn for planned exploratory biomarker research. 
This sample will not be collected at the site if there is either a local law or regulation 
prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for 
these purposes. If the sample is collected, leftover extracted DNA will be stored for future 
biomedical research if the participant signs the future biomedical research consent. If the 
genetic sample collection is not approved, but future biomedical research is approved and 
consent is given, this sample will be collected for the purpose of future biomedical research
Future Biomedical Research Sample Collection 
If the participant signs the future biomedical research consent, the following specimens will 
be obtained as part of future biomedical research:

DNA for future research

Leftover RNA

Leftover plasma or derivative for ctDNA

Leftover study tumor tissue

Leftover plasma from plasma biomarker analyses

Leftover serum from serum biomarker analyses
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Tumor Tissue Collection 
A tumor tissue sample (core, incisional, or excisional biopsy) must be provided to the central 
laboratory within 42 days prior to treatment allocation. 
FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archival
tissue. In cases where the core, incisional, or excisional biopsy is not available or cannot be 
obtained due to anatomical location of tumor, a cell block obtained through EUS/EBUS may 
be submitted after sponsor consultation. If submitting unstained cut slides, newly cut slides 
must be submitted to the testing laboratory within 14 days from the date slides are cut.
Details pertaining to tumor tissue submission can be found in the Procedures Manual.
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for planned genetic analysis samples 
will be provided in the Procedures Manual. The timing of the samples is listed in the SoA.
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
above in Section 8.
8.12.1 Screening
Approximately 42 days prior to treatment allocation, potential participants will be evaluated 
to determine that they fulfill the entry requirements as set forth in Section 5. 
Screening procedures may be repeated once after consultation with the Sponsor Clinical 
Director and documentation of the approval via a Sponsor Communication Form.
Participants who are rescreened will retain their original screening number.
Written consent must be obtained prior to performing any protocol-specific procedure. 
Results of a test performed prior to the participant signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. Screening procedures are to be completed within approximately 42 days prior to the 
first dose of study treatment except for the following:

Evaluation of ECOG is to be performed within 10 days prior to the first dose of study 
treatment.

For WOCBP, a urine or serum pregnancy test will be performed within 72 hours (or 
within 24 hours in those regions where it is required) prior to the first dose of study 
treatment. If urine pregnancy results cannot be confirmed as negative, a serum 
pregnancy test performed by the local study site laboratory, will be required.

Laboratory tests are to be performed within 10 days prior to the first dose of study 
treatment. 

Tumor imaging must be performed within 42 days prior to the first dose of study 
treatment.
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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. 
8.12.2 Treatment Period
Visit requirements are outlined in Section 1.3 SoA. Specific procedure-related details are 
provided in Section 8. 
Unless otherwise specified, assessments/procedures are to be performed prior to the first dose 
of treatment for each cycle. Unless otherwise specified, the window for each visit is ±3 days.
8.12.3 Post-treatment Period
At the end of treatment, each participant will be followed for a minimum of 30 days for AE 
monitoring. Serious AEs occurring within 90 days following cessation of treatment, or 30 
days following cessation of treatment if the participant initiates new anticancer therapy, 
will be collected, whichever is earlier.
Participants will have post-treatment follow-up for disease status, including radiographic 
imaging, until initiating a non-study anti-cancer treatment, experiencing disease 
progression, death, withdrawing consent, becoming lost to follow-up, or end of study.
All participants will be followed for overall survival until death, loss to follow up or 
withdrawal of consent. 
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
30 Day Safety Follow-up Visit
The mandatory 30-day Safety Follow-up Visit must be conducted approximately 30 days 
after the last dose of study treatment or before the initiation of a new anticancer treatment, 
whichever comes first. 
If a participant has a discontinuation visit ≥27 days after the last dose of study treatment, the 
Safety Follow-up Visit is not required.
Follow-up Visits
Participants who discontinue study treatment for a reason other than documented PD will 
move into the Follow-up Phase. Follow-up visits after treatment discontinuation must
coincide with imaging schedule until disease progression, death or end of study. Information 
regarding post-study anticancer treatment will be collected if a new treatment is initiated.
Every effort must be made to collect imaging until the start of new anticancer therapy, 
confirmed PD, or death. Information regarding post-study anticancer treatment will be 
collected if new treatment is initiated.
Survival Follow-up
Participants who experience confirmed PD or start a new anticancer therapy, will move into 
the Survival Follow-up Phase and must be contacted by telephone approximately every 12 
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weeks (± 14 days) to assess for survival status until death, withdrawal of consent, or the end 
of the trial, whichever occurs first.
Participants may withdraw their consent at any time from any or all portions of the study. 
Participants who withdraw consent for treatment and/or imaging are encouraged to remain on 
the non-invasive Survival Follow-up portion of the study. The only procedures associated 
with this phase are telephone contacts to assess survival status and the current state of the 
participant’s NSCLC. The non-invasive nature and societal benefit of Survival Follow-up 
must be explained to the participant by the site staff, particularly when discontinuing 
treatment and imaging.
Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested at any time during the course of the study by the 
Sponsor. For example, updated survival status may be requested prior to but not limited to an 
external DMC review, interim and/or final analysis. Upon Sponsor notification, all 
participants who do not/will not have a scheduled study visit or study contact during the 
Sponsor defined time period will be contacted for their survival status (excluding participants 
that have a previously recorded death event in the electronic data collection tool).
9. Statistical Analysis Plan 
This section outlines the statistical analysis strategy and procedures for the study. If changes 
are made to primary and/or key secondary hypotheses or the statistical methods related to 
those hypotheses after the study has begun, but prior to final database lock, the protocol will 
be amended (consistent with ICH guideline E9). 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 Statistical Analysis Plan (sSAP) and referenced 
in the Clinical Study Reports (CSR) for the study. Post hoc exploratory analyses will be 
clearly identified in the CSR. Separate analysis plans (ie, separate documents from the sSAP) 
will be developed to detail PK and biomarker analyses.
Statistical Analysis Plan Summary
Key elements of the Statistical Analysis Plan are summarized. The comprehensive plan is 
provided in Section 9.2 through Section 9.12.
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Study Design 
Overview
A Phase 2, open-label, multi-center, nonrandomized, multi-
cohort, parallel group, uncontrolled study of pembrolizumab in 
combination with platinum doublet chemotherapy and standard 
thoracic radiotherapy in participants with unresectable locally 
advanced Stage III NSCLC.
Treatment 
Assignment
Approximately 216 participants will be enrolled into 2 cohorts
(108 participants per cohort). The choice of chemotherapy will be 
determined by the investigator prior to treatment allocation. 
Participant with squamous NSCLC are eligible only for Cohort 
A.
Cohort A: Participants will receive 1 cycle of carboplatin AUC6 
with paclitaxel 200 mg/m2 and pembrolizumab 200 mg on Day 1.
Approximately 3 weeks later participants will receive carboplatin 
AUC2 with paclitaxel 45 mg/m2 administered weekly for 6 weeks 
with 2 cycles of pembrolizumab 200 mg administered every Q3W
in conjunction with standard TRT. To conclude the study 
treatments, participants will receive an additional 14 cycles of 
pembrolizumab 200 mg administered Q3W.
Cohort B: Participants will receive 3 cycle of cisplatin 75 mg/m2
with pemetrexed 500 mg/m2 and pembrolizumab 200 mg on 
Day 1. Treatment will be given in conjunction with standard TRT
in Cycles 2 and 3. To conclude the study treatments, participants 
will receive an additional 14 cycles of pembrolizumab 200 mg 
administered Q3W.
Analysis Population
Efficacy: All Participants as Treated (APaT)
Safety: All Participants as Treated (APaT)
Primary Endpoints
-
Grade 3 or higher pneumonitis
-
Confirmed complete response or partial response based on 
RECIST 1.1 as assessed by BICR. 
Secondary Endpoints
-
PFS based on RECIST 1.1 as assessed by BICR
-
OS
Statistical Method for 
Key Efficacy 
Analyses
The point estimate of ORR and a 90% CI will be provided using 
the Clopper-Pearson method. Confidence intervals of 80% and 
95% will be provided as additional summaries.
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Statistical Method for 
Key Safety Analyses
For the primary endpoint of percentage of participants with Grade
3 or higher pneumonitis, the point estimate and a 90% CI will be 
provided using the Clopper-Pearson method. Confidence intervals 
of 80% and 95% will be provided as additional summaries. The 
overall analysis of safety will follow a tiered approach. Other 
than percentage of participants with Grade 3 or higher
pneumonitis, there are no Tier 1 safety parameters in this trial. All 
other safety parameters are considered either Tier 2 or Tier 3. 
Tier 2 parameters will be assessed via point estimates with 95% 
CIs based on Clopper-Pearson method. Only point estimates will 
be provided for Tier 3 safety parameters.
Interim Analyses
Multiple interim analyses based on sequential monitoring 
procedure will be performed to allow the study to stop if the 
percentage of participants with Grade 3 or higher pneumonitis is 
unacceptably high, stop for futility if the ORR is low, or stop to 
enable rapid progression to Phase 3 if the percentage of 
participants with Grade 3 or higher pneumonitis is very low and 
the ORR is high. The decision rule and other statistical details are 
further described in Section 9.7. 
The 2 cohorts might be combined for the study analysis if the 
pneumonitis rates in 2 cohorts are similar.
Results will be reviewed by an external DMC.
Multiplicity
No multiplicity adjustment is planned. 
Sample size
The planned sample size is approximately 216 participants in 2
treatment cohorts (108 participants per cohort). At overall one-
sided 5% alpha level and with maximum sample size of 108, the 
study will provide 83% power to demonstrate Grade 3 or higher
pneumonitis is less than 10% if the true rate is 3% in a cohort.
Responsibility for Analyses/In-house Blinding
The interim and final statistical analyses of the data from this study will be the responsibility 
of the Clinical Biostatistics Department of the Sponsor.
The trial will be conducted as an open-label study. There is no randomization in the study. 
The treatment assignment and allocation will be tracked in interactive response technology.
Planned interim analyses are described in Section 9.7.
To supplement the study monitoring outlined in this protocol, an external DMC will monitor 
the interim data from this study. The details regarding the external DMC is provided in 
Section 10.1.7 of this protocol and in DMC charter. The interim analyses performed by the 
clinical Biostatistics Department of the Sponsor internally will be reviewed by DMC
periodically. The DMC will make recommendations to the Executive Oversight Committee 
(EOC) regarding steps to ensure both participant safety and the continued ethical integrity of 
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the study. Also, the DMC will review interim study results, consider the overall risk and 
benefit to study participants and recommend to the EOC whether the study should continue 
in accordance with the protocol.. 
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated are listed below. 
9.4.1
Primary Endpoints
Grade 3 or higher pneumonitis: percentage of participants with Grade 3 or higher 
pneumonitis is percent of participants who have developed Grade 3 to 5 pneumonitis.
Confirmed complete response or partial response: ORR is the proportion of participants who 
have a confirmed CR or PR per RECIST 1.1 based on BICR.
9.4.2
Secondary Endpoints
Progression-free survival: the time from enrollment to the first documented local recurrence 
or distant metastasis per RECIST 1.1 based on BICR (modified to follow a maximum of 10 
target lesions and a maximum of 5 target lesions per organ) or death due to any cause, 
whichever occurs first. See Section 9.6.1 for the definition of censoring.
Overall survival: the time from enrollment to death due to any cause.
Safety and tolerability: AEs and discontinuations due to AEs.
9.4.3
Tertiary/Exploratory Endpoints
1. Time to distant metastases: the time from enrollment to the first documented distant
metastases per RECIST 1.1 based on BICR or death due to any cause, whichever 
occurs first. 
2. Germline genetic variation, genetic (DNA) mutations from tumor, tumor and blood 
RNA variation, proteomics and IHC, and other biomarkers
Analysis Populations
9.5.1
Efficacy Analysis Populations
The APaT population will serve as the population for the primary efficacy analysis. All 
enrolled participants who received at least 1 dose of study treatment will be included in this 
population. 
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 enrolled participants who received at least 1 dose of study 
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treatment. Participants will be analyzed in the treatment cohort corresponding to the study 
treatment they actually received. For most participants, this will be the study treatment cohort
to which they are enrolled. Participants who take incorrect study treatment cohort for the 
entire treatment period will be included in the treatment corresponding to the study treatment 
actually received. Any participant who receives the incorrect study medication for 1 cycle, 
but receives the correct treatment for all other cycles, will be analyzed according to the 
correct treatment cohort and a narrative will be provided for any event that occurs during the 
cycle for which the participant is incorrectly dosed.
At least 1 laboratory measurement obtained subsequent to at least 1 dose of study treatment 
is required for inclusion in the analysis of each specific parameter. To assess change from 
baseline, a baseline measurement is also required.
Statistical Methods
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives based on efficacy parameters including ORR, PFS and OS. Methods related to 
exploratory objectives will be described in the sSAP. 
For the primary endpoint of ORR, the point estimate and a 90% CI will be provided using the 
Clopper-Pearson method [Clopper, C.J. 1934]. Confidence intervals of 80% and 95% using
the Clopper-Pearson method will be provided as additional summaries. Binomial sequential 
testing will be conducted to evaluate ORR, assuming a null ORR of 35% and alternative 
ORR of 50%, with 1-sided type I error of 5% and 1-sided type II error of 5%. An ORR of 
35% was set as the lower threshold based on historical data (Table 1) and an alternative ORR 
rate of 50% was set as the upper threshold for monitoring based on the improvement in ORR 
expected from the study treatment regimen. Participants in APaT population with missing
ORR data will be counted as non-responders.
For the secondary endpoint of PFS, Kaplan-Meier (KM) curves and median estimates from 
the KM curves will be provided as appropriate. Since the disease progression is assessed 
periodically, PD (either local recurrence or distant metastasis) can occur any time in the time 
interval between the last assessment where PD was not documented and the assessment when 
PD is documented. The true date of disease progression will be approximated by the date of 
the first assessment at which PD is objectively documented per RECIST 1.1 by BICR. Death 
is always considered as confirmed PD events. Participants who do not experience a PFS 
event will be censored at the last disease assessment. Sensitivity analyses will be performed 
for comparison of PFS based on the investigator’s assessment.
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 as assessed by BICR, 
2 sensitivity analyses with a different set of censoring rules from the primary analysis will be 
performed. For the primary analysis, if the events (PD or death) are immediately after more 
than 1 missed disease assessment, the data are censored at the last disease assessment prior to 
the missing visits. Also data after new anti-cancer therapy are censored at the last disease 
assessment prior to the initiation of new anti-cancer therapy. The first sensitivity analysis 
follows the intention-to-treat principle. That is, PDs/deaths are counted as events regardless 
of missed study visits or initiation of new anti-cancer therapy. The second sensitivity analysis
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considers discontinuation of treatment or initiation of an anti-cancer treatment subsequent to 
discontinuation of study-specified treatments, whichever occurs later, to be a PD event for 
participants without documented PD or death. If a participant meets multiple criteria for 
censoring, the censoring criterion that occurs earliest will be applied. The censoring rules for
the primary and sensitivity analyses are summarized in 
Table 13.
Table 13
Censoring Rules for Primary and Sensitivity Analyses of Progression-free 
Survival
Situation
Primary Analysis
Sensitivity Analysis 1
Sensitivity Analysis 2
PD or death 
documented after ≤1
missed disease 
assessment, and 
before new anticancer 
therapy, if any
Progressed at date 
of documented PD 
or death
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or 
death
PD or death 
documented 
immediately after ≥2 
consecutive missed 
disease assessments
or after new 
anticancer therapy, if 
any
Censored at last 
disease assessment
prior to the earlier 
date of ≥2 
consecutive missed 
disease assessment 
and new anticancer 
therapy, if any
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or 
death
No PD and no death; 
new anticancer 
treatment is not 
initiated
Censored at last 
disease assessment
Censored at last disease 
assessment
Progressed at treatment 
discontinuation due to 
reasons other than 
complete response; 
otherwise censored at 
last disease assessment 
if still on study
treatment or completed 
study treatment.
No PD and no death; 
new anticancer 
treatment is initiated
Censored at last 
disease assessment 
before new 
anticancer 
treatment.
Censored at last disease 
assessment
Progressed at date of 
new anticancer 
treatment 
PD = progressive disease
For the secondary endpoint of OS, the non-parametric KM method will be used to estimate 
the survival curves. The median estimates from the KM curves will be provided as 
appropriate. Participants without documented death at the time of analysis will be censored at 
the last known alive date. In practice, the date of last known contact will be used.
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A summary of the efficacy analysis methods for the key efficacy endpoints is provided in 
Table 14.
Table 14
Efficacy Analysis Methods for Key Efficacy Endpoints
Endpoint/Variables
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Efficacy Endpoints
ORR - RECIST 1.1 by 
BICR
Exact method based on 
binomial distribution 
(Clopper-Pearson 
method)
APaT
Participants with missing data 
are considered non-
responders.
Secondary Efficacy Endpoints
PFS – RECIST 1.1 by 
BICR
Summary statistics using 
KM method
APaT
Censored according to rules 
in Table 13. 
-
Primary censoring rule
-
Sensitivity analysis 1
-
Sensitivity analysis 2
OS
Summary statistics using 
KM method
APaT
Censored at last known alive 
date
APaT = All Participants as Treated; BICR = blinded independent central review; KM = Kaplan-Meier; ORR=objective 
response rate; OS = overall survival; PFS=progression-free survival; RECIST 1.1 = Response Evaluation Criteria in Solid 
Tumors
9.6.2
Statistical Method for Safety Analyses
Percentage of participants with Grade 3 or higher pneumonitis will be evaluated as primary 
endpoint. The point estimate and a 90% CI will be provided using the Clopper-Pearson 
method [Clopper, C.J. 1934]. Confidence intervals of 80% and 95% will be provided as 
additional summaries. A percentage of participants with Grade 3 or higher pneumonitis of 
10% or more is considered unacceptable, while a percentage of 3% or less is most desirable 
pneumonitis rate. Binomial sequential testing will be conducted to evaluate pneumonitis, 
assuming a null pneumonitis rate of 10% and alternative pneumonitis rate of 3% with 1-sided 
type I error of 5% and 1-sided type II error of 5%. The 2 cohorts might be combined for the 
study analysis if the pneumonitis rates in 2 cohorts are similar at interim analysis.
Safety and tolerability will also be assessed by clinical review of all relevant parameters 
including AEs and laboratory tests.
The analysis of safety results will follow a tiered approach (Table 15). The tiers differ with 
respect to the analyses that will be performed. Percentage of participants with Grade 3 or 
higher pneumonitis is Tier 1 event. Safety parameters including AEs of special interest 
(AEOSI) will be considered Tier 2 or Tier 3. Tier 2 parameters by cohort and combined 
treatment group will be assessed via point estimates with 95% CIs based on Clopper-Pearson 
method; only point estimates by cohort and combined treatment group are provided for Tier 
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3. Membership in Tier 2 requires that at least 10% participants in any cohort, all other AEs
and predefined limits of change will belong to Tier 3.
The threshold of at least 10% participants is chosen for Tier 2 event because participants 
enrolled in this study are in critical conditions and usually experience various adverse events 
of similar types, events reported less frequent than 10% of participants would obscure the 
assessment of overall safety profile and add little to the meaningful interpretation. Because 
many 95% CIs may be provided without adjustment for multiplicity, the CI should be 
regarded as helpful descriptive measure to be used in review, not a formal statistical method 
for AEs and pre-defined limit of change.
Continuous measures such as changes from baseline in laboratory will be considered Tier 3 
safety parameters. Summary statistics for baseline, on-treatment, and change from baseline 
values will be provided by cohort and combined treatment group if appropriate in table 
format.
The percentage of participants with any AE, an AEs of special interest, a drug-related AE, an 
SAE, a Grade 3 to 5 AE, an AE that is both Grade 3 to 5 and drug-related, an AE that is both 
drug-related and serious, an AE that results in dose modification, death, and who 
discontinued due to an AE, will be considered Tier 2 endpoints, 95% CIs will be estimated 
using Clopper-Pearson method.
Table 15
Analysis Strategy for Safety Parameters Excluding Primary Endpoint (Percentage 
of Participants with Grade 3 or Higher Pneumonitis)
Safety 
Tier
Safety Endpoints†
p-values
95% CI per Cohort 
and Combined 
Treatment Group 
if Needed
Descriptive
Statistics
Tier 2
Any AE
X
X
Any Grade 3 to 5 AE
X
X
Any serious AE
X
X
Any drug-related AE
X
X
Any serious and drug-related AE
X
X
Any Grade 3 to 5 and drug-related AE
X
X
Dose modification due to AE
X
X
Discontinuation due to AE
X
X
Death
X
X
Specific AEs, SOC or PDLCs‡  
(incidence ≥10% in one of cohort) 
X
X
Tier 3
Specific AEs, SOCs or PDLCs‡
(incidence <10% in both cohorts)
X
Change from baseline results (labs)
X
† Adverse event references apply to both clinical and laboratory AEs.
‡ Includes only those endpoints not pre-specified as Tier 1 or not already pre-specified as Tier 2 endpoints. 
AE = adverse event; CI = confidence interval; PDLC = Pre-defined limits of change; SOC = system organ class; X = 
results will be provided.
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9.6.3
Summaries of Baseline Characteristics and Demographics
The number and percentage of participants screened, allocated, the primary reasons for 
screening failure, and primary reasons for discontinuation will be displayed. Demographic 
variables, baseline characteristics, and prior and concomitant therapies will be summarized
by descriptive statistics or categorical tables by cohort and combined treatment group if 
appropriate.
Interim Analyses
Continuous interim analyses using binomial sequential testing will be performed in the study 
to allow either treatment cohort to stop if the percentage of participants with Grade 3 or 
higher pneumonitis is unacceptably high (Table 17), stop for futility if the ORR is low
(Table 18), or stop to enable rapid progression to Phase 3 if the percentage of participants 
with Grade 3 or higher pneumonitis is very low (Table 16) and the ORR is high (Table 19). 
The first interim analysis will take place when at least 36 participants have a minimum of 15 
weeks of follow up in either cohort. If the rates of enrollment in two cohorts are different, the 
first interim analysis will occur when the first cohort meets these criteria. The sequential 
monitoring procedure with binomial sequential testing [Romeu, JL 2013] will be used to 
evaluate for percentage of participants with Grade 3 or higher pneumonitis and ORR 
according to rules outlined in Table 16 through Table 19. In the evaluation of pneumonitis, 
number of participants in APaT population will be considered as the monitoring point in the 
binomial sequential testing (Table 16 and Table 17). In the evaluation of ORR, number of 
participants in APaT population, who have a minimum of 15 weeks of follow-up, will be 
considered as the monitoring point in the binomial sequential testing (Table 18 and 
Table 19). 
If 1 of cohorts is dropped due to high pneumonitis rate or low ORR rate, the remaining 
cohort will continue as planned.
The estimated time for the sequential monitoring procedure to start will be approximately 9 
months after the first participant is enrolled. However, the incidence of Grade 3 or higher 
pneumonitis will be closely monitored throughout the study. If Grade 3 or higher 
pneumonitis is observed in 5 or more participants prior to the first interim analysis within a 
cohort, the cohort may be stopped early. The estimated time of the final analysis of the 
sequential monitoring procedure with a maximum of sample size of 108 per cohort will be 
approximately 16 months after the first participant is enrolled.
Timelines assume the 2 cohorts will enroll participants at a reasonably similar pace. In 
reality, enrollment of 1 cohort could be much slower than the other cohort. Enrollment will 
not be paused in either cohort if its enrollment is faster. The similarity of 2 treatment cohorts
will be continuously evaluated after at least 36 participants have completed a minimum of 15 
weeks of follow-up in each cohort. If at an interim analysis the difference of Grade 3 or 
higher pneumonitis rates is observed within 1% between 2 cohorts, then the 2 cohorts will be 
considered similar, and be combined for study analysis. The trial stops when a stopping rule 
is met or once 108 participants have been enrolled. If combination rule is not met, the 
analysis will be based on each cohort. 
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Table 16
Decision Rules for Stopping the Trial for Low Percentage of Participants with 
Grade 3 or Higher Pneumonitis
Monitoring  
Points (# 
Participants)
# Participants 
with Grade 3 
or higher 
Pneumonitis 
to Indicate 
Low 
Pneumonitis 
Rate
Boundary Rates (90% CIsa) for 
the Corresponding Sample Size
Boundary Rates (90% CIsa) for 
the Corresponding Sample Size
36 – 39
-
--
--
40 – 56
0
0% (0%, 7.2%) for N=40
0% (0%, 5.2%) for N=56
57 – 73
1 or less
1.8% (0.1%, 8.1%) for N=57
1.4% (0.1%, 6.3%) for N=73
74 – 90
2 or less
2.7% (0.5%, 8.3%) for N=74
2.2% (0.4%, 6.8%) for N=90
91 – 107
3 or less
3.3% (0.9%, 8.3%) or N=91
2.8% (0.8%, 7.1%) for N=107
108
4 or less
3.7% (1.3%, 8.3%) for N=108
--
Abbreviations:  CI = confidence interval
Decision rule for stopping the trial is not applicable due to insufficient sample size if only 36-39 participants are available.
Monitoring points will be based on number of the participants in APaT population.
The sequential monitoring Procedure will be performed for each cohort, respectively. Once the combination rule is met, 
two cohorts will be pooled for evaluation at the bound specified. 
Design assumes overall Type I error of 5% (1-sided) at null hypothesis rate of 10% and 83% power at true rate of 3%.
a 90% CIs based on Clopper-Pearson (exact) method are provided
Table 17
Decision Rules for Stopping the Trial for High Percentage of Participants with 
Grade 3 or Higher Pneumonitis
Monitoring  
Points (# 
Participants)
# Participants 
with Grade 3 
or Higher 
Pneumonitis 
to indicate 
High 
Pneumonitis 
Rate
Boundary Rates (90% CIsa) for 
the Corresponding Sample Size
Boundary Rates (90% CIsa) for 
the Corresponding Sample Size
36 – 46
5 or higher
13.9% (5.6%, 27.0%) for N=36
10.9% (4.4%, 21.5%) for N=46
47 – 63
6 or higher
12.8% (5.7%, 23.7%) for N=47
9.5% (4.2%, 17.9%) for N=63
64 – 80
7 or higher
10.9% (5.3%, 19.6%) for N=64
8.8% (4.2%, 15.8%) for N=80
81 – 97
8 or higher
9.9% (5.0%, 17.1%) for N=81
8.2% (4.2%, 14.4%) for N=97
98 – 108
9 or higher
9.2% (4.9%, 15.5%) for N=98
8.3% (4.4%, 14.1%) for N=108
Abbreviations:  CI = confidence interval
Monitoring points will be based on number of the participants in APaT population.
The sequential monitoring procedure will be performed for each cohort, respectively. Once the combination rule is met, 2
cohorts will be pooled for evaluation at the bound specified. 
a 90% CIs based on Clopper-Pearson (exact) method are provided
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Table 18
Decision Rules for Stopping the Trial due to a Low ORR
Monitoring  
Points (# 
Participants)
# Participants 
with Response 
to Conclude 
ORR <50%
Boundary ORR (90% CIs a) for the 
Corresponding Sample Size
Boundary ORR (90% CIs a) for the 
Corresponding Sample Size
36 – 37
10 or less
27.8% (15.9%, 42.6%) for N=36
27.0% (15.5%, 41.5%) for N=37
38 – 39
11 or less
28.9% (17.2%, 43.3%) for N=38
28.2% (16.7%, 42.3%) for N=39
40 – 41
12 or less
30.0% (18.3%, 44.0%) for N=40
29.3% (17.8%, 43.1%) for N=41
42 – 44
13 or less
31.0% (19.4%, 44.6%) for N=42
29.5% (18.5%, 42.8%) for N=44
45 – 46
14 or less
31.1% (19.9%, 44.3%) for N=45
30.4% (19.4%, 43.4%) for N=46
47 – 48
15 or less
31.9% (20.8%, 44,8%) for N=47
31.3% (20.4%, 44.0%) for N=48
49 – 51
16 or less
32.7% (21.7%, 45.3%) for N=49
31.4% (20.8%, 43.7%) for N=51
52 – 53
17 or less
32.7% (22.0%, 4.9%) for N=52
32.1% (21.6%, 44.1%) for N=53
54 – 56
18 or less
33.3% (22.8%, 45.3%) for N=54
32.1% (21.9%, 43.9%) for N=56
57 – 58
19 or less
33.3% (23.1%, 45.0%) for N=57
32.8% (22.6%, 44.3%) for N=58
59 – 60
20 or less
33.9% (23.7%, 45.3%) for N=59
33.3% (23.3%, 44.7%) for N=60
61 – 63
21 or less
34.4% (24.4%, 45.7%) for N=61
33.3% (23.5%, 44.3%) for N=63
64 – 65
22 or less
34.4% (24.5%, 45.3%) for N=64
33.8% (24.1%, 44.7%) for N=65
66 – 67
23 or less
34.8% (25.1%, 45.6%) for N=66
34.3% (24.7%, 45.0%) for N=67
68 – 70
24 or less
35.3% (25.7%, 45.9%) for N=68
34.3% (24.9%, 44.7%) for N=70
71 – 72
25 or less
35.2% (25.8%, 45.6%) for N= 1
34.7% (25.4%, 45.0%) for N=72
73 – 74
26 or less
35.6% (26.3%, 45.8%) for N=73
35.1% (25.9%, 45.3%) for N=74
75 – 77
27 or less
36.0% (26.8%, 46.1%) for N=75
35.1% (26.0%, 45.0%) for N=77
78 – 79
28 or less
35.9% (26.9%, 45.8%) for N=78
35.4% (26.5%, 45.2%) for N=79
80 – 82
29 or less
36.3% (27.3%, 46.0%) for N=80
35.4% (26.6%, 45.0%) for N=82
83 – 84
30 or less
36.1% (27.4%, 45.7%) for N=83
35.7% (27.0%, 45.2%) for N=84
85 – 86
31 or less
36.5% (27.8%, 45.9%) for N=85
36.0% (27.4%, 45.4%) for N=86
87 – 89
32 or less
36.8% (28.2%, 46.1%) for N=87
36.0% (27.5%, 45.1%) for N=89
90 – 91
33 or less
36.7% (28.2%, 45.8%) for N=90
36.3% (27.9%, 45.4%) for N=91
92 – 93
34 or less
37.0% (28.6%, 46.0%) for N=92
36.6% (28.2%, 45.6%) for N=93
94 – 96
35 or less
37.2% (28.9%, 46.2%) for N=94
36.5% (28.3%, 45.3%) for N=96
97 – 98
36 or less
37.1% (28.9%, 45.9%) for N=97
36.7% (28.6%, 45.5%) for N=98
99 – 100
37 or less
37.4% (29.2%, 46.1%) for N=99
37.0% (28.9%, 45.7%) for N=100
101 – 103
38 or less
37.6% (29.6%, 46.2%) for N=101
36.9% ( 29.0%, 45.4%) for N=103
104 – 105
39 or less
37.5% (29.6%, 46.0%) for N=104
37.1% (29.3%, 45.6%) for N=105
106 – 107
40 or less
37.7% (29.9%, 46.1%) for N=106
37.4% (29.6%, 45.7%) for N=107
108
41 or less
38.0% (30.1%, 46.3%) for N=108
--
Abbreviations:  CI = confidence interval
Monitoring points will be based on number of the participants in APaT population who have minimum of 15 weeks of 
follow-up..
Sequential monitoring procedure will be performed for each cohort, respectively. Once the combination rule is met, two 
cohorts will be pooled for evaluation at the bound specified. 
a 90% CIs based on Clopper-Pearson (exact) method are provided
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Table 19
Decision Rules for Stopping the Trial due to a High ORR
Monitoring  
Points (# 
Participants)
#Participants 
with 
Response to 
Indicate High 
ORR
Boundary ORR (90% CIs a) for the 
Corresponding Sample Size
Boundary ORR (90% CIs a) for the 
Corresponding Sample Size
36 – 38
21 or higher
58.3% (43.3%, 72.3%) for N=36
55.3% (40.7%, 69.1%) for N=38
39 – 40
22 or higher
56.4% (42.1%, 70.0%) for N=39
55.0% (40.9%, 68.5%) for N=40
41 – 43
23 or higher
56.1% (42.1%, 69.4%) for N=41
53.5% (39.9%, 66.7%) for N=43
44 – 45
24 or higher
54.5% (41.1%, 67.5%) for N=44
53.3% (40.1%, 66.2%) for N=45
46 – 47
25 or higher
54.3% (41.3%, 67.0%) for N=46
53.2% (40.3%, 65.8%) for N=47
48 – 50
26 or higher
54.2% (41.4%, 66.6%) for N=48
52.0% (39.5%, 64.3%) for N=50
51 – 52
27 or higher
52.9% (40.6%, 65.0%) for N=51
51.9% (39.7%, 64.0%) for N=52
53 – 54
28 or higher
52.8% (40.7%, 64.7%) for N=53
51.9% (39.9%, 63.7%) for N=54
55 – 57
29 or higher
52.7% (40.9%, 64.4%) for N=55
50.9% (39.3%, 62.4%) for N=57
58 – 59
30 or higher
51.7% (40.2%, 63.1%) for N=58
50.8% (39.5%, 62.2%) for N=59
60 – 61
31 or higher
51.7% (40.3%, 62.9%) for N=60
50.8% (39.6%, 62.0%) for N=61
62 – 64
32 or higher
51.6% (40.5%, 62.6%) for N=62
50.0% (39.1%, 60.9%) for N=64
65 – 66
33 or higher
50.8% (39.9%, 61.5%) for N=65
50.0% (39.3%, 60.7%) for N=66
67 – 68
34 or higher
50.7% (40.1%, 61.4%) for N=67
50.0% (39.4%, 60.6%) for N=68
69 – 71
35 or higher
50.7% (40.2%, 61.2%) for N=69
49.3% (39.0%, 59.6%) for N=71
72 – 73
36 or higher
50.0% (39.8%, 60.2%) for N=72
49.3% (39.2%, 59.5%) for N=73
74 – 76
37 or higher
50.0% (39.9%, 60.1%) for N=74
48.7% (38.8%, 58.7%) for N=76
77 – 78
38 or higher
49.4% (39.5%, 59.3%) for N=77
48.7% (38.9%, 58.6%) for N=78
79 – 80
39 or higher
49.4% (39.6%, 59.1%) for N=79
48.8% (39.1%, 58.5%) for N=80
81 – 83
40 or higher
49.4% (39.8%, 59.0%) for N=81
48.2% (38.7%, 57.8%) for N=83
84 – 85
41 or higher
48.8% (39.4%, 58.3%) for N=84
48.2% (38.9%, 57.7%) for N=85
86 – 87
42 or higher
48.8% (39.5%, 58.2%) for N=86
48.3% (39.0%, 57.6%) for N=87
88 – 90
43 or higher
48.9% (39.7%, 58.1%) for N=88
47.8% (38.7%, 56.9%) for N=90
91 – 92
44 or higher
48.4% (39.3%, 57.5%) for N=91
47.8% (38.9%, 56.9%) for N=92
93 – 94
45 or higher
48.4% (39.5%, 57.4%) for N=93
47.9% (39.0%, 56.8%) for N=94
95 – 97
46 or higher
48.4% (39.6%, 57.3%) for N=95
47.4% (38.7%, 56.2%) for N=97
98 – 99
47 or higher
48.0% (39.3%, 56.7%) for N=98
47.5% (38.9%, 56.2%) for N=99
100 – 102
48 or higher
48.0% (39.4%, 56.7%) for N=100
47.1% (38.6%, 55.7%) for N=102
103 – 104
49 or higher
47.6% (39.1%, 56.1%) for N=103
47.1% (38.7%, 55.6%) for N=104
105 – 106
50 or higher
47.6% (39.3%, 56.1%) for N=105
47.2% (38.9%, 55.6%) for N=106
107 – 108
51 or higher
47.7% (39.4%, 56.0%) for N=107
47.2% (39.0%, 55.6%) for N=108
Abbreviations:  CI = confidence interval
Monitoring points will be based on number of the participants in APaT population who have a minimum of 15 weeks of 
follow-up.
The sequential monitoring procedure will be performed for each cohort, respectively. Once the combination rule is met, two 
cohorts will be pooled for evaluation at the bound specified.
Design assumes overall Type I error of 5% (1-sided) at null hypothesis rate of 35%, and 84% power at true rate of 50%.
Trial is not necessary to stop if the ORR is greater than upper bound.
a 90% CIs based on Clopper-Pearson (exact) method are provided
The interim analyses will be performed by the clinical Biostatistics Department of the 
Sponsor internally and data will be monitored closely by the study team. The DMC will serve 
as an additional reviewer of the results of the interim analyses and will make 
recommendations to the EOC to continue, modify, or end the study according to the protocol, 
considering overall risk benefit to study participants. The DMC responsibilities, review 
schedules, and additional logistical details will be provided in the DMC Charter.
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Multiplicity
Although there are 2 primary endpoints, there is only 1 hypothesis in the study. There are 2 
cohorts in the study, testing of each cohort is controlled by 5% of Type I error (1-sided). 
Because this is a Phase 2 study, no multiplicity adjustment is planned to control the overall 
Type I error for the testing of the two cohorts.
Sequential monitoring approach will be used to handle multiplicity issue in interim analyses. 
Sample Size and Power Calculations
Approximately 216 total participants in 2 cohorts (108 participants per cohort) will be 
enrolled to receive pembrolizumab in combination with platinum-based chemo-radiotherapy. 
With an approximate maximum of 108 participants enrolled within each cohort, the study 
provides 83% power to demonstrate that the percentage of participants with Grade 3 or 
higher pneumonitis is less than 10% if the true rate of Grade 3 or higher pneumonitis is 3% at 
an overall one-sided 5% alpha-level. 
The power calculation is based on the binomial SPRT function in the gsDesign package and 
is carried out using R assuming a null pneumonitis rate of 10%, and alternative pneumonitis 
rate of 3%, 1-sided type I error of 0.05 and type II error of 0.05. Since both type I error and 
type II error are set as 0.05, the binomial SPRT with null pneumonitis rate of 10% and 
alternative pneumonitis rate of 3% have the same boundary results as the binomial SPRT 
with null pneumonitis rate of 3% and alternative pneumonitis rate of 10%. Thus, 
binomialSPRT(p0=0.03, p1=0.10, alpha=0.05, beta=0.05, minn=36, maxn=108) is used for 
calculation. The average sample size needed for the binomial sequential testing procedure 
within each cohort ranges from 60 to 81 if the true pneumonitis rate is between 3% and 10%. 
Table 20 summarizes the power and average sample size under various assumptions for 
pneumonitis.
Table 20
Operating Characteristics of the Sequential Monitoring Approach (Percentage of 
Participants with Grade 3 or Higher Pneumonitis)
True Rate
Probability of 
stopping to indicate 
low pneumonitis
Probability of 
stopping to indicate 
high pneumonitis
Average Sample 
Size
3%
0.83
0.02
69
4%
0.65
0.08
77
5%
0.47
0.18
81
6%
0.31
0.31
81
7%
0.20
0.47
77
8%
0.12
0.61
72
9%
0.07
0.74
66
10%
0.04
0.83
60
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Using sequential testing, with an approximate maximum of 108 participants enrolled within 
each cohort, the study also provides 84% power to demonstrate that the ORR exceeds 35% at 
an overall one-sided 5% alpha-level, if the true ORR is 50%. 
The power calculation is based on the binomial SPRT function in the gsDesign package and 
is carried out using R assuming a null ORR of 35%, and alternative ORR of 50%, 1-sided 
type I error of 0.05 and type II error of 0.05 (binomialSPRT(p0=0.35, p1=0.50, alpha=0.05, 
beta=0.05, minn=36, maxn=108)). The average sample size for binomial sequential testing 
procedure within each cohort ranges from 61 to 76 if the true ORR is between 35% and 50%. 
Table 21 summarized the power and average sample size under various assumptions for 
ORR.
Table 21
Operating Characteristics of the Sequential Monitoring Approach (ORR)
True ORR
Probability of 
stopping to indicate 
low ORR
Probability of 
stopping to indicate 
high ORR
Average Sample 
Size
35%
0.84
0.03
62
40%
0.50
0.18
76
45%
0.17
0.51
75
50%
0.03
0.84
61
The sample size of the study will be between 36 and 108 participants per cohort. If the 
stopping bounds are not reached, the maximum sample size of 108 will provide a 95% CI for
percentage of participants with Grade 3 or higher pneumonitis of 3% to 10% with a half-
width ranging from 3.2% to 5.7%, and a 95% CI for ORR of 35% to 50% with half-width 
ranging from 9.0% to 9.4%.
The similarity of the 2 treatment cohorts will be continuously evaluated after at least 36 
participants have completed a minimum of 15 weeks of follow-up in each cohort. If at an 
interim analysis the difference of Grade 3 or higher pneumonitis rates is observed within 1% 
between 2 cohorts, then the 2 cohorts will be considered similar, and be combined for study 
analysis. The trial stops when a stopping rule is met or once 108 participants have been 
enrolled. If combination rule is not met, the analysis will be based on each cohort. The 
sample size varies due to different enrollment rate in 2 cohorts and whether the 2 cohorts will 
be combined.
Subgroup Analyses
The estimate of the treatment effect for the primary endpoints will be estimated and/or 
plotted within each category of the following classification variables:

Age category (< 65 versus ≥65 years)

Sex (female, male)

Stage (Stage IIIA versus Stage IIIB versus Stage IIIC)
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
ECOG performance status (0 versus 1)

Predominant tumor histology (squamous versus non-squamous)

Smoking status (never versus former/current smoker)

PD-L1 status (TPS <1% versus ≥1%)

Physician choice of treatment in non-squamous participants
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
Extent of Exposure
Extent of exposure for a participant is defined as number of cycles in which the participant 
receives the study medication. Summary statistics will be provided on extent of exposure for 
the APaT population.
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10. Supporting Documentation and Operational Considerations
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
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted in 
compliance with local and/or national regulations (including all applicable data protection laws and regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or which 
are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the full control 
of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial.
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities and 
staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, sites are 
evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to successfully conduct 
the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts to 
raise awareness of clinical trial opportunities in various communities. MSD will seek to engage underrepresented 
groups and those disproportionately impacted by the disease under study. MSD will support clinical trial 
investigators to enroll underrepresented groups and expand access to those who will ultimately use the products 
under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus source 
documentation according to standard operating procedures. Per MSD policies and procedures, if potential fraud, 
scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related Significant Quality Issues are 
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reported, such matters are investigated. When necessary, appropriate corrective and/or preventative actions are 
defined and regulatory authorities and/or ethics review committees are notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important to 
patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather than 
hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be underpowered 
and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority acceptance/authorization 
prior to implementation of the trial or amendment, in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an immediate 
hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. MSD will 
inform regulatory authorities of such new measures to protect participant safety, in compliance with local and/or 
national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a 
minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all applicable 
data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on behalf of 
MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records that might 
identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to enroll 
participants in its trials. However, when enrollment is particularly challenging, additional payments may be made to 
compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent on 
chart review and medical evaluation to identify potentially eligible participants.
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B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may wish 
to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As noted 
above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
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, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3 Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.4 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 
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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.
10.1.5 Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents in 
order to verify worksheet/CRF data. By signing the consent form, the participant agrees to 
this process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.6 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.
10.1.7 Committees Structure
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide upon any recommendations made by the DMC regarding the study.
External Data Monitoring Committee
To supplement the 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 
study results, consider the overall risk and benefit to study participants (Section 9.7 [Interim 
Analyses]) 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 
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of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.8 Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments. 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.9 Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and site contact information. 
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.10
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use Good Clinical Practice: Consolidated Guideline and other 
generally accepted standards of GCP); and all applicable federal, state and local laws, rules 
and regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
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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.
10.1.11
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
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. 
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Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor. 
10.1.12
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
10.1.13
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP. 
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
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Appendix 2: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways drugs/vaccines may interact with
o
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in the 
future biomedical research substudy.
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 
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participant will be kept at the clinical study site under secure storage for regulatory 
reasons. 
A template of each study site’s approved informed consent will be stored in the Sponsor’s 
clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured in 
the eCRFs. Any specimens for which such an informed consent cannot be verified will be 
destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined in 
the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research 
In order to optimize the research that can be conducted with future biomedical research
specimens, it is critical to link participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like gender, age, medical history and treatment outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical study site, unique codes will be placed on the future biomedical research
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube. 
5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in this substudy. 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 Research 
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the principal investigator for the main study. If medical 
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records for the main study are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for future biomedical research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable. 
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed. 
7. Retention of Specimens 
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
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 Participants
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 Population
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 Research 
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Conference on Harmonization [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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Appendix 3:  Contraceptive Guidance and Pregnancy Testing
Definitions 
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below) 
Women in the following categories are not considered WOCBP:
●
Premenarchal
●
Premenopausal female with 1 of the following:
○
Documented hysterectomy
○
Documented bilateral salpingectomy
○
Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
●
Postmenopausal female
○
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
▪
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required. 
○
Females on HRT and whose menopausal status is in doubt will be required to use 1 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.
Contraception Requirements
Male Participants
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to 1 of the following during the protocol defined time frame in Section 5.1: 
●
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent.
●
Use a male condom plus partner use of an additional contraceptive method when having 
penile-vaginal intercourse with a WOCBP who is not currently pregnant.
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o
The following are not acceptable methods of contraception:
▪
Periodic abstinence (calendar, symptothermal, postovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
method (LAM).
▪
Male condom with cap, diaphragm or sponge with spermicide.
▪
Male and female condom cannot be used together.
○
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration.
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 22
during the protocol-defined time frame in Section 5.1. 
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Table 22
Highly Effective Contraception Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly.
●
Combined (estrogen- and progestogen- containing ) hormonal contraception b, c
○
Oral 
○
Intravaginal 
○
Transdermal 
○
Injectable
●
Progestogen-only hormonal contraception b, c
○
Oral 
○
Injectable 
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.
●
Progestogen-only contraceptive implant b, c 
●
Intrauterine hormone-releasing system (IUS) b
●
Intrauterine device (IUD)
●
Bilateral tubal occlusion
●
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the WOCBP and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used. 
●
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatment. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods 
for participants of clinical studies. 
a) Typical use failure rates are higher than perfect-use failure rates (ie, when used 
consistently and correctly). 
b) If hormonal contraception efficacy is potentially decreased due to interaction with study 
treatment, condoms must be used in addition to the hormonal contraception during the 
treatment period and for at least at least 180 days after the last dose of study medication 
in Cycles 1 through 3 or for 120 days after the last dose of study medication in Cycle 4 
through the end of treatment.
c) If locally required, in accordance with Clinical Trial Facilitation Group guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation. 
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Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test within 72 hours prior to treatment allocation. Note: Pregnancy tests within 24 hours prior 
to randomization or treatment allocation to determine eligibility will be required only in 
those regions where this is required via documented regulatory request, subsequently 
approved by the Sponsor.
Following initiation of treatment additional pregnancy testing will be performed following 
local regulations and guidelines during the treatment period and at least 180 days after the 
last dose of study medication in Cycles 1 through 3 or for 120 days after the last dose of 
study medication in Cycle 4 through the end of treatment. Pregnancy testing will be 
performed whenever an expected menstrual cycle is missed or when pregnancy is otherwise 
suspected.
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Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definition of AE
AE definition
●
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study treatment, whether or not considered related 
to the study treatment.
●
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
●
NOTE: for purposes of AE definition, study treatment (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, device, 
diagnostic agent or protocol specified procedure whether investigational (including 
placebo or active comparator product) or marketed, manufactured by, licensed by, 
provided by or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
●
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, or are considered clinically significant in the 
medical and scientific judgment of the investigator.
●
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
●
New conditions detected or diagnosed after study treatment administration even though 
it may have been present before the start of the study.
●
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
●
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. 
●
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose of 
study treatment without any associated clinical symptoms or abnormal laboratory results 
is reported using the terminology “accidental or intentional overdose without adverse 
effect.”
●
Any new cancer (that is not a condition of the study). Progression of the cancer under 
study is not a reportable event. Refer to Section 8.4.5 for additional details.
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Events NOT meeting the AE definition 
●
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
●
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
●
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
●
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
●
Refer to Section 8.4.5 for protocol specific exceptions
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met 
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
●
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
●
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the patient’s 
medical history.
d. Results in persistent or significant disability/incapacity
●
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
●
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
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e.
Is a congenital anomaly/birth defect
●
in offspring of participant taking the product regardless of time to diagnosis
f.
Other important medical events:
●
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse.
Additional Events Reported in the Same Manner as SAE
Additional events which require reporting in the same manner as SAE
●
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs 
to meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Recording AE and SAE
AE and SAE recording
●
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
●
The investigator will record all relevant AE/SAE information on the AE
CRFs/worksheets at each examination.
●
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.
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●
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
●
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
●
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI Common Terminology Criteria for Adverse 
Events (CTCAE), version 4.0. Any AE which changes CTCAE grade over the course of a 
given episode will have each change of grade recorded on the AE CRFs/worksheets.
●
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
●
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL).
●
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
●
Grade 4: Life threatening consequences; urgent intervention indicated.
●
Grade 5: Death related to AE.
Assessment of causality
●
Did the Sponsor's product cause the AE?
●
The determination of the likelihood that the Sponsor's product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s 
signed/dated initials on the source document or worksheet that supports the causality 
noted on the AE form, ensures that a medically qualified assessment of causality was 
done. This initialed document must be retained for the required regulatory time frame. 
The criteria below are intended as reference guidelines to assist the investigator in 
assessing the likelihood of a relationship between the test product and the AE based 
upon the available information
●
The following components are to be used to assess the relationship between the 
Sponsor's product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor's 
product caused the AE:
●
Exposure:  Is there evidence that the participant was actually exposed to the 
Sponsor's product such as:  reliable history, acceptable compliance assessment 
(pill count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
●
Time Course:  Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor's product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal 
product)?
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●
Likely Cause:  Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors
●
Dechallenge: Was the Sponsor's product discontinued or 
dose/exposure/frequency reduced?
●
If yes, did the AE resolve or improve?
●
If yes, this is a positive dechallenge. 
●
If no, this is a negative dechallenge.
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or 
permanent disability; (2) the AE resolved/improved despite continuation of the 
Sponsor's product; (3) the study is a single-dose drug study); or (4) Sponsor's 
product(s) is/are only used one time.)
●
Rechallenge:  Was the participant re-exposed to the Sponsor's product in this 
study?
●
If yes, did the AE recur or worsen?
●
If yes, this is a positive rechallenge. 
●
If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study); or (3) Sponsor's 
product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN AE WHICH WAS SERIOUS AND 
WHICH MAY HAVE BEEN CAUSED BY THE SPONSOR'S PRODUCT, OR IF RE-
EXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE 
APPROVED IN ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.
●
Consistency with Study treatment Profile:Is the clinical/pathological 
presentation of the AE consistent with previous knowledge regarding the 
Sponsor's product or drug class pharmacology or toxicology?
●
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
●
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor's product relationship).
●
Yes, there is a reasonable possibility of Sponsor's product relationship:
There is evidence of exposure to the Sponsor's product. The temporal sequence of the 
AE onset relative to the administration of the Sponsor's product is reasonable. The 
AE is more likely explained by the Sponsor's product than by another cause. 
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●
No, there is not a reasonable possibility of Sponsor's product relationship:
Participant did not receive the Sponsor's product OR temporal sequence of the AE 
onset relative to administration of the Sponsor's product is not reasonable OR the AE 
is more likely explained by another cause than the Sponsor’s product. (Also entered 
for a participant with overdose without an associated AE.)
●
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
●
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
●
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
●
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements
●
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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Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
●
The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool. 
●
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
●
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form. 
●
Reference Section 8.4.1 for reporting time requirements 
●
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
●
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
●
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
●
Contacts for SAE reporting can be found in the Investigator Trial File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
●
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
●
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
●
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
●
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Trial File Binder (or equivalent).
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Appendix 5: ECOG Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(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 MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden 
ET, Carbone PP: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin 
Oncol. 1982;5:649-655. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair.
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Appendix 6: Clinical Laboratory Tests 

The tests detailed in Table 23 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, required by local regulations, or as per approved 
chemotherapy local practice or label.
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Table 23
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
PT/INR and aPTT/PTT
Chemistry
Blood Urea 
Nitrogen (BUN)
or urea if BUN 
is not available 
or acceptable a
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT)
Total bilirubin 
(and direct 
bilirubin, if 
total bilirubin is 
elevated above 
the upper limit 
of normal)
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-
Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose, 
nonfasting
Calcium
Alkaline 
phosphatase
Routine 
Urinalysis
Specific gravity
pH, glucose, protein, blood, ketones, by dipstick
Microscopic examination (if blood or protein is abnormal)

Pregnancy test, as needed for women of childbearing potential 
(WOCBP) within 72 hours prior to first dose of trial treatment. A serum 
test can be considered if a urine test is not appropriate. Monthly 
pregnancy testing should be conducted as per local regulation where 
applicable. Refer to Appendix 7 for country-specific details
Other Tests

Thyroid panel: TSH, T3/FT3, and T4/FT4
a. If urea is obtained instead of BUN, a Sponsor Consultation Form should be completed at 
screening and submitted to the Clinical Director.
Investigators must document their review of each laboratory safety report.
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Appendix 7:  Country-specific Requirements
France
1.3.2
Cohort B Schedule: Screening and Treatment Cycle 1 to 3
Audiogram to be completed at screening.
5.2
Exclusion Criteria
Cohort A only:
a.
Participants who experience hemorrhage from tumor
b. Participants who use phenytoïn, or fosphénytoïn .
Cohort B only: 
a.
Participants with a hearing impairment
b. Participants with pathologies that are a contraindication to hyperhydration prior to 
chemotherapy administration.
c.
Participants who are unable to tolerate use of phenytoïn 
6.5.2 Prohibited Concomitant Medications
Investigators must refer to the up-to-date SMPc of registered products used in this study, 
regarding forbidden medications or medications to be used with precaution.
8.3.6.2 Pregnancy Test
Monthly and end of treatment pregnancy testing must be conducted as per local regulations.
6.6.1.1 Dose Modification and Toxicity Management for Immune-related AEs Associated 
With Pembrolizumab
Participants should be discontinued from study treatment if any of the following AEs occur:

Grade 4 skin rash

Stevens-Johnson syndrome

Toxic epidermal necrolysis
10.3
Appendix 3, Contraceptive Guidance and Pregnancy Testing
Monthly and end of treatment pregnancy testing must be conducted as per local regulations.
Germany
5.2 Exclusion Criteria
Has a known history of human immunodeficiency virus (HIV) infection. HIV testing is 
required as mandated by local regulation.
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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. Testing for Hepatitis B or Hepatitis C is required at screening.
Has a known history of active tuberculosis (TB; Bacillus tuberculosis). Testing for 
tuberculosis is required at screening.
8.3.6.2 Pregnancy Test
Monthly and end of treatment pregnancy testing must be conducted as per local regulations.
8.12.1 Screening
Laboratory tests are to be performed within 10 days prior to the first dose of study 
intervention. Exceptions are HIV, hepatitis, and tuberculosis testing which may be done up to 
28 days prior to the first dose of study intervention.
For WOCBP, a urine pregnancy test will be performed within 72 hours 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 trial site laboratory). Monthly 
pregnancy testing must be conducted.
10.3
Appendix 3, Contraceptive Guidance and Pregnancy Testing
WOCBP must only be included after a negative highly sensitive urine or serum pregnancy 
test.
Monthly and end of treatment pregnancy testing must be conducted.
10.6
Appendix 6, Clinical Laboratory Tests
Other screening tests: serology (HIV-RNA, hepatitis B surface antigen, hepatitis C virus 
antibody, and tuberculosis), amylase, lipase.
Poland
8.3.6.2 Pregnancy Test
Pregnancy testing must be conducted monthly during treatment, at the end of treatment, and 
through 120 days after the last dose of study medication as per local regulations.
10.3
Appendix 3, Contraceptive Guidance and Pregnancy Testing
Pregnancy testing must be conducted monthly during treatment, at the end of treatment, and 
through 120 days after the last dose of study medication as per local regulations.
United Kingdom
1.3.2
Cohort B Schedule: Screening and Treatment Cycle 1 to 3
Audiogram to be completed at screening.
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Full and directed physical examinations are to include neurologic examination performed by 
the treating physician or designee.
6.5.2
Prohibited Concomitant Medications
Live vaccines are prohibited through 3 months after the end of study treatment.
Caution must be exercised when administering cisplatin together with other nephrotoxic 
agents (eg, aminoglycosides, diuretics, antihypertensives, other chemotherapy specified in 
the study, anti-gout therapy) or ototoxic agents (eg, aminoglycosides, loop diuretics) and 
dose reductions of such concomitant treatments should be considered.
8.3.1.1 Full Physical Exam
Participants in Cohort B who are receiving cisplatin will have a neurologic examination 
performed by the treating physician or designee at the time of the full physical examination.
8.3.1.2 Directed Physical Exam
Participants in Cohort B who are receiving cisplatin will have a neurologic examination 
performed by the treating physician or designee at the time of the directed physical 
examination, while cisplatin treatment is ongoing.
8.3.6.2 Pregnancy Test
Monthly and end of treatment pregnancy testing must be conducted as per local regulations.
10.3
Appendix 3, Contraceptive Guidance and Pregnancy Testing
Monthly and end of treatment pregnancy testing must be conducted as per local regulations.
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Appendix 8: Abbreviations
Abbreviation
Expanded Term
3DCRT
3-dimensional conformal radiotherapy
ABC
active breathing device
ADA
anti-pembrolizumab antibodies
AE
adverse event
ALT
alanine aminotransferase
APAT
All Participants as Treated
AST
aspartate aminotransferase
AUC
area under curve
BCG
Bacillus Calmette-Guérin
BICR
Blinded independent central review
cCTRT
concurrent chemotherapy with radiotherapy
CD
cluster of differentiation
CFR
Code of Federal Regulations
CI
confidence interval
CONSORT
Consolidated Standards of Reporting Trials
CP
carboplatin and pemetrexed
CR
complete response
CrCl
creatinine clearance
CRF
case report form 
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor DNA
CTLA-4
cytotoxic t-lymphocyte-associated protein 4
CTV
clinical target volume
DILI
drug-induced liver injury
DLCO
diffusing capacity of the lungs for carbon monoxide
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid 
EBUS
endobronchial ultrasound
ECG
electrocardiogram 
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Abbreviation
Expanded Term
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data collection 
EGFR
epidermal growth factor receptor
ELISA
enzyme-linked immunoassay
EMA
European Medicines Agency
EOC
Executive Oversight Committee
EUS
endoscopic ultrasound
FDAAA
Food and Drug Administration Amendments Act
FDG
fluorodeoxyglucose
FEV1
forced expiratory volume in 1 second
FFPE
formalin-fixed, paraffin-embedded
FSH
Follicle-stimulating hormone 
GCP
Good Clinical Practice 
GTV
Gross tumor volume
Gy
Gray
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
hazard ratio
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
informed consent form 
ICH
International Conference on Harmonization
iCPD
immune confirmed progressive disease
IEC
Independent Ethics Committee
Ig
immunoglobulin
IHC
immunohistochemistry
IMP
investigational medicinal product
IMRT
intensity modulated radiotherapy
IND
investigational new drug 
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Abbreviation
Expanded Term
irAE
immune-related adverse event
IRB
Institutional Review Board 
iRECIST
Modified Response Evaluation Criteria in Solid Tumors version 1.1 for 
immune-based therapeutics
ITV
internal target volume
IUD
intrauterine device
iUPD
immune unconfirmed progressive disease
IUS
intrauterine hormone-releasing system
IV
intravenous
IVD
in vitro diagnostic
KM
Kaplan-Meier
MASCC
Multinational Association of Supportive Care in Cancer
MRI
magnetic resonance imaging
MSI
microsatellite instability
MTD
maximum tolerated dose 
MV
megavolts
NIMP
non-investigational medicinal product
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PBPK
physiologically-based pharmacokinetic
PD
progressive disease
PD-1
programmed cell death protein 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
PR
partial response
PTV
planning target volume
QA
Quality Assurance
Q2W
every 2 weeks
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Abbreviation
Expanded Term
Q3W
every 3 weeks
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
RR
response rate
RT
radiotherapy
RTOG
Radiation Therapy Oncology Group
SAE
serious adverse event 
SLAB
supplemental laboratory test(s)
SNP
single nucleotide polymorphism
SoA
Schedule of Activities
SOC
standard of care
sSAP
supplemental statistical analysis plan
TB
tuberculosis
TPS
tumor proportion score
TRT
thoracic radiotherapy
US
United States
WOCBP
woman/women of childbearing potential 
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