A Phase 3, Randomized, Double-blind Trial of Pembrolizumab (MK-3475) With or Without Lenvatinib (E7080/MK-7902) in Participants With Treatment-naïve, Metastatic Nonsmall Cell Lung Cancer (NSCLC) Whose Tumors Have a Tumor Proportion Score (TPS) Greater Than or Equal to 1% (LEAP-007)
Phase: PHASE3
Conditions: Non-small Cell Lung Cancer
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
NCT04676412
18-Aug-2022
A Phase 3, randomized, double-blind trial of pembrolizumab (MK-3475) 
with or without lenvatinib (E7080/MK-7902) in participants with 
treatment-naïve, metastatic nonsmall cell lung cancer (NSCLC) whose 
tumors have a tumor proportion score (TPS) greater than or equal to 1% 
(LEAP-007

PRODUCT: MK-7902 (E7080/lenvatinib) and MK-3475 (pembrolizumab) 
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PROTOCOL/AMENDMENT NO.: 007-07 (E7080-G000-314)
MK-7902-007-07 FINAL PROTOCOL
18-AUG-2022
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 3, randomized, double-blind trial of pembrolizumab (MK-3475) 
with or without lenvatinib (E7080/MK-7902) in participants with treatment-naïve, metastatic 
nonsmall cell lung cancer (NSCLC) whose tumors have a tumor proportion score (TPS) 
greater than or equal to 1% (LEAP-007)
Protocol Number: 007-07 (E7080-G000-314)
Compound Number: MK-7902 (E7080/lenvatinib) and MK-3475 (pembrolizumab)
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
The study is co-funded by MSD and Eisai.
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
140221
EudraCT
2018-003794-98
Approval Date: 18 August 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 07
18-AUG-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.
Amendment 06
15-SEP-2021
Data from an interim safety and futility eDMC for LEAP-007 (data cutoff: 
19-MAY-2021) indicated the study met the prespecified nonbinding 
futility criteria for OS for the combination of lenvatinib plus 
pembrolizumab compared with placebo plus pembrolizumab and the 
benefit-risk assessment was not considered positive to continue the study.
This futility analysis was requested at a previous eDMC meeting and 
conducted as described in the sSAP. Based upon these data, MSD 
implemented this amendment to unblind the study and remove lenvatinib
and matching placebo from the study. In addition, the Second-course 
Treatment Phase was discontinued and collection of ePRO data stopped.
The study will remain open to allow ongoing participants to continue 
treatment with open-label pembrolizumab monotherapy up to a maximum 
of 35 administrations.
Amendment 05
02-MAR-2021
To update the assumptions and timing of the analyses in the SAP, allow 
sufficient duration of follow-up, and to remove the initial alpha of ORR 
and reallocate to primary endpoints of PFS and OS
Amendment 04 – China-specific
11-FEB-2020
Extension of the enrollment period beyond the global study to achieve 
required exposure and number of events to investigate efficacy and safety 
in Chinese 1L NSCLC participants
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Document
Date of Issue
Overall Rationale
Amendment 03
16-DEC-2019
Alignment with Lenvatinib and Pembrolizumab (LEAP) program protocol 
standards and Health Authority request
Amendment 02
27-JUN-2019
Alignment with Lenvatinib and Pembrolizumab (LEAP) program protocol 
standards
Amendment 01
17-JAN-2019
Alignment with Lenvatinib and Pembrolizumab (LEAP) program protocol 
standards
Original Protocol
09-NOV-2018
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 07
Overall Rationale for the Amendments:
Sponsor underwent an entity name change and update to the address.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Title Page
Section 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.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................5
1
PROTOCOL SUMMARY ............................................................................................15
1.1
Synopsis.................................................................................................................15
1.2
Schema ..................................................................................................................21
1.3
Schedule of Activities (SoA)................................................................................22
1.3.1
Initial Treatment Phase ................................................................................22
1.3.2
Second-course Treatment Phase ..................................................................33
2
INTRODUCTION..........................................................................................................34
2.1
Study Rationale....................................................................................................34
2.2
Background ..........................................................................................................36
2.2.1
Pharmaceutical and Therapeutic Background .............................................36
2.2.1.1
Lenvatinib ..........................................................................................36
2.2.1.2
Pembrolizumab ..................................................................................37
2.2.1.3
Pembrolizumab With Lenvatinib.......................................................37
2.2.2
Preclinical and Clinical Studies ...................................................................38
2.2.2.1
Completed Studies With Pembrolizumab and Lenvatinib.................38
2.2.3
Ongoing Clinical Studies of Pembrolizumab and Lenvatinib .....................38
2.3
Benefit/Risk Assessment......................................................................................39
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................39
4
STUDY DESIGN............................................................................................................42
4.1
Overall Design......................................................................................................42
4.2
Scientific Rationale for Study Design.................................................................44
4.2.1
Rationale for Endpoints ...............................................................................44
4.2.1.1
Efficacy Endpoints.............................................................................44
4.2.1.1.1
RECIST 1.1..............................................................................44
4.2.1.1.2
Adjusted RECIST 1.1 for Immune-based Therapeutics 
iRECIST...................................................................................44
4.2.1.2
Safety Endpoints................................................................................45
4.2.1.3
Patient-reported Outcomes.................................................................45
4.2.1.3.1
EORTC QLQ-C30 ...................................................................45
4.2.1.3.2
EORTC QLQ-LC13.................................................................46
4.2.1.3.3
EuroQoL EQ-5D-5L ................................................................46
4.2.1.4
Pharmacokinetic Endpoints ...............................................................46
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4.2.1.5
.........................................47
4.2.2
Rationale for the Use of Comparator/Placebo .............................................48
4.3
Justification for Dose...........................................................................................49
4.3.1
Maximum Dose/Exposure for This Study ...................................................49
4.3.2
Rationale for Dose Interval and Study Design ............................................49
4.3.2.1
Lenvatinib Dosing..............................................................................49
4.3.2.2
Pembrolizumab Dosing......................................................................50
4.4
Beginning and End of Study Definition .............................................................50
4.4.1
Clinical Criteria for Early Study Termination .............................................51
5
STUDY POPULATION ................................................................................................51
5.1
Inclusion Criteria.................................................................................................51
5.2
Exclusion Criteria................................................................................................55
5.3
Lifestyle Considerations......................................................................................58
5.3.1
Meals and Dietary Restrictions....................................................................58
5.3.2
Contraception...............................................................................................58
5.3.3
Pregnancy.....................................................................................................58
5.3.4
Use in Nursing Women................................................................................59
5.4
Screen Failures.....................................................................................................59
5.5
Participant Replacement Strategy......................................................................59
6
STUDY INTERVENTION............................................................................................59
6.1
Study Intervention(s) Administered...................................................................59
6.1.1
Medical Devices...........................................................................................61
6.2
Preparation/Handling/Storage/Accountability .................................................61
6.2.1
Dose Preparation..........................................................................................61
6.2.2
Handling, Storage, and Accountability........................................................61
6.3
Measures to Minimize Bias: Randomization and Blinding..............................62
6.3.1
Intervention Assignment..............................................................................62
6.3.2
Stratification.................................................................................................62
6.3.3
Blinding........................................................................................................62
6.3.3.1
Pembrolizumab ..................................................................................62
6.4
Study Intervention Compliance..........................................................................63
6.5
Concomitant Therapy..........................................................................................63
6.5.1
Allowed Concomitant Medications .............................................................63
6.5.2
Prohibited Concomitant Medications ..........................................................64
6.5.3
Drug Interactions .........................................................................................64
6.5.4
Rescue Medications and Supportive Care ...................................................65
6.5.4.1
Systemic Corticosteroid Use..............................................................65
6.6
Dose Modification ................................................................................................65
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6.6.1
Immune-related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................65
6.6.1.1
Dose Modification and Toxicity Management for Immune-related 
AEs Associated with Pembrolizumab................................................65
6.6.1.2
Dose Modification and Toxicity Management of Infusion 
Reactions Related to Pembrolizumab................................................71
6.6.2
Other Allowed Dose Interruptions...............................................................74
6.7
Intervention After the End of the Study............................................................74
6.8
Clinical Supplies Disclosure................................................................................74
6.9
Standard Policies..................................................................................................74
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................74
7.1
Discontinuation of Study Intervention...............................................................74
7.1.1
Second-course Treatment Phase ..................................................................75
7.2
Participant Withdrawal From the Study...........................................................75
7.3
Lost to Follow-up .................................................................................................76
8
STUDY ASSESSMENTS AND PROCEDURES........................................................76
8.1
Administrative and General Procedures ...........................................................77
8.1.1
Informed Consent.........................................................................................77
8.1.1.1
General Informed Consent.................................................................77
8.1.2
Inclusion/Exclusion Criteria ........................................................................78
8.1.3
Participant Identification Card.....................................................................78
8.1.4
Medical History ...........................................................................................78
8.1.4.1
General Medical History....................................................................78
8.1.4.2
Oncologic Disease Details.................................................................78
8.1.5
Prior and Concomitant Medications Review...............................................79
8.1.5.1
Prior Medications...............................................................................79
8.1.5.2
Prior Oncologic Treatment ................................................................79
8.1.5.3
Concomitant Medications..................................................................79
8.1.6
Assignment of Screening Number...............................................................79
8.1.7
Assignment of Treatment/Randomization Number.....................................80
8.1.8
Study Intervention Administration ..............................................................80
8.1.8.1
Timing of Dose Administration.........................................................80
8.1.8.1.1
Lenvatinib/Matching Placebo..................................................80
8.1.8.1.2
Pembrolizumab ........................................................................80
8.1.8.2
Lenvatinib Compliance......................................................................81
8.1.9
Discontinuation and Withdrawal .................................................................81
8.1.10
Participant Blinding/Unblinding..................................................................81
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8.1.11
Calibration of Equipment.............................................................................81
8.2
Efficacy/Immunogenicity Assessments ..............................................................81
8.2.1
Tumor Scans and Assessment of Disease....................................................81
8.2.1.1
Initial Tumor Scans............................................................................82
8.2.1.2
Tumor Scans During the Study..........................................................83
8.2.1.3
End of Treatment and Follow-up Tumor Scans.................................83
8.2.1.4
Second-course Treatment Tumor Scans ............................................83
8.2.1.5
RECIST 1.1 Assessment of Disease..................................................84
8.2.1.6
iRECIST Assessment of Disease.......................................................85
8.2.1.7
Tumor Tissue Collection for PD-L1 Status .......................................88
8.2.2
Patient-reported Outcomes...........................................................................88
8.3
Safety Assessments...............................................................................................89
8.3.1
Physical Examinations.................................................................................89
8.3.2
Vital Signs....................................................................................................89
8.3.3
Electrocardiograms ......................................................................................89
8.3.4
Echocardiograms or Multigated Acquisition Scans.....................................90
8.3.5
Clinical Safety Laboratory Assessments .....................................................90
8.3.5.1
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis)..........................................................................................90
8.3.5.2
Pregnancy Test...................................................................................91
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................91
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................91
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......94
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...94
8.4.4
Regulatory Reporting Requirements for SAE .............................................94
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................94
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................95
8.4.7
Events of Clinical Interest (ECIs)................................................................95
8.5
Treatment of Overdose........................................................................................95
8.6
Pharmacokinetics.................................................................................................96
8.7
Pharmacodynamics..............................................................................................96
8.8
Planned Genetic Analysis Sample Collection....................................................96
8.9
...........................................................................................................96
8.10
Medical Resource Utilization and Health Economics.......................................97
8.11
Visit Requirements...............................................................................................97
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8.11.1
Screening......................................................................................................97
8.11.2
Initial Treatment Phase ................................................................................97
8.11.3
Second-course Treatment Phase ..................................................................98
8.11.4
Discontinued Participants Continuing to be Monitored in the Study ..........98
8.11.5
Poststudy......................................................................................................98
8.11.5.1
Safety Follow-up Visit.......................................................................98
8.11.5.2
Efficacy Follow-up Visits..................................................................98
8.11.5.3
Survival Follow-up Assessments.......................................................98
9
STATISTICAL ANALYSIS PLAN .............................................................................99
9.1
Statistical Analysis Plan Summary.....................................................................99
9.2
Responsibility for Analyses/In-house Blinding ...............................................101
9.3
Hypotheses/Estimation ......................................................................................101
9.4
Analysis Endpoints.............................................................................................101
9.4.1
Efficacy Endpoints.....................................................................................101
9.4.1.1
Primary Endpoints ...........................................................................101
9.4.1.2
Secondary Endpoints .......................................................................101
9.4.1.3
.....................................................................102
9.4.2
Safety Endpoints........................................................................................102
9.4.3
Patient-reported Outcome Endpoints.........................................................102
9.5
Analysis Populations..........................................................................................103
9.5.1
Efficacy Analysis Populations...................................................................103
9.5.2
Safety Analysis Populations ......................................................................103
9.5.3
Patient-reported Outcome Analysis Population.........................................103
9.5.4
Pharmacokinetic Analysis Population .......................................................104
9.6
Statistical Methods.............................................................................................104
9.6.1
Statistical Methods for Efficacy Analyses.................................................104
9.6.1.1
Progression-free Survival.................................................................105
9.6.1.2
Overall Survival...............................................................................106
9.6.1.3
Objective Response Rate .................................................................107
9.6.1.4
Duration of Response.......................................................................107
9.6.2
Statistical Methods for Safety Analyses ....................................................107
9.6.3
Statistical Methods for Patient-reported Outcome Analyses.....................109
9.6.4
Demographic and Baseline Characteristics ...............................................110
9.7
Interim Analyses ................................................................................................110
9.7.1
Safety Interim Analyses.............................................................................110
9.8
Multiplicity .........................................................................................................110
9.9
Sample Size and Power Calculations ...............................................................110
9.10
Subgroup Analyses.............................................................................................111
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9.11
Compliance (Medication Adherence)...............................................................112
9.12
Extent of Exposure.............................................................................................112
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................113
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......113
10.1.1
Code of Conduct for Clinical Trials...........................................................113
10.1.2
Financial Disclosure...................................................................................115
10.1.3
Data Protection...........................................................................................115
10.1.3.1
Confidentiality of Data ....................................................................116
10.1.3.2
Confidentiality of Participant Records.............................................116
10.1.3.3
Confidentiality of IRB/IEC Information..........................................116
10.1.4
Committees Structure.................................................................................116
10.1.4.1
Steering Committee .........................................................................116
10.1.4.2
Executive Oversight Committee......................................................117
10.1.4.3
External Data Monitoring Committee .............................................117
10.1.5
Publication Policy......................................................................................117
10.1.6
Compliance with Study Registration and Results Posting Requirements .118
10.1.7
Compliance with Law, Audit, and Debarment ..........................................118
10.1.8
Data Quality Assurance .............................................................................119
10.1.9
Source Documents .....................................................................................120
10.1.10
Study and Site Closure...............................................................................120
10.2
Appendix 2: Clinical Laboratory Tests............................................................121
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................123
10.3.1
Definition of AE ........................................................................................123
10.3.2
Definition of SAE ......................................................................................124
10.3.3
Additional Events Reported in the Same Manner as SAE.........................125
10.3.4
Recording AE and SAE .............................................................................125
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................129
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................131
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................132
10.5.1
Definitions..................................................................................................132
10.5.2
Contraception Requirements......................................................................133
10.5.3
Pregnancy Testing......................................................................................133
10.6
Appendix 6: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................135
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10.7
Appendix 7: Country-specific Requirements..................................................139
10.7.1
Japan-specific Requirements .....................................................................139
10.7.2
France-specific Requirements....................................................................139
10.7.3
Canada-specific Requirements...................................................................139
10.8
Appendix 8: Abbreviations ...............................................................................140
11
REFERENCES.............................................................................................................144
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values ...........................................54
Table 2
Study Interventions....................................................................................60
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations .........................................................67
Table 4
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ..................................................................................................72
Table 5
Summary of Imaging and Treatment Requirements After First 
Radiologic Evidence of Progression..........................................................87
Table 6
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................93
Table 7
Analysis Methods for Key Efficacy Endpoints .......................................105
Table 8
Censoring Rules for Primary and Sensitivity Analyses of Progression-
free Survival.............................................................................................106
Table 9
Censoring Rules for Duration of Response .............................................107
Table 10
Analysis Strategy for Safety Parameters..................................................109
Table 11
Protocol-Required Safety Laboratory Assessments.................................122
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LIST OF FIGURES
Figure 1
Original and Updated Study Design: Initial Treatment Phase...................21
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, randomized, double-blind trial of pembrolizumab (MK-3475) 
with or without lenvatinib (E7080/MK-7902) in participants with treatment-naïve, metastatic 
nonsmall cell lung cancer (NSCLC) whose tumors have a tumor proportion score (TPS) 
greater than or equal to 1% (LEAP-007)
Short Title: Pembrolizumab with or without lenvatinib in TPS ≥1% NSCLC
Acronym: Protocol 007 (LEAP-007)
Hypotheses, Objectives, and Endpoints:
NOTE: As of Amendment 007-06, lenvatinib and matching placebo have been removed 
from the study. All participants remaining on study will continue on open-label 
pembrolizumab monotherapy. No further analyses of efficacy endpoints will be 
performed. Exploratory objectives may not be pursued.
Participants were screened for up to 28 days, then randomized, and continued study 
treatment until discontinuation (defined in Section 7.1) OR stop/unblinding of study 
intervention due to the futility analysis criterion for OS being met.
In adult participants with treatment-naïve, metastatic NSCLC expressing PD-L1 (TPS ≥1%):
Primary Objectives
Primary Endpoints
- Objective: To compare progression-free 
survival (PFS) as assessed by blinded 
independent central review (BICR) according 
to Response Evaluation Criteria in Solid 
Tumors, version 1.1 (RECIST 1.1), adjusted 
to follow a maximum of 10 target lesions and 
a maximum of 5 target lesions per organ, for 
the combinations of pembrolizumab + 
lenvatinib versus pembrolizumab + matching 
placebo
- Hypothesis (H1): The combination of 
pembrolizumab + lenvatinib has superior PFS 
per RECIST 1.1, as defined in Section 
4.2.1.1.1, based on BICR
- PFS, defined as the time from 
randomization to the first documented 
progressive disease (PD) or death due to any 
cause, whichever occurs first*
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- Objective: To compare overall survival (OS) 
for the combinations of pembrolizumab + 
lenvatinib versus pembrolizumab + matching 
placebo.
- Hypothesis (H2): The combination of 
pembrolizumab + lenvatinib has superior OS
- OS, defined as the time from 
randomization to death due to any cause*
Secondary Objectives
Secondary Endpoints
- Objective: To compare objective response 
rate (ORR) as assessed by BICR according to 
RECIST 1.1, as defined in Section 4.2.1.1.1, 
for the combinations of pembrolizumab + 
lenvatinib versus pembrolizumab + matching 
placebo
- Hypothesis (H3): The combination of 
pembrolizumab + lenvatinib has superior 
ORR per RECIST 1.1, as defined in Section 
4.2.1.1.1, based on BICR
- Objective response (OR), defined as a 
confirmed complete response (CR) or 
partial response (PR)
- Objective: To evaluate the safety and 
tolerability for the combinations of 
pembrolizumab + lenvatinib versus 
pembrolizumab + matching placebo
- Adverse events (AEs) and study 
intervention discontinuation due to AEs
- Objective: To compare the mean change 
from baseline in the global health 
status/quality of life (QoL), cough, chest pain, 
dyspnea, and physical functioning for the 
combinations of pembrolizumab + lenvatinib 
versus pembrolizumab + matching placebo
- Change from baseline for the following 
patient-reported outcomes (PROs) 
scales/items: global health status/QoL 
(EORTC QLQ-C30 items 29 and 30), cough 
(EORTC QLQ-LC13 item 31), chest pain 
(EORTC QLQ-LC13 item 40), dyspnea 
(EORTC QLQ-C30 item 8), and physical 
functioning (EORTC QLQ-C30 items 1-5)
- Objective: To compare the time to true 
deterioration (TTD) in global health 
status/QoL, cough, chest pain, dyspnea, and
physical functioning for the combinations of 
pembrolizumab + lenvatinib versus 
pembrolizumab + matching placebo
- TTD, defined as the time from baseline to 
the first onset of a ≥10-point deterioration 
from baseline with confirmation by the 
subsequent visit of a ≥10-point deterioration 
from baseline in global health status/QoL 
(EORTC QLQ-C30 items 29 and 30), cough 
(EORTC QLQ-LC13 item 31), chest pain 
(EORTC QLQ-LC13 item 40), dyspnea 
(EORTC QLQ-C30 item 8), and physical 
functioning (EORTC QLQ-C30 items 1-5)
0843R7
08SHQL

PRODUCT: MK-7902 (E7080/lenvatinib) and MK-3475 (pembrolizumab)
17
PROTOCOL/AMENDMENT NO.: 007-07 (E7080-G000-314)
MK-7902-007-07 FINAL PROTOCOL
18-AUG-2022
- TTD in the composite endpoint 
(combination of cough [QLQ-LC13 item 
31], chest pain [QLQ-LC13 item 40], or 
dyspnea [QLQ-C30 item 8]) defined as the 
time to first onset of a ≥10-point 
deterioration from baseline in any one of 3
scale items with confirmation by the 
subsequent visit of a ≥10-point deterioration 
from baseline in the same scale as the first 
onset
*This study will be considered to have met its success criteria if the combination of 
pembrolizumab + lenvatinib is superior to pembrolizumab + matching placebo in PFS or OS.
Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
First-line treatment of metastatic NSCLC with PD-L1
expression (TPS ≥1%)
Population
Adult participants with treatment-naïve, metastatic NSCLC
(TPS ≥1%)
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Active Control with Placebo
NOTE: As of Amendment 007-06, the placebo treatment 
is removed from the study.
Study Blinding
Double-blind
NOTE: As of Amendment 007-06, the study is 
unblinded.
Masking
Participant or Subject
Investigator
Sponsor
0843R7
08SHQL

PRODUCT: MK-7902 (E7080/lenvatinib) and MK-3475 (pembrolizumab)
18
PROTOCOL/AMENDMENT NO.: 007-07 (E7080-G000-314)
MK-7902-007-07 FINAL PROTOCOL
18-AUG-2022
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 5 years from the time the first participant (or 
their legally acceptable representative) provides 
documented informed consent until the last participant’s
last study-related contact.
Extension Study in China: The Sponsor estimates that the 
study will require approximately an additional 1 year 
(beyond the global study’s last participant last study-related 
contact) from the time the first participant (or their legally 
acceptable representative) provides documented informed 
consent until the last participant's last study-related contact.
NOTE: As of Amendment 007-06, enrollment in the 
Extension Study in China has been stopped.
Number of Participants:
Global Study: Approximately 620 participants will be randomized.
Extension Study in China: Approximately 120 Chinese participants overall will be enrolled 
in the global study and the extension study.
NOTE: As of Amendment 007-06, enrollment in the Extension Study in China has been 
stopped.
Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Level
Route of 
Admin.
Regimen/ 
Treatment 
Period
Use
Arm A
Pembrolizumab
100 mg/vial
200 mg
IV 
Infusion
Q3W
Standard of 
care/Experimental
Lenvatinib
10 mg/4 mg
20 mg
Oral
QD
Experimental
Arm B
Pembrolizumab
100 mg/vial
200 mg
IV 
Infusion
Q3W
Standard of 
care/Experimental
Placebo
NA
NA
Oral
QD
Placebo
Abbreviations: NA = not applicable; Q3W = every 3 weeks; QD = daily.
NOTE: As of Amendment 007-06, lenvatinib and matching placebo have been removed 
from the treatment groups. Participants remaining on treatment will receive open-label 
pembrolizumab monotherapy as per protocol.
0843R7
08SHQL

PRODUCT: MK-7902 (E7080/lenvatinib) and MK-3475 (pembrolizumab)
19
PROTOCOL/AMENDMENT NO.: 007-07 (E7080-G000-314)
MK-7902-007-07 FINAL PROTOCOL
18-AUG-2022
Total 
Number of 
Intervention 
Groups/Arms
2 arms
Duration of 
Participation
NOTE: As of Amendment 007-06, lenvatinib and matching placebo have 
been removed from the study. This section has been updated
accordingly.
After a screening phase of up to 28 days, each participant received assigned 
study intervention until one of the conditions for discontinuation of study 
intervention was met (defined in Section 7.1).
Participants will be permitted to continue study intervention beyond RECIST 
1.1-defined PD as long as the treating investigator considers that the 
participant may experience clinical benefit with continued treatment as per 
iRECIST, and the participant is tolerating study intervention, until PD is 
confirmed by iRECIST. All decisions to continue treatment beyond 
confirmed PD by iRECIST must be approved by the Sponsor.
Participants who have been on pembrolizumab for at least 24 weeks and
attain a CR may consider stopping pembrolizumab treatment. 
After the end of treatment, each participant will be followed for the 
occurrence of AEs and spontaneously reported pregnancy, as described in
Section 8.4.5. Participants will not be required to continue with posttreatment 
follow-up imaging for disease status.
All participants will be followed for OS until death, withdrawal of consent, 
lost to follow-up, or the end of the study. The end of the study will be 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).
Study Governance Committees:
Steering Committee
Yes
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
0843R7
08SHQL

PRODUCT: MK-7902 (E7080/lenvatinib) and MK-3475 (pembrolizumab)
20
PROTOCOL/AMENDMENT NO.: 007-07 (E7080-G000-314)
MK-7902-007-07 FINAL PROTOCOL
18-AUG-2022
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 8.
0843R7
08SHQL

PRODUCT: MK-7902 (E7080/lenvatinib) and MK-3475 (pembrolizumab)
21
PROTOCOL/AMENDMENT NO.: 007-07 (E7080-G000-314) 
MK-7902-007-07 FINAL PROTOCOL
18-AUG-2022
1.2
Schema
NOTE: As of Amendment 007-06, lenvatinib and matching placebo and the Second-course Treatment Phase have been 
removed from the study. The original study design and updates to this design as of Amendment 007-06 (indicated by 
strikethrough) are depicted in Figure 1.
Figure 1
Original and Updated Study Design: Initial Treatment Phase
0843R7
08SHQL

PRODUCT: MK-7902 (E7080/lenvatinib) and MK-3475 (pembrolizumab)
22
PROTOCOL/AMENDMENT NO.: 007-07 (E7080-G000-314)
MK-7902-007-07 FINAL PROTOCOL
18-AUG-2022
1.3
Schedule of Activities (SoA)
1.3.1
Initial Treatment Phase
NOTE: As of Amendment 007-06, lenvatinib and matching placebo have been removed from the study. Participants who 
remain on treatment will receive open-label pembrolizumab monotherapy as per protocol. Administration of lenvatinib and 
placebo, collection of ePRO data, and collection of most of the blood biomarkers have been removed from the SoA. Other 
study procedures specific to lenvatinib/matching have also been removed.
Study Period
Screening
Treatment
Cycle = 21 Days
EOT
Posttreatment
Notes
Safety
Follow-
up
Follow-
up
Survival
Follow-
up
All procedures are to 
be performed before 
study intervention
administration unless 
otherwise indicated.
Refer to Section 8.11 
for visit details.
Visit Timing/
Cycle Number
-28 to -1
1
2
3
4
5
6 to 35
At 
DC
30 Days 
post last 
dose
Every
12 weeks
Every
12 weeks
Cycle Day
(±3 days unless 
otherwise specified)
1
8
15
1
15
1
1
1
1

Scheduling Window 
(Days)
+ 3
± 3
±3
± 3
± 3
± 3
± 3
± 3
± 3
+ 7
± 7
± 14
Administrative and General Procedures
Informed consent
X
ICF must be signed 
before any protocol-
specific screening 
procedures are
performed. Additional 
consent is required at 
PD.
Inclusion/exclusion 
criteria
X
Participant 
identification card
X
X
Update at C1D1.
Demographic and 
medical history
X
0843R7
08SHQL

PRODUCT: MK-7902 (E7080/lenvatinib) and MK-3475 (pembrolizumab)
23
PROTOCOL/AMENDMENT NO.: 007-07 (E7080-G000-314)
MK-7902-007-07 FINAL PROTOCOL
18-AUG-2022
Study Period
Screening
Treatment
Cycle = 21 Days
EOT
Posttreatment
Notes
Safety
Follow-
up
Follow-
up
Survival
Follow-
up
All procedures are to 
be performed before 
study intervention
administration unless 
otherwise indicated.
Refer to Section 8.11 
for visit details.
Visit Timing/
Cycle Number
-28 to -1
1
2
3
4
5
6 to 35
At 
DC
30 Days 
post last 
dose
Every
12 weeks
Every
12 weeks
Cycle Day
(±3 days unless 
otherwise specified)
1
8
15
1
15
1
1
1
1

Scheduling Window 
(Days)
+ 3
± 3
±3
± 3
± 3
± 3
± 3
± 3
± 3
+ 7
± 7
± 14
Prior/concomitant 
medications
X
Prior concomitant 
medications received 
within 30 days before the 
first dose of study 
intervention through 
30 days after the last 
dose of study 
intervention (or 90 days 
if used to treat an SAE)
will be recorded.
Treatment 
randomization
X
Dose within 3 days of 
randomization.
0843R7
08SHQL

PRODUCT: MK-7902 (E7080/lenvatinib) and MK-3475 (pembrolizumab)
24
PROTOCOL/AMENDMENT NO.: 007-07 (E7080-G000-314)
MK-7902-007-07 FINAL PROTOCOL
18-AUG-2022
Study Period
Screening
Treatment
Cycle = 21 Days
EOT
Posttreatment
Notes
Safety
Follow-
up
Follow-
up
Survival
Follow-
up
All procedures are to 
be performed before 
study intervention
administration unless 
otherwise indicated.
Refer to Section 8.11 
for visit details.
Visit Timing/
Cycle Number
-28 to -1
1
2
3
4
5
6 to 35
At 
DC
30 Days 
post last 
dose
Every
12 weeks
Every
12 weeks
Cycle Day
(±3 days unless 
otherwise specified)
1
8
15
1
15
1
1
1
1

Scheduling Window 
(Days)
+ 3
± 3
±3
± 3
± 3
± 3
± 3
± 3
± 3
+ 7
± 7
± 14
Study Intervention Administration
Pembrolizumab 
administration
X
X
X
X
X
X
Pembrolizumab 200 mg 
IV Q3W.
Tumor Scans
Tumor scans and 
response assessment
(thorax, abdomen, 
pelvis)
X*
X
*Perform Q9W 
(63±7 days) from 
randomization through 
Week 54, then Q12W 
(84 ±7 days) 
subsequently (ie, after 
Weeks 9, 18, 27, 36, 45, 
54, 66, 78, 90, etc.).
-Schedule should be 
followed regardless of 
treatment delays.
-If imaging was obtained 
within 4 weeks before 
DC, scan at DC is not 
mandatory.
0843R7
08SHQL

PRODUCT: MK-7902 (E7080/lenvatinib) and MK-3475 (pembrolizumab)
25
PROTOCOL/AMENDMENT NO.: 007-07 (E7080-G000-314)
MK-7902-007-07 FINAL PROTOCOL
18-AUG-2022
Study Period
Screening
Treatment
Cycle = 21 Days
EOT
Posttreatment
Notes
Safety
Follow-
up
Follow-
up
Survival
Follow-
up
All procedures are to 
be performed before 
study intervention
administration unless 
otherwise indicated.
Refer to Section 8.11 
for visit details.
Visit Timing/
Cycle Number
-28 to -1
1
2
3
4
5
6 to 35
At 
DC
30 Days 
post last 
dose
Every
12 weeks
Every
12 weeks
Cycle Day
(±3 days unless 
otherwise specified)
1
8
15
1
15
1
1
1
1

Scheduling Window 
(Days)
+ 3
± 3
±3
± 3
± 3
± 3
± 3
± 3
± 3
+ 7
± 7
± 14
Brain MRI
X
-Required at screening.
-Follow-up MRI is 
required if clinically 
indicated and at time of 
CR in participants with 
brain metastasis at 
Screening.
-If MRI is 
contraindicated or cannot 
be performed, CT of the 
head with contrast is 
acceptable.
0843R7
08SHQL

PRODUCT: MK-7902 (E7080/lenvatinib) and MK-3475 (pembrolizumab)
26
PROTOCOL/AMENDMENT NO.: 007-07 (E7080-G000-314)
MK-7902-007-07 FINAL PROTOCOL
18-AUG-2022
Study Period
Screening
Treatment
Cycle = 21 Days
EOT
Posttreatment
Notes
Safety
Follow-
up
Follow-
up
Survival
Follow-
up
All procedures are to 
be performed before 
study intervention
administration unless 
otherwise indicated.
Refer to Section 8.11 
for visit details.
Visit Timing/
Cycle Number
-28 to -1
1
2
3
4
5
6 to 35
At 
DC
30 Days 
post last 
dose
Every
12 weeks
Every
12 weeks
Cycle Day
(±3 days unless 
otherwise specified)
1
8
15
1
15
1
1
1
1

Scheduling Window 
(Days)
+ 3
± 3
±3
± 3
± 3
± 3
± 3
± 3
± 3
+ 7
± 7
± 14
Efficacy Procedures
Subsequent 
antineoplastic 
therapy status
X
X
X
X
-All anticancer therapy 
will be recorded until 
time of death or 
termination of survival 
follow-up.
-If a clinic visit is not 
feasible, follow-up 
information may be 
obtained via telephone or 
e-mail.
Survival status
X
Participants may be 
contacted for survival 
status at any time during 
the course of the study.
Tumor Tissue Collection
Newly 
obtained/archival 
tissue sample for PD-
L1 analysis
X
-May use archival tissue 
sample obtained before 
screening period as part 
of the participant’s SOC.
-Central PD-L1 result 
will be blinded to the 
site.
0843R7
08SHQL

PRODUCT: MK-7902 (E7080/lenvatinib) and MK-3475 (pembrolizumab)
27
PROTOCOL/AMENDMENT NO.: 007-07 (E7080-G000-314)
MK-7902-007-07 FINAL PROTOCOL
18-AUG-2022
Study Period
Screening
Treatment
Cycle = 21 Days
EOT
Posttreatment
Notes
Safety
Follow-
up
Follow-
up
Survival
Follow-
up
All procedures are to 
be performed before 
study intervention
administration unless 
otherwise indicated.
Refer to Section 8.11 
for visit details.
Visit Timing/
Cycle Number
-28 to -1
1
2
3
4
5
6 to 35
At 
DC
30 Days 
post last 
dose
Every
12 weeks
Every
12 weeks
Cycle Day
(±3 days unless 
otherwise specified)
1
8
15
1
15
1
1
1
1

Scheduling Window 
(Days)
+ 3
± 3
±3
± 3
± 3
± 3
± 3
± 3
± 3
+ 7
± 7
± 14
EGFR, ALK, and 
ROS1 molecular 
status
X
-Not required for 
participants with 
squamous histology or 
K-ras mutation.
-May send tumor tissue 
to central laboratory for 
molecular testing if 
status is unknown and 
cannot be determined 
locally.
Clinical Procedures/Assessments
All screening 
procedures should be 
performed within 
28 days of 
randomization, unless 
otherwise noted.
Full physical 
examination
X*
X
*To be performed within 
7 days before start of 
study intervention.
Directed physical 
examination
X
X
X
X
X
X
X
X
X
0843R7
08SHQL

PRODUCT: MK-7902 (E7080/lenvatinib) and MK-3475 (pembrolizumab)
28
PROTOCOL/AMENDMENT NO.: 007-07 (E7080-G000-314)
MK-7902-007-07 FINAL PROTOCOL
18-AUG-2022
Study Period
Screening
Treatment
Cycle = 21 Days
EOT
Posttreatment
Notes
Safety
Follow-
up
Follow-
up
Survival
Follow-
up
All procedures are to 
be performed before 
study intervention
administration unless 
otherwise indicated.
Refer to Section 8.11 
for visit details.
Visit Timing/
Cycle Number
-28 to -1
1
2
3
4
5
6 to 35
At 
DC
30 Days 
post last 
dose
Every
12 weeks
Every
12 weeks
Cycle Day
(±3 days unless 
otherwise specified)
1
8
15
1
15
1
1
1
1

Scheduling Window 
(Days)
+ 3
± 3
±3
± 3
± 3
± 3
± 3
± 3
± 3
+ 7
± 7
± 14
Phone contact
X
Participants will be 
contacted by telephone 
on C1D8 to assess for 
development of early 
toxicity. If early toxicity 
is suspected, an 
unscheduled visit can 
occur before C1D15 if 
deemed necessary by the 
investigator.
Height
X
Vital signs, weight
X
X
X
X
X
X
X
X
X
X
X
Vital signs must be taken 
in the clinic.
12-lead ECG with 
QTc measurement
X
X
X
X
ECG at screening, C1D1, 
C2D1, D1 of every 
fourth cycle (12 weeks) 
thereafter (eg, C6, C10, 
C14, etc.) up until 
discontinuation. ECGs 
are only required at the 
EOT Visit for those 
participants that had 
received lenvatinib. 
ECHO/MUGA
X
X
Additional assessments 
may be performed as 
clinically indicated.
ECOG performance 
status
X
X
X
X
X
X
X
X
X
At screening, perform 
within 7 days before C1 
but before 
randomization.
0843R7
08SHQL

PRODUCT: MK-7902 (E7080/lenvatinib) and MK-3475 (pembrolizumab)
29
PROTOCOL/AMENDMENT NO.: 007-07 (E7080-G000-314)
MK-7902-007-07 FINAL PROTOCOL
18-AUG-2022
Study Period
Screening
Treatment
Cycle = 21 Days
EOT
Posttreatment
Notes
Safety
Follow-
up
Follow-
up
Survival
Follow-
up
All procedures are to 
be performed before 
study intervention
administration unless 
otherwise indicated.
Refer to Section 8.11 
for visit details.
Visit Timing/
Cycle Number
-28 to -1
1
2
3
4
5
6 to 35
At 
DC
30 Days 
post last 
dose
Every
12 weeks
Every
12 weeks
Cycle Day
(±3 days unless 
otherwise specified)
1
8
15
1
15
1
1
1
1

Scheduling Window 
(Days)
+ 3
± 3
±3
± 3
± 3
± 3
± 3
± 3
± 3
+ 7
± 7
± 14
AE monitoring
X
X
Report AEs occurring 
within 30 days after the 
last dose of study 
intervention.
Report SAEs occurring 
within 90 days after the 
last dose of study 
intervention, or 30 days 
after the last dose of 
study intervention if a 
new anticancer therapy is 
initiated, whichever is 
earlier.
Laboratory Procedures/Assessments: Analysis by Local Laboratory
All screening 
procedures should be 
performed within 
28 days of 
randomization, unless 
otherwise noted.
0843R7
08SHQL

PRODUCT: MK-7902 (E7080/lenvatinib) and MK-3475 (pembrolizumab)
30
PROTOCOL/AMENDMENT NO.: 007-07 (E7080-G000-314)
MK-7902-007-07 FINAL PROTOCOL
18-AUG-2022
Study Period
Screening
Treatment
Cycle = 21 Days
EOT
Posttreatment
Notes
Safety
Follow-
up
Follow-
up
Survival
Follow-
up
All procedures are to 
be performed before 
study intervention
administration unless 
otherwise indicated.
Refer to Section 8.11 
for visit details.
Visit Timing/
Cycle Number
-28 to -1
1
2
3
4
5
6 to 35
At 
DC
30 Days 
post last 
dose
Every
12 weeks
Every
12 weeks
Cycle Day
(±3 days unless 
otherwise specified)
1
8
15
1
15
1
1
1
1

Scheduling Window 
(Days)
+ 3
± 3
±3
± 3
± 3
± 3
± 3
± 3
± 3
+ 7
± 7
± 14
Serum β-HCG or 
urine pregnancy test
(WOCBP only)
X
X
X
X
X
X
X
X
WOCBP require 
negative test prior to 
randomization. If more 
than 24 hours have 
elapsed prior to first dose 
of study intervention, 
another pregnancy test is 
required prior to starting 
study intervention.
A serum or urine 
pregnancy test will be 
performed per Appendix 
2. Refer to Sections 5.1, 
5.2, 8.3.5 and 10.5.3.
HIV, hepatitis B and 
C screen
X
Required at baseline if 
mandated by local health 
authority.
Hematology and 
clinical chemistry 
laboratory 
assessment
X
X
X
X
X
X
X
X
X
-Performed locally 
within 10 days before 
first dose.
-After C1, collect within 
3 days before dosing.
0843R7
08SHQL

PRODUCT: MK-7902 (E7080/lenvatinib) and MK-3475 (pembrolizumab)
31
PROTOCOL/AMENDMENT NO.: 007-07 (E7080-G000-314)
MK-7902-007-07 FINAL PROTOCOL
18-AUG-2022
Study Period
Screening
Treatment
Cycle = 21 Days
EOT
Posttreatment
Notes
Safety
Follow-
up
Follow-
up
Survival
Follow-
up
All procedures are to 
be performed before 
study intervention
administration unless 
otherwise indicated.
Refer to Section 8.11 
for visit details.
Visit Timing/
Cycle Number
-28 to -1
1
2
3
4
5
6 to 35
At 
DC
30 Days 
post last 
dose
Every
12 weeks
Every
12 weeks
Cycle Day
(±3 days unless 
otherwise specified)
1
8
15
1
15
1
1
1
1

Scheduling Window 
(Days)
+ 3
± 3
±3
± 3
± 3
± 3
± 3
± 3
± 3
+ 7
± 7
± 14
Urinalysis/urine 
dipstick testing
X
X
X
X
X
X
-Performed locally 
within 7 days before first 
dose.
After C1, collect within 
3 days before dosing.
-Urinalysis is required at 
screening and every 4 
cycles for participants 
who received
lenvatinib/matching 
placebo. After C1, 
collect within 3 days 
before dosing.
PT/INR and 
aPTT/PTT
X
-Screening samples 
collected within 10 days 
of treatment initiation.
-Additional testing to be 
conducted as clinically 
indicated for participants 
taking anticoagulant 
therapy.
0843R7
08SHQL

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Study Period
Screening
Treatment
Cycle = 21 Days
EOT
Posttreatment
Notes
Safety
Follow-
up
Follow-
up
Survival
Follow-
up
All procedures are to 
be performed before 
study intervention
administration unless 
otherwise indicated.
Refer to Section 8.11 
for visit details.
Visit Timing/
Cycle Number
-28 to -1
1
2
3
4
5
6 to 35
At 
DC
30 Days 
post last 
dose
Every
12 weeks
Every
12 weeks
Cycle Day
(±3 days unless 
otherwise specified)
1
8
15
1
15
1
1
1
1

Scheduling Window 
(Days)
+ 3
± 3
±3
± 3
± 3
± 3
± 3
± 3
± 3
+ 7
± 7
± 14
Thyroid function 
(T3, T4, and TSH)
X
X
X
X
X
X
At Screening, C2D1, 
then every 2 cycles 
thereafter.
-Screening samples to be 
collected within 10 days
before first dose.
-Participants may be 
dosed in subsequent 
cycles after C1D1 while 
thyroid function tests are 
pending.
-After C1, collect within 
3 days before dosing.
-Free T3 and Free T4 are
acceptable.
-May use central 
laboratory only if local 
laboratory is not 
capable.
Biomarkers: Analysis by Central Laboratory
Blood for genetic 
analysis
X
-Collect before study 
intervention. 
Abbreviations: AE = adverse event; ALK = anaplastic lymphoma kinase gene; ANC = absolute neutrophil count; aPTT = activated partial thromboplastin time; BP = blood 
pressure; CT = computed tomography; CXDY= Cycle X Day Y; DC = discontinuation; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative 
Oncology Group; EGFR = epidermal growth factor receptor; EOT = end of treatment; ePRO = electronic patient-reported outcome; FSH = follicle-stimulating hormone; 
FT3 = free triiodothyronine; FT4 = free thyroxine; β-HCG = β human chorionic gonadotropin; HIV = human immunodeficiency virus; ICF = informed consent form; 
INR = international normalized ratio; IV = intravenous; K-ras = Kirsten rat sarcoma oncogene; MRI = magnetic resonance imaging; MUGA = multigated acquisition; 
PD = progressive disease; PD-L1 = programmed cell death ligand 1; PK = pharmacokinetic(s); PO = oral(ly); PT = prothrombin time; PTT = partial thromboplastin time; 
QXW = every X weeks; QD = once daily; ROS1 = ROS proto-oncogene 1; SAE = serious adverse event; ; T3 = triiodothyronine; T4 = thyroxine; WOCBP = women of 
childbearing potential; SoA = schedule of activities; SOC = standard of care.
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1.3.2
Second-course Treatment Phase
NOTE: As of Amendment 007-06, the Second-course Treatment Phase has been removed from the study.
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2
INTRODUCTION
NOTE: As of Amendment 007-06, lenvatinib and matching placebo have been removed 
from the study. Subsections 2.1 Study Rationale and 2.2 Background are based on the 
original study design and have been left unchanged for reference.
2.1
Study Rationale
The global incidence of lung cancer was 1.8 million in 2012, resulting in an estimated 
1.6 million deaths [World Health Organization 2012]. In the United States, the 2018
estimated incidence of new diagnoses was 234,030, and the estimated number of deaths was 
154,050 [National Cancer Institute 2018]. NSCLC represents approximately 80% to 85% of 
all lung cancers. Of patients with NSCLC, tumor histology is approximately 40% to 60% 
adenocarcinoma, 10% to 15% squamous, 5% neuroendocrine, and the rest, not otherwise 
specified [Sulpher, J. A., et al 2013].
Approximately 80% of patients with NSCLC have advanced disease not amenable to surgical 
resection at the time of diagnosis. The 5-year relative survival for patients with any lung 
cancer overall and metastatic lung cancer specifically has been reported to be 18.6% and 
4.7%, respectively [National Cancer Institute 2018].
Pembrolizumab monotherapy is the current standard of care (SOC) for the treatment of 
patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
and previously untreated advanced or metastatic NSCLC with programmed cell death 
ligand 1 (PD-L1) TPS ≥50% and with no epidermal growth factor receptor (EGFR) or 
anaplastic lymphoma kinase (ALK) genomic tumor aberrations. Approximately 30% of 
patients with newly diagnosed, advanced NSCLC highly express PD-L1 with a TPS ≥50% 
[Reck, M., et al 2016].
KEYNOTE-024, a Phase 3, randomized, open-label study, compared pembrolizumab 
monotherapy to standard first-line (1L) platinum-doublet therapy in 305 previously untreated 
participants with advanced NSCLC and PD-L1 TPS ≥50%. Results from KEYNOTE-024 
indicated a significant PFS benefit for pembrolizumab over platinum-doublet therapy, with a 
hazard ratio (HR) of 0.50 (95% confidence interval [CI], 0.37-0.68, p<0.001). Median PFS 
was 10.3 months (95% CI, 6.7 months to not reached) with pembrolizumab and 6.0 months 
(95% CI, 4.2-6.2 months) with platinum-doublet. Additionally, there was an OS benefit, with 
an HR of 0.60 (95% CI, 0.41-0.89; p=0.005); median OS was not reached in either treatment 
arm. The Kaplan-Meier estimates showed 80.2% (95% CI, 72.9%-85.7%) of participants 
treated with pembrolizumab and 72.4% (95% CI, 64.5%-78.9%) of participants treated with 
platinum-doublet therapy were alive at 6 months. Furthermore, the ORR was higher in the 
pembrolizumab arm than in the platinum-doublet arm (44.8% vs 27.8%, respectively) [Reck, 
M., et al 2016].
The results from KEYNOTE-024 established pembrolizumab as 1L therapy for patients 
whose tumors have a TPS ≥50% with no EGFR or ALK genomic tumor aberrations.
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Additionally, KEYNOTE-042, a randomized, open-label, Phase 3 study, compared 
pembrolizumab monotherapy to SOC platinum-based chemotherapy in previously untreated 
participants with advanced or metastatic NSCLC whose tumors express PD-L1 TPS ≥1%,
confirmed the OS treatment effect of pembrolizumab monotherapy observed in participants 
with TPS ≥50% NSCLC in KEYNOTE-024, and extended these benefits to a broader 
population with TPS ≥1% NSCLC. Results from KEYNOTE-042 indicated a significant OS 
benefit for pembrolizumab over platinum-doublet therapy, with an HR of 0.81 (95% CI, 
0.71-0.93, p=0.0018). Median OS was 16.7 months (95% CI, 13.9-19.7 months) with 
pembrolizumab and 12.1 months (95% CI, 11.3-13.3 months) with platinum-doublet [Lopes, 
G., et al 2018]. The Kaplan-Meier estimates showed 39.3% of participants treated with 
pembrolizumab and 28.0% of participants treated with platinum-doublet therapy were alive 
at 6 months (data on file).
While the benefits observed in KEYNOTE-024 (in participants with advanced or metastatic 
NSCLC whose tumors expressed PD-L1 TPS ≥50 %) and KEYNOTE-042 (in participants 
with advanced or metastatic NSCLC whose tumors expressed PD-L1 TPS ≥1%) were 
substantial for these participants with NSCLC, the benefits may be improved further in 
metastatic NSCLC with PD-L1 TPS ≥1% population, possibly through the combination of 
pembrolizumab with other therapies such as lenvatinib, a multiple RTKi with a potentially 
differentiated profile.
Lenvatinib has been studied as both monotherapy and in combination with chemotherapy for 
the treatment of advanced NSCLC. As a single agent, a randomized Phase 2 study of 
lenvatinib versus placebo was conducted in 135 participants with locally advanced or 
metastatic nonsquamous NSCLC who had failed to respond to at least 2 systemic anticancer 
regimens. Eighty-nine participants received 24 mg of lenvatinib QD and 46 received placebo; 
all participants received best supportive care in addition to study intervention. Median OS 
was 38.4 weeks for lenvatinib and 24.1 weeks for placebo, median PFS was 20.9 weeks for 
lenvatinib and 7.9 weeks for placebo, ORR was 10.1% for lenvatinib and 2.2% for placebo, 
and the disease control rate (DCR) was 42.7% for lenvatinib and 19.6% for placebo. Grade 3
and/or 4 AEs occurred in 69% of lenvatinib recipients and 50% of placebo recipients. Grade 
3 and/or 4 AEs were dyspnea and pneumonia in both treatment groups, as well as 
hypertension in the lenvatinib group [Havel, L., et al 2014].
Lenvatinib was studied in combination with chemotherapy in a multicenter, open-label,
Phase 1, dose-finding study (Study E7080-J081-110). This study, conducted in Japanese 
participants with chemotherapy-naïve NSCLC, investigated lenvatinib in combination with 
carboplatin/paclitaxel to establish the maximum tolerated dose (MTD). The MTD of 
lenvatinib was determined to be 4 mg BID after dose-limiting toxicities (DLTs) were 
experienced at 6 mg BID (febrile neutropenia, gingival infection [n=2]). A dose-expansion 
cohort was added and 28 participants were dosed in total: 12 in the dose-finding cohort and 
16 participants in the dose-expansion cohort. In total, 22 participants were dosed at 4 mg BID 
with 6 at 6 mg BID. The ORR was 61% (95% CI: 41%, 79%) and comprised 1 CR and 
16 partial responses (PRs). The median PFS was reported as 9 months. Of the 22 participants 
in the 4-mg BID dose level, the most frequently reported AEs were thrombocytopenia, 
neutropenia, leukopenia, peripheral sensory neuropathy, arthralgia, and alopecia. The most 
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frequently reported Grade 3 or 4 AEs were neutropenia, leukopenia, hypertension, 
thrombocytopenia, and febrile neutropenia. No AEs resulting in death were reported [Nishio, 
M., et al 2013].
The present study is designed to further evaluate the safety and efficacy of combination 
therapy of lenvatinib and pembrolizumab in adult participants with treatment-naïve, 
metastatic NSCLC with a TPS ≥1%. The outcomes for participants evaluated in this study 
would be further improved if the safety profile of a pembrolizumab plus lenvatinib 
combination remains acceptable and is shown to improve outcomes compared with
pembrolizumab monotherapy; thus, this study could support the regulatory approval of this 
combination in this patient population.
2.2
Background
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to the 
PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in 
vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an IV immunotherapy for advanced malignancies. Keytruda® (pembrolizumab) is indicated 
for the treatment of patients across a number of indications. For more details on specific 
indications, refer to the pembrolizumab Investigator’s Brochure (IB).
Lenvatinib (also known as E7080 or MK-7902) inhibits the kinase activities of vascular 
endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and 
VEGFR3 (FLT4). Lenvatinib inhibits other kinases that have been implicated in pathogenic 
angiogenesis, tumor growth, and cancer progression in addition to their normal cellular 
functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; platelet-
derived growth factor receptor alpha (PDGFRα), KIT, and RET. Lenvatinib also exhibited 
antiproliferative activity in cell lines dependent on activated FGFR signaling with a 
concurrent inhibition of FGF-receptor substrate 2α phosphorylation. Once daily (QD) dosing 
of lenvatinib combined with pembrolizumab is currently being developed for the treatment of 
metastatic NSCLC. Refer to the respective IBs/approved labeling for detailed background 
information on pembrolizumab and lenvatinib.
2.2.1
Pharmaceutical and Therapeutic Background
2.2.1.1
Lenvatinib
Angiogenesis, the formation of new blood vessels from a pre-existing vascular network, is 
essential for tumor growth and metastasis. VEGF and its family of receptors (VEGFRs 1-3) 
play a major role in tumor angiogenesis [Ferrara, N., et al 2003] [Ellis, L. M. and Hicklin, D. 
J. 2008] [Tammela, T. and Alitalo, K. 2010]. Accumulated evidence suggests that FGF and 
its receptor tyrosine kinase, FGFR, also play important roles in tumor angiogenesis [Cross, 
M. J. and Claesson-Welsh L. 2001] [Lieu, C., et al 2011] [Limaverde-Sousa, G., et al 2014].
Lenvatinib is a potent multiple RTKi that selectively inhibits VEGF receptors, VEGFR1 
(FLT1), VEGFR2 (KDR), VEGFR3 (FLT4), FGFR1-4, PDGFRα, c-kit, and RET. Among 
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known kinase inhibitors in clinical use, lenvatinib is one of the only inhibitors currently 
labeled with a mechanism of action as an inhibitor of not only VEGFRs but also FGFRs, 
both of which are currently believed to be very important for tumor angiogenesis.
Lenvatinib inhibited cell free kinase activities for VEGFR1-3 and FGFR1-3 with Ki values 
around 1 nmol/L, and 8-22 nmol/L, respectively. In cell-based assays, lenvatinib inhibited 
VEGF-derived and FGF-derived tube formation of HUVEC with IC50 values of 2.1 and 7.3 
nmol/L, respectively. Analysis of the signal transduction molecules revealed that lenvatinib 
inhibited both the MAPK pathway and the mTOR-S6K-S6 pathway in HUVECs triggered by 
activated VEGFR and FGFR. Furthermore, lenvatinib (10, 30 mg/kg) significantly inhibited 
both VEGF- and FGF-driven angiogenesis in a murine in vivo model [Yamamoto, Y., et al 
2014]. In vivo, lenvatinib exhibited antitumor activity against various human tumor 
xenografts in athymic mice including 5 types of thyroid carcinomas (differentiated [papillary 
and follicular], anaplastic, squamous, and medullary thyroid carcinomas), RCC, HCC, 
melanoma, gastric cancer, NSCLC, ovarian cancer, Ewing’s sarcoma, and osteosarcoma. In 
addition, the antitumor activity of lenvatinib in combination with other anticancer agents in 
several xenograft models was greater than that of lenvatinib or the other agents alone.
In summary, lenvatinib inhibited VEGF-driven VEGFR2 phosphorylation and suppressed 
proliferation and tube formation in human umbilical vein endothelial cell (HUVEC) models. 
Antitumor activity of lenvatinib in vivo has been shown in numerous xenograft animals. 
These results suggest that lenvatinib may be a novel anticancer therapy through inhibition of 
angiogenesis and may be useful as either monotherapy or in combination with other 
anticancer drugs.
2.2.1.2
Pembrolizumab
Keytruda® (pembrolizumab) is indicated for the treatment of patients across a number of 
indications. For more details on specific indications, refer to the pembrolizumab IB.
2.2.1.3
Pembrolizumab With Lenvatinib
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved 
prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and 
pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. 
Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable 
objective tumor responses in cancers such as melanoma [Dudley, M. E., et al 2005] [Hunder, 
N. N., et al 2008]. In preclinical models, lenvatinib decreased the tumor-associated 
macrophage (TAM) population, which is known as an immune-regulator in the tumor 
microenvironment. The decrease in TAM population was accompanied by increases in 
activated cytotoxic T-cell populations through stimulation of interferon-gamma signaling, 
resulting in increased immune activation [Kimura, T., et al 2018]. The immune-modulating 
effect of lenvatinib may result in a potent combination effect with PD-1/L1 signal inhibitors. 
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The effect of combining lenvatinib with an antihuman PD-1 humanized mAb was 
investigated in 4 murine tumor isograft models, which showed significant tumor growth 
inhibition compared with control. In the RAG murine tumor isograft tumor model, survival 
in the group treated with the combination was significantly longer than that of the respective 
monotherapy groups. In the CT26 murine tumor isograft model, treatment with the 
combination significantly increased the population of activated cytotoxic T-cells compared 
with that of the respective monotherapy groups [Kato, Y., et al 2019]. All treatments were 
well tolerated and severe body weight loss was not observed.
2.2.2
Preclinical and Clinical Studies
2.2.2.1
Completed Studies With Pembrolizumab and Lenvatinib
Refer to the respective IBs for further information on completed studies with lenvatinib and 
pembrolizumab.
2.2.3
Ongoing Clinical Studies of Pembrolizumab and Lenvatinib
Pembrolizumab is under evaluation in patients with NSCLC as monotherapy and in 
combination with chemotherapy, immunotherapy, and targeted therapies. Lenvatinib is being
studied in patients with different types of solid tumors, including NSCLC, and in 
combination with other therapies, including PD-1-targeted therapies. A full list of ongoing 
studies can be found in the respective IBs of pembrolizumab [IB Edition 16 2018] and 
lenvatinib [IB Edition 15-Eisai 2018]. Details of the ongoing study 111/KEYNOTE-146 are 
outlined below.
Study 111/KEYNOTE-146
Study 111/KEYNOTE-146, is a multicenter, open-label, Phase 1b/2 clinical study to evaluate 
the efficacy and safety of lenvatinib in combination with pembrolizumab. The primary 
objective of the Phase 1b portion of the study is to determine the MTD in participants with 
unresectable solid tumors (endometrial cancer, melanoma, NSCLC, RCC, squamous cell 
carcinoma of the head and neck, and urothelial cancer) who have progressed after treatment 
with approved therapies or for which there are no available standard effective therapies. The 
primary endpoint of the initial part of Phase 2 is ORR after 24 weeks of treatment, with select 
secondary endpoints, including OR, DCR, PFS, and duration of response (DOR).
As of the data cutoff of 01-DEC-2017, 20 participants with NSCLC were enrolled (data on 
file). Of the enrolled participants, 9 (45%) were PD-L1(+) (TPS ≥1%), 5 (25%) were 
PD-L1(), and 6 (30%) were not tested; 3 (15%) were treatment-naïve; and 6 (30%), 
9 (45%), and 2 (10%) had 1, 2, and ≥3 prior lines of systemic therapy, respectively. The 
primary endpoint of ORR at Week 24 was 30.0% (95% CI, 11.9%–54.3%). Grade 3 and 4 
treatment-related AEs occurred in 11 participants (55%) and 1 participant (5%), respectively 
(ie, increased aspartate aminotransferase [AST]). There was 1 fatal treatment-related AE 
(exsanguination that was deemed possibly related to study intervention). The most common 
Grade 3 treatment-related AEs were hypertension (30% [6 of 20 subjects]) and fatigue, 
diarrhea, and hyponatremia (15% [3 of 20 subjects]). These findings indicate that the 
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combination of lenvatinib with pembrolizumab shows promising clinical activity with a 
manageable safety profile in previously treated patients with metastatic NSCLC who were 
not preselected for PD-L1 status.
2.3
Benefit/Risk Assessment
NOTE: Data from an interim safety and futility eDMC for LEAP-007 (data cutoff: 
19-MAY-2021) indicated that the study met the prespecified nonbinding futility criteria 
for OS for the combination of lenvatinib plus pembrolizumab compared with placebo 
plus pembrolizumab and the benefit-risk assessment was not considered positive to 
continue the study as designed. Therefore, the benefit-risk assessment of 
pembrolizumab plus lenvatinib is no longer applicable and has been removed from this 
section.
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.
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
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
NOTE: As of Amendment 007-06, lenvatinib and matching placebo have been removed 
from the study. All participants remaining on study will continue on open-label 
pembrolizumab monotherapy. No further analyses of efficacy endpoints will be 
performed. Exploratory objectives may not be pursued.
Participants were screened for up to 28 days, then randomized, and continued study 
treatment until discontinuation (defined in Section 7.1) OR stop/unblinding of study 
intervention due to the futility analysis criterion for OS being met.
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In adult participants with treatment-naïve, metastatic NSCLC expressing PD-L1 (TPS ≥1%):
Objectives
Endpoints
Primary

Objective: To compare progression-free 
survival (PFS) as assessed by blinded 
independent central review (BICR) 
according to Response Evaluation 
Criteria in Solid Tumors, version 1.1 
(RECIST 1.1), adjusted to follow a 
maximum of 10 target lesions and a 
maximum of 5 target lesions per organ,
for the combinations of pembrolizumab + 
lenvatinib versus pembrolizumab + 
matching placebo
−
Hypothesis (H1): The combination of 
pembrolizumab + lenvatinib has 
superior PFS per RECIST 1.1, as 
defined in Section 4.2.1.1.1, based on 
BICR

PFS, defined as the time from 
randomization to the first documented 
progressive disease (PD) or death due to 
any cause, whichever occurs first*

Objective: To compare overall survival 
(OS) for the combinations of 
pembrolizumab + lenvatinib versus 
pembrolizumab + matching placebo
−
Hypothesis (H2): The combination of 
pembrolizumab + lenvatinib has
superior OS

OS, defined as the time from 
randomization to death due to any cause*
Secondary

Objective: To compare objective response
rate (ORR) as assessed by BICR 
according to RECIST 1.1, as defined in 
Section 4.2.1.1.1, for the combinations of 
pembrolizumab + lenvatinib versus 
pembrolizumab + matching placebo
−
Hypothesis (H3): The combination of 
pembrolizumab + lenvatinib has 
superior ORR per RECIST 1.1, as 
defined in Section 4.2.1.1.1, based on 
BICR

Objective response (OR), defined as a 
confirmed complete response (CR) or 
partial response (PR)
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Objectives
Endpoints

Objective: To evaluate the safety and
tolerability for the combinations of
pembrolizumab + lenvatinib versus 
pembrolizumab + matching placebo

Adverse events (AEs) and study 
intervention discontinuation due to AEs

Objective: To compare the mean change 
from baseline in the global health 
status/quality of life (QoL), cough, chest 
pain, dyspnea, and physical functioning 
for the combinations of pembrolizumab + 
lenvatinib versus pembrolizumab + 
matching placebo

Change from baseline for the following 
patient-reported outcomes (PROs)
scales/items: global health status/QoL 
(EORTC QLQ-C30 items 29 and 30), 
cough (EORTC QLQ-LC13 item 31), 
chest pain (EORTC QLQ-LC13 item 40), 
dyspnea (EORTC QLQ-C30 item 8), and 
physical functioning (EORTC QLQ-C30 
items 1-5)

Objective: To compare the time to true 
deterioration (TTD) in global health 
status/QoL, cough, chest pain, dyspnea, 
and physical functioning for the 
combinations of pembrolizumab + 
lenvatinib versus pembrolizumab + 
matching placebo

TTD, defined as the time from baseline 
to the first onset of a ≥10-point 
deterioration from baseline with 
confirmation by the subsequent visit of a 
≥10-point deterioration from baseline in 
global health status/QoL (EORTC 
QLQ-C30 items 29 and 30), cough 
(EORTC QLQ-LC13 item 31), chest pain 
(EORTC QLQ-LC13 item 40), dyspnea 
(EORTC QLQ-C30 item 8), and physical 
functioning (EORTC QLQ-C30 items 
1-5)

TTD in the composite endpoint 
(combination of cough [QLQ-LC13 item 
31], chest pain [QLQ-LC13 item 40], or 
dyspnea [QLQ-C30 item 8]) defined as 
the time to first onset of a ≥10-point 
deterioration from baseline in any one of 
3 scale items with confirmation by the 
subsequent visit of a ≥10-point 
deterioration from baseline in the same 
scale as the first onset
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Objectives
Endpoints
Tertiary/Exploratory
*This study will be considered to have met its success criteria if the combination of 
pembrolizumab + lenvatinib is superior to pembrolizumab + matching placebo in PFS or OS.
4
STUDY DESIGN
4.1
Overall Design
NOTE: As of Amendment 007-06, lenvatinib and matching placebo have been removed 
from the study. Participants who remain on treatment will receive open-label 
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pembrolizumab monotherapy, as per protocol. The Second-course Treatment Phase is 
removed from the study. This section has been updated accordingly.
The original study design was a randomized, double-blind, active-control with placebo, 
parallel-group, multisite study of IV pembrolizumab and oral lenvatinib in participants with 
Stage IV NSCLC and PD-L1 TPS ≥1% who have not had previously received systemic 
therapy for metastatic disease, whose tumors express PD-L1 with a TPS ≥1%, and in whom 
EGFR-, ALK-, or ROS proto-oncogene 1 (ROS1)-directed therapy is not indicated. 
Participants were randomized 1:1 to Arm A (pembrolizumab + lenvatinib) or Arm B
(pembrolizumab + matching placebo). Randomization was stratified by site geographic
region (East Asia vs non-East Asia), ECOG PS (0 vs 1), and TPS (1%-49% vs ≥50%).The 
original study design is depicted in Figure 1 (Initial Treatment Phase).
As of Amendment 007-06, lenvatinib and matching placebo have been removed from the 
treatment arms (Figure 1). All participants remaining on treatment in the study will receive 
open-label pembrolizumab monotherapy. Treatment with pembrolizumab will continue up to 
Cycle 35 or until reaching a discontinuation criterion (defined in Section 7.1). Imaging will 
continue until progression by local investigator has been determined.
Participants will be evaluated with radiographic imaging to assess response to treatment 
every 9 weeks from randomization through 54 weeks, then every 12 weeks until PD,
initiation of a new anticancer regimen, or completion of 35 cycles. All imaging obtained on 
study will be submitted to the imaging vendor for BICR, which will assess the images using 
RECIST 1.1 (see Section 8.2.1.5) for determination of OR, PFS, and DOR. After amendment 
007-06, imaging obtained on study will be submitted to the imaging vendor but these will not 
be assessed, similarly, verification of PD is no longer needed before treatment 
discontinuation. Treatment-based decisions may use site-assessed iRECIST, as described in 
Section 8.2.1.6, which allows for participants with initial site-assessed PD to continue 
treatment until PD is confirmed by the site 4 to 8 weeks later.
Adverse event monitoring will be ongoing throughout the study, and AEs will be graded by
severity according to the guidelines outlined in the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.0.
The study will be conducted in conformance with Good Clinical Practice (GCP).
Extension Study in China
NOTE: As of Amendment 007-06, enrollment in the Extension Study in China has been 
stopped; the planned enrollment goal of 120 participants was not reached.
Lenvatinib and matching placebo are removed from the extension study and it will proceed
identical to the global study as per this protocol amendment (eg, study endpoints, primary 
and secondary objectives, study procedures), with the exception of an additional 
supplemental statistical analysis plan (sSAP), which will provide details of analyses specific 
to Chinese participants.
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Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This Phase 3 study is being conducted to evaluate the efficacy and safety of pembrolizumab 
in metastatic NSCLC when administered in combination with lenvatinib. Lenvatinib (20 mg 
QD) will be evaluated in combination with the standard dose of pembrolizumab (200 mg 
Q3W).
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
This study will use PFS based on RECIST 1.1 criteria, adjusted to follow a maximum of 
10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR as a
primary endpoint and OR as a secondary efficacy endpoint. PFS and OR are acceptable 
measures of clinical benefit for a late-stage study that demonstrates superiority of a new 
antineoplastic therapy, especially if the magnitude of the effect is large and the therapy has 
an acceptable risk/benefit profile. The use of BICR and RECIST 1.1 to assess PFS and OR 
are typically considered acceptable by regulatory authorities. Images will be read by a central 
imaging vendor blinded to treatment assignment to minimize bias in the response 
assessments. In addition, the final determination of radiologic progression will be based on 
the central assessment of progression, rather than a local site investigator/radiology 
assessment. Real time determination of radiologic progression as determined by central 
review will be communicated to the site.
The primary efficacy endpoint OS has been recognized as the gold standard for the 
demonstration of superiority of a new antineoplastic therapy in randomized clinical studies.
For additional details about assessing efficacy endpoints using RECIST 1.1 and iRECIST, 
see Appendix 6.
4.2.1.1.1
RECIST 1.1
RECIST 1.1 will be used by the BICR when assessing images for efficacy measures and by 
the local site when determining eligibility (Section 8.2.1.5). Although traditional RECIST 1.1 
references a maximum of 5 target lesions in total and 2 per organ, this protocol has 
implemented an adjustment to RECIST 1.1 to follow a maximum of 10 target lesions in total
and 5 per organ.
4.2.1.1.2
Adjusted RECIST 1.1 for Immune-based Therapeutics iRECIST
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
following treatment with pembrolizumab (Section 8.2.1.6). Immunotherapeutic agents such 
as pembrolizumab may produce antitumor effects by potentiating endogenous cancer-specific 
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immune responses. The response patterns seen with such an approach may extend beyond the 
typical time course of responses seen with cytotoxic agents, and patients treated with 
pembrolizumab may manifest a clinical response after an initial increase in tumor burden or 
even the appearance of new lesions. Thus, standard RECIST 1.1 may not fully capture the 
treatment benefits from immunotherapeutic agents such as pembrolizumab. Based on an 
analysis of participants with melanoma enrolled in KEYNOTE-001 (KN001), 7% of 
evaluable participants experienced delayed or early tumor pseudoprogression. Of note, 
participants who had PD by RECIST 1.1 but not by the immune-related response criteria 
[Wolchok, J. D., et al 2009] had longer OS than participants with PD by both criteria [Hodi, 
F. S., et al 2014]. Additionally, the data suggest that RECIST 1.1 may underestimate the 
benefit of pembrolizumab in approximately 15% of participants. These findings support the 
need to apply an adjustment to RECIST 1.1 that takes into account the unique patterns of 
atypical responses in immunotherapy and enables treatment beyond initial radiographic 
progression, if the participant is clinically stable.
iRECIST assessment has been developed and published by the RECIST Working Group, 
with input from leading experts from industry and academia, along with participation from 
the United States Food and Drug Administration (FDA) and the European Medicines Agency 
(EMA) [Seymour, L., et al 2017]. The unidimensional measurement of target lesions, 
qualitative assessment of nontarget lesions, and response categories are identical to RECIST 
1.1, until progression is seen by RECIST 1.1. However, if a participant is clinically stable, 
additional imaging may be performed to confirm radiographic progression. iRECIST will be 
used by investigators to assess tumor response and progression and make treatment decisions 
as well as for exploratory efficacy analyses where specified.
4.2.1.2
Safety Endpoints
Safety parameters commonly used for evaluating investigational systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of AEs/serious AEs (SAEs); and changes in vital signs and laboratory 
values. Adverse events will be assessed as defined by the NCI Common Terminology 
Criteria for Adverse Events (CTCAE), Version 4.0.
4.2.1.3
Patient-reported Outcomes
NOTE: As of Amendment 007-06, ePRO data are no longer being collected.
Symptomatic improvement is considered a clinical benefit and accepted by health authorities. 
As part of the analyses for this study, participants will provide information regarding their 
health-related quality of life (HRQoL) via the following assessment tools: European 
Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC QLQ-
LC13, and EuroQoL EQ-5D-5L questionnaires. The ePROs are not pure efficacy or safety 
endpoints because they are affected by both PD and treatment tolerability.
4.2.1.3.1
EORTC QLQ-C30
EORTC QLQ-C30 is the most widely used cancer-specific, HRQoL instrument, which 
contains 30 items and measures 5 functional dimensions (physical, role, emotional, cognitive, 
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and social), 3 symptom items (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, 
sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), and a global 
health and QoL scale [Aaronson, N. K., et al 1993]. The EORTC QLQ-C30 is a 
psychometrically and clinically validated instrument appropriate for assessing QoL in 
oncology studies [Aaronson, N. K., et al 1993].
4.2.1.3.2
EORTC QLQ-LC13
The EORTC Quality of Life Questionnaire and Lung Cancer Module 13 (QLQ-LC13), a 
supplemental lung cancer-specific module used in combination with QLQ-C30, comprises 
multi-item and single-item measures of lung cancer-associated symptoms (cough, 
hemoptysis, dyspnea, and site-specific pain) and treatment-related symptoms (sore mouth, 
dysphagia, peripheral neuropathy, and alopecia) [Bergman, B., et al 1994]. It is scored on a 
4-point scale (1 = not at all, 2 = a little, 3 = quite a bit, 4 = very much) and has been 
translated and validated into more than 60 languages.
The EORTC QLQ-C30 and QLQ-LC13 are the most frequently used PRO measures in lung 
cancer clinical studies. The reliability, validity, and practicality of these instruments have 
been reported [Bergman, B., et al 1994] [Aaronson, N. K., et al 1993].
4.2.1.3.3
EuroQoL EQ-5D-5L
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome and will 
provide data to develop health utilities for use in health economic analyses [Rabin, R. and de 
Charro, F. 2001]. The 5 health state dimensions in the EQ-5D-5L include the following: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension 
is rated on a 5 point scale from 1 (no problem) to 5 (unable to/extreme problems). The EQ-
5D-5L also includes a graded (0 to 100) vertical visual analog scale on which the participant 
rates his or her general state of health at the time of the assessment. This instrument has been 
used extensively in cancer studies and published results from these studies support its 
validity and reliability [Pickard, A. S., et al 2007]. 
4.2.1.4
Pharmacokinetic Endpoints
Prior to Amendment 05, blood samples were obtained to measure the PK of pembrolizumab 
and lenvatinib. The Sponsor has determined sufficient pembrolizumab/lenvatinib PK data in 
NSCLC participants have been collected. As such, no further PK samples will be collected. 
Standard PK parameters of clearance (CL) and volume of distribution (V) at steady state are 
planned to be calculated for lenvatinib when coadministered with pembrolizumab, using the 
accepted mixed-effects modeling approach. PK data from this study may be combined with 
data from other studies and analyzed using standard population PK techniques to further 
characterize basic PK parameters, evaluate the effect of extrinsic and intrinsic factors in 
support of the proposed dosing regimen, and evaluate safety in the proposed participant 
population.
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4.2.1.5
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4.2.2
Rationale for the Use of Comparator/Placebo
Based on the results of KEYNOTE-024, pembrolizumab monotherapy has become the SOC 
for treating Stage IV NSCLC in patients with PD-L1 TPS ≥50% with no EGFR or ALK
genomic tumor aberrations. The study resulted in a significant PFS benefit for 
pembrolizumab over the SOC at the time (platinum-doublet therapy), with an HR of 
0.50 (95% CI, 0.37-0.68; p<0.001; median PFS, 10.3 months [95% CI, 6.7 to not reached] 
with pembrolizumab and 6.0 months [95% CI, 4.2-6.2 months] with platinum-doublet), as 
well as an OS benefit with an HR of 0.60 (95% CI 0.41-0.89; p=0.005; median OS was not 
reached in either treatment arm) [Reck, M., et al 2016]. The results from KEYNOTE-024 
established pembrolizumab as 1L therapy for patients whose tumors have a TPS ≥50% and in 
whom EGFR- or ALK-directed therapies are not indicated, and the regimen has received 
regulatory approval for this use by the FDA and EMA. Additionally, based on results from 
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KEYNOTE-042, pembrolizumab monotherapy is considered one of the treatment options in 
treating Stage IV NSCLC in patients with PD-L1 TPS ≥1% with no EGFR or ALK genomic 
tumor aberrations. The study resulted in a significant OS benefit for pembrolizumab over the 
SOC at the time (platinum-doublet therapy), with an HR of 0.81 (95% CI, 0.71-0.93;
p=0.0018). Median OS was 16.7 months (95% CI, 13.9-19.7 months) with pembrolizumab 
and 12.1 months (95% CI, 11.3-13.3 months) with platinum-doublet therapy [Lopes, G., et al 
2018].
The use of a lenvatinib matching placebo in combination with pembrolizumab will ensure the 
objectivity of the local investigators’ treatment decision and AE causality assessments, while 
still providing participants the SOC treatment.
4.3
Justification for Dose
4.3.1
Maximum Dose/Exposure for This Study
NOTE: As of Amendment 007-06, lenvatinib, matching placebo, and Second-course
treatment have been removed from the study. This section has been updated 
accordingly.
The maximum dose/exposure of pembrolizumab allowed in this study is 200 mg Q3W up to 
35 cycles (approximately 2 years) for the Initial Treatment Phase.
4.3.2
Rationale for Dose Interval and Study Design
4.3.2.1
Lenvatinib Dosing
NOTE: As of Amendment 007-06, lenvatinib and matching placebo have been removed 
from the study. This section is no longer applicable, but has been left unchanged for 
reference.
The dosing regimen of lenvatinib was selected based on the results of the Phase 1b portion of 
Phase 1b/2 Study 111/KEYNOTE-146, of which the primary endpoint was to determine the 
MTD and RP2D for lenvatinib in combination with pembrolizumab 200 mg Q3W. Thirteen 
participants (lenvatinib 24 mg/day + pembrolizumab 200 mg IV Q3W: n=3; lenvatinib 20 
mg/day + pembrolizumab 200 mg: n=10) were enrolled into the Phase 1b portion of the 
study. Eight of the participants had RCC, 2 had NSCLC, 2 had endometrial cancer, and 1 had 
melanoma. There were 2 DLTs at the dose of lenvatinib 24 mg/day + pembrolizumab 200 mg 
IV Q3W (1 participant had Grade 3 arthralgia and another had Grade 3 fatigue); hence, this 
was defined as the toxic dose. No DLTs were reported in the next 10 participants (expansion 
part), all of whom received the lenvatinib 20 mg/day + pembrolizumab 200 mg Q3W dose.
Based on review of all of the clinical data from these 13 participants, the MTD and RP2D 
were determined to be 20 mg of lenvatinib daily in combination with a fixed dose of 200 mg 
of pembrolizumab given Q3W. Based on the promising antitumor efficacy and tolerable 
safety profile seen in both the endometrial carcinoma and RCC expansion cohorts from 
Study 111/KEYNOTE-146 [Makker, V., et al 2018], 2 Phase 3 studies have been initiated for 
both of these tumor types, Study E7080-G000-309/KEYNOTE-775 and Study E7080-G000-
307/KEYNOTE-581.
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4.3.2.2
Pembrolizumab Dosing
The rationale for the use of a fixed dose of pembrolizumab in participants with solid tumors 
was based on the following:

Similar efficacy and safety of pembrolizumab when dosed at 2 mg/kg Q3W, 
10 mg/kg Q3W, or 10 mg/kg every 2 weeks in participants with melanoma and 
NSCLC

Flat exposure-response relationships of pembrolizumab for both efficacy and safety in 
the dose range of 2 mg/kg Q3W to 10 mg/kg Q3W

The lack of clinically relevant effect of tumor burden or indication on distribution 
behavior of pembrolizumab (as assessed by the population pharmacokinetics [PopPK] 
model)

Pharmacology data showing full target saturation in both systemic circulation 
(inferred from PK data) and tumor (inferred from physiologically based PK analysis) 
at 200 mg Q3W
The choice of pembrolizumab 200 mg Q3W as an appropriate fixed dose was based on 
simulations performed using the PopPK model of pembrolizumab, which showed the 
following for a fixed dose of 200 mg Q3W:

Provide 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

Maintain individual participant exposures in the exposure range associated with
maximal efficacy response that was established in participants with melanoma and 
NSCLC

Result in individual participant exposures within a range that was well tolerated and 
safe in participants with melanoma and NSCLC
Clinical data have shown meaningful improvement in benefit-risk, including OS, at 200 mg 
Q3W across multiple indications. Additionally, a fixed-dose regimen simplified the dosing 
regimen to be more convenient for physicians and to reduce the potential for dosing errors. A 
fixed-dosing scheme also reduced complexity in the logistical chain at treatment facilities 
and reduced wastage.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
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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 an unacceptably high number of discontinuations or withdrawals due to administrative 
reasons.
5
STUDY POPULATION
Male and female participants with Stage IV NSCLC, who express PD-L1 (TPS ≥1%), have 
received no systemic anticancer therapy for their Stage IV NSCLC, 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.
5.1
Inclusion Criteria
To be eligible for inclusion in this study, the participant must:
Type of Participant and Disease Characteristics
1. Have a histologically or cytologically confirmed diagnosis of NSCLC.
Note: Mixed tumors will be categorized by the predominant cell type; if small-cell 
elements are present, the participant is ineligible.
2. Have Stage IV NSCLC (American Joint Committee on Cancer [AJCC], version 8).
3. Have confirmation that EGFR-, ALK-, or ROS1-directed therapy is not indicated as 
primary therapy (documentation of the absence of tumor-activating EGFR mutations [eg, 
DEL19 or L858R], AND absence of ALK and ROS1 gene rearrangements OR presence of 
a Kirsten rat sarcoma [K-ras] mutation).
Note: If participant’s tumor is known to have a predominantly squamous histology, 
molecular testing for EGFR mutation and ALK and ROS1 translocations will not be 
required, as this is not part of current diagnostic guidelines.
4. Have measurable disease based on RECIST 1.1, as determined by the local site.
Note: Lesions that appear measurable but are situated in a previously irradiated area can 
be considered measurable (eligible for selection as target lesions) if they have shown 
documented growth since the completion of radiation.
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5. Tumor tissue that demonstrates PD-L1 expression in ≥1% of tumor cells (TPS ≥1%) as 
assessed by IHC 22C3 pharmDx at a central laboratory.
Note: Assessment of PD-L1 expression must be made from provided archival tumor 
tissue sample or newly obtained core or excisional biopsy of a tumor lesion not 
previously irradiated. (A fine-needle aspirate, frozen sample, plastic-embedded sample, 
cell block, clot, bone, bone marrow, cytologic specimen, or decalcified or formalin-fixed 
sample that was frozen at any point will not be acceptable for analysis). Formalin-fixed, 
paraffin-embedded tissue blocks are preferred to slides. Newly obtained biopsies are 
preferred to archived tissue.
Demographics
6. Be ≥18 years of age, inclusive, at the time of signing the ICF.
7. Have a life expectancy of at least 3 months.
8. Have an ECOG performance status of 0 or 1 within 7 days before the first dose of study 
intervention but before randomization.
Contraceptive use 
Contraceptive use by men and women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. If the contraception 
requirements in the local label for any of the study interventions is more stringent than the 
requirements above, the local label requirements are to be followed.
Male Participants
9. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 7 days after the last dose of lenvatinib/matching 
placebo:

Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent
OR

Must agree to use contraception unless confirmed to be azoospermic (vasectomized 
or secondary to medical cause [Appendix 5]) as detailed below:
−
Agree to use a male condom plus partner use of an additional contraceptive 
method when having penile-vaginal intercourse with a woman of childbearing 
potential (WOCBP) who is not currently pregnant.
Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each 
episode of penile-vaginal penetration.
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−
Please note that 7 days after lenvatinib/matching placebo is stopped, if the 
participant is on pembrolizumab only, no male contraception measures are 
needed.
Female Participants
10. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:

Is not a WOCBP.
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), with low user dependency, or be abstinent from heterosexual 
intercourse as their preferred and usual lifestyle (abstinent on a long term and 
persistent basis), as described in Appendix 5 during the intervention period and for at 
least 120 days post pembrolizumab or 30 days post lenvatinib/matching placebo, 
whichever occurs last. The investigator should evaluate the potential for contraceptive 
method failure (ie, noncompliance, recently initiated) in relationship to the first dose 
of study intervention.

A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 24 hours before the first dose of study 
intervention.

If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.

Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 2.

The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
Informed Consent
11. The participant (or legally acceptable representative if applicable) has provided
documented informed consent/assent for the study.
Additional Categories
12. Have adequately controlled blood pressure (BP) with or without antihypertensive 
medications, defined as BP ≤150/90 mm Hg and no change in antihypertensive 
medications within 1 week prior to randomization.
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13. Have adequate organ function as defined in the following table (Table 1). Specimens 
must be collected within 10 days before the start of study intervention.
Table 1
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
Creatinine or
Measured or calculatedb CrCl
(GFR can also be used in place of creatinine or 
CrCl)
≤1.5 × ULN or
≥30 mL/min for participant with creatinine 
levels >1.5 × institutional ULN
Hepatic
Total bilirubin
≤1.5 × ULN or direct bilirubin ≤ULN for 
participants with total bilirubin levels 
>1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with 
liver metastases)
Coagulation
INR or PT
aPTT/PTT
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as INR/PT or 
aPTT/PTT 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; ULN = upper limit of normal.
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.
a
Criteria must be met without erythropoietin dependency and without packed red blood cell transfusion 
within last 2 weeks.
b
CrCl should be calculated per institutional standard.
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5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has known untreated central nervous system metastases and/or carcinomatous 
meningitis. Participants with previously treated brain metastases may participate provided 
they are radiologically stable ie, without evidence of progression for at least 4 weeks by 
repeat imaging (note: repeat imaging should be performed during study screening), 
clinically stable, and without requirement of steroid treatment for at least 14 days before
first dose of study intervention.
2. Has clinically significant hemoptysis (at least 0.5 teaspoon of bright red blood) or tumor 
bleeding within 2 weeks before the first dose of study intervention.
3. Has radiographic evidence of encasement or invasion of a major blood vessel, or of 
intratumoral cavitation. 
NOTE: 

The degree of proximity to major blood vessels should be considered because of 
the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis 
following lenvatinib therapy.

In the chest, major blood vessels include the main pulmonary artery, the left and 
right pulmonary arteries, the 4 major pulmonary veins, the superior or inferior 
vena cava, and the aorta.  
4. Has a known history of an additional malignancy, except if the participant has undergone 
potentially curative therapy with no evidence of that disease recurrence for at least 
3 years since initiation of that therapy.
Note: The time requirement for no evidence of disease for at least 3 years does not apply 
to the NSCLC for which a participant is enrolled in the study. The time requirement also 
does not apply to participants who underwent successful definitive resection of basal cell 
carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, in 
situ cervical cancer, or other in situ cancers.
5. Has an active autoimmune disease that has required systemic treatment in the past 2 years 
(ie, with the use of disease-modifying agents, corticosteroids, or immunosuppressive 
drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment and is allowed.
6. Has had an allogeneic tissue/solid organ transplant.
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7. Has a known history of human immunodeficiency virus (HIV) infection; HIV testing is 
not required unless mandated by the local health authority.
8. Has a history of (noninfectious) pneumonitis that required systemic steroids or current 
pneumonitis/interstitial lung disease.
9. Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] 
reactive or hepatitis B virus [HBV]-DNA detected) or known active hepatitis C virus 
(HCV, defined as HCV-RNA [qualitative] detected or HCV antibody reactive, if 
HCV-RNA is not the local SOC) infection.
-
Note: No testing for hepatitis B and hepatitis C is required unless mandated by the 
local health authority.
10. Has a history of a gastrointestinal condition or procedure that in the opinion of the
investigator may affect oral study drug absorption.
11. Has significant cardiovascular impairment within 12 months of the first dose of study 
intervention, such as a history of congestive heart failure greater than New York Heart 
Association Class II, unstable angina, myocardial infarction, cerebrovascular accident 
(CVA)/stroke, or cardiac arrhythmia associated with hemodynamic instability.
12. Has not recovered adequately from any toxicity and/or complications from major surgery 
before starting therapy.
13. Has a known history of active tuberculosis (TB).
14. Has an active infection requiring systemic therapy.
15. Has a known psychiatric or substance abuse disorder that would interfere with the
participant’s cooperation for the requirements of the study.
16. Previously had a severe hypersensitivity reaction to treatment with an mAb or has a 
known sensitivity or intolerance to any component of lenvatinib or pembrolizumab.
17. WOCBP who has a positive urine pregnancy test within 24 hours before the first dose of 
study intervention. If the urine test is positive or cannot be confirmed as negative, a
serum pregnancy test will be required.
Note: If more than 24 hours have elapsed between the screening pregnancy test and the 
first dose of study intervention, another pregnancy test (urine or serum) must be 
performed and must be negative for the participant to start receiving study intervention.
Prior/Concomitant Therapy
18. Has received prior systemic chemotherapy or other targeted or biological antineoplastic 
therapy for their metastatic NSCLC.
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Note: Prior treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant 
or chemoradiation therapy for nonmetastatic NSCLC is allowed as long as therapy was 
completed at least 6 months before the diagnosis of metastatic NSCLC.
19. 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) or has received lenvatinib as monotherapy or in combination with 
anti-PD-1 agents.
20. Has received radiotherapy within 14 days before the first dose of study intervention or 
received lung radiation therapy of >30 Gy within 6 months before the first dose of study 
intervention.
Note: Participants must have recovered from all radiation-related toxicities to Grade 1 or 
less, not require corticosteroids, and not have had radiation pneumonitis.
21. Has a diagnosis of immunodeficiency or is receiving any form of immunosuppressive 
therapy within 7 days before the first dose of study intervention.
22. Is receiving systemic steroid therapy (doses exceeding 10 mg daily of prednisone 
equivalent) within 7 days before the first dose of study intervention.
23. Has received a live or attenuated vaccine within 30 days before the first dose of study 
intervention. Note: Killed vaccines are allowed.
Prior/Concurrent Clinical Study Experience
Not applicable.
Diagnostic Assessments
24. Participants with proteinuria >1+ on urine dipstick testing/urinalysis will undergo 
24-hour urine collection for quantitative assessment of proteinuria. Participants with 
urine protein ≥1 g/24 hours will be ineligible.
Prolongation of QTc interval to >480 ms and/or left ventricular ejection fraction (LVEF) 
below the institutional normal range as determined by a multigated acquisition scan 
(MUGA) or echocardiogram (ECHO).
Other Exclusions
25. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study or interfere with the participant's ability to 
participate for the full duration of the study, or it is not in the best interest of the 
participant to participate, in the opinion of the treating investigator.
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26. Has had major surgery within 3 weeks prior to first dose of study intervention. Note: 
Adequate wound healing after major surgery must be assessed clinically, independent of 
time elapsed for eligibility. 
27. Has pre-existing ≥Grade 3 gastrointestinal or nongastrointestinal fistula.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participant should maintain a normal diet unless modifications are required to manage an AE,
such as diarrhea, nausea, or vomiting.
5.3.2
Contraception
Based on its mechanism of action, lenvatinib can cause fetal harm when administered to a 
pregnant woman. Lenvatinib may also result in reduced fertility in females of reproductive 
potential and may result in damage to male reproductive tissues leading to reduced fertility of 
unknown duration. In animal reproduction studies, oral administration of lenvatinib during 
organogenesis at doses below the recommended human dose resulted in embryotoxicity, 
fetotoxicity, and teratogenicity in rats and rabbits.
Participants should be informed that taking the study intervention may involve unknown 
risks to the fetus (unborn baby) if pregnancy were to occur during the study. To participate in 
the study, WOCBP must adhere to the contraception requirement (Appendix 5) from the day 
of study intervention initiation throughout the study period up to 120 days post 
pembrolizumab or 30 days post lenvatinib/matching placebo, whichever occurs last. If there 
is any question that a WOCBP will not reliably comply with the requirements for 
contraception, that participant should not be entered into the study.
5.3.3
Pregnancy
If a participant inadvertently becomes pregnant while on study intervention, the participant 
will be immediately discontinued from study intervention. 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 an SAE (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 a 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 8.4.5.
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5.3.4
Use in Nursing Women
It is unknown whether lenvatinib or pembrolizumab is excreted in human milk. Since many 
drugs are excreted in human milk and because of the potential for serious adverse reactions 
in the nursing infant, participants who are breastfeeding are not eligible for enrollment.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention will not be replaced.
6
STUDY INTERVENTION
NOTE: As of Amendment 007-06, lenvatinib and matching placebo have been removed 
from the study; the portions of this section referring to these treatments are no longer 
applicable. This section has been updated accordingly.
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (pembrolizumab ) will be packaged to support enrollment as required.
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 2.
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Table 2
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment
Period
Use
IMP/
NIMP
Sourcing
Arm A 
and B
Experimental
Pembrolizumab
(MK-3475)
Drug
Solution for 
Infusion
25 mg/mL
200 mg
IV Infusion
Q3W
Standard of 
care/ 
Experimental
IMP
Provided 
centrally 
by the 
Sponsor
Arm A
Experimental
Lenvatinib
(E7080/
MK-7902)
Drug
Capsule
10 mg/4 mg
20 mg
Oral
QD
Experimental
IMP
Provided 
centrally 
by the 
Sponsor
Arm B
Placebo 
Comparator
Placebo
Drug
Capsule
NA
NA
Oral
QD
Placebo
IMP
Provided 
centrally 
by the 
Sponsor
Abbreviations: EEA = European Economic Area; IMP = investigational medicinal product; IV = intravenous; NA = not applicable; NIMP = noninvestigational medicinal product; 
Q3W = every 3 weeks; QD = once daily.
The classification of IMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with respect to the 
definition/classification of IMP/NIMP may exist. In these circumstances, local legislation is followed.
NOTE: As of Amendment 007-06, lenvatinib and matching placebo have been removed from the treatment groups. Participants remaining on treatment will receive 
open-label pembrolizumab monotherapy as per protocol. The original study interventions and updates are indicated by strikethrough in the table.
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All supplies indicated in Table 2 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
All placebos were created by the Sponsor to match the active product.
6.1.1
Medical Devices
This section is not applicable.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on the preparation and administration of pembrolizumab are provided in the 
Pharmacy Manual. Lenvatinib is a capsule for oral administration and does not require
preparation. Before protocol amendment 007-06, site’s staff referred to the Pharmacy Manual 
for lenvatinib administration.
The rationale for selection of doses to be used in this study is provided in Section 4.3.
6.2.2
Handling, Storage, and Accountability
Details on preparation and administration of IV pembrolizumab are provided in the
Pharmacy Manual. Participants/caregivers were given instructions on how to handle and 
store lenvatinib/matching placebo capsules at home until it was discontinued as per Protocol 
Amendment 007-06.
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
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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 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention allocation/randomization will occur centrally using an interactive response 
technology (IRT) system. There are 2 study intervention arms. Participants will be assigned 
randomly in a 1:1 ratio to pembrolizumab + lenvatinib or pembrolizumab + matching 
placebo, respectively.
NOTE: as of Amendment 007-06, the study is unblinded. All participants remaining on 
treatment will receive open-label pembrolizumab monotherapy.
6.3.2
Stratification
Intervention allocation/randomization will be stratified according to the following factors:
1. Geographic region of the enrolling site: East Asia vs non-East Asia
2. ECOG Performance Score: 0 vs 1
3. TPS: 1% to 49% vs ≥50%
6.3.3
Blinding
NOTE: As of Amendment 007-06, lenvatinib and matching placebo have been removed 
from the study and the study is unblinded. This section has been updated accordingly.
6.3.3.1
Pembrolizumab
Pembrolizumab will be administered open label; therefore, its identity will be known by the 
participant, the investigator, the Sponsor, and delegate(s) who are involved in study 
intervention administration or the clinical evaluation of participants.
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6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment plan for >12 weeks (pembrolizumab)
require consultation between the investigator and the Sponsor and written documentation of 
the collaborative decision on participant management.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the treatment period. If there is a clinical indication for any medication or vaccination 
specifically prohibited, discontinuation from study intervention may be required. The 
investigator is to discuss prohibited medication/vaccination with the Sponsor’s Clinical 
Director. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician, but the decision to continue the 
participant on study intervention requires the mutual agreement of the investigator, the 
Sponsor, and the participant.
All prior medications (including over-the-counter medications) administered within 30 days 
before the first dose of study drug and any concomitant therapy administered to the 
participant during the course of the study (starting at the date of informed consent) until 
30 days after the final dose (or 90 days if used to treat an SAE) of study drug will be 
recorded. Additionally, all diagnostic, therapeutic, or surgical procedures relating to 
malignancy should be recorded. Any medication that is considered necessary for the 
participant’s health and that is not expected to interfere with the evaluation of or interact with 
the study interventions may be continued during the study.
6.5.1
Allowed Concomitant Medications
Treatment of complications or AEs, or therapy to ameliorate symptoms (including blood 
products, blood transfusions, fluid transfusions, antibiotics, and antidiarrheal drugs), may be 
given at the discretion of the investigator, unless it is expected to interfere with the evaluation 
of (or to interact with) the study intervention. Antiemetic or any other prophylaxis should be 
considered in accordance with institutional guidelines.
The following concomitant medications are also allowed:

Hormone replacement therapy (HRT)

Thyroid hormone suppressive therapy

Anticoagulants, including low molecular weight heparin, warfarin, and anti-Xa agents

Anti-inflammatory agents

Bisphosphonates or denosumab
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
Antihypertensive therapy (including additional antihypertensive treatment as 
appropriate if BP increases once the participant is enrolled)
6.5.2
Prohibited Concomitant Medications
Participants are prohibited from receiving the following therapies during the screening and 
treatment phases of the study:

Concurrent anticancer therapies, such as chemotherapy, targeted therapies, antitumor 
interventions (surgical resection, surgical debulking of tumor, etc.), or cancer 
immunotherapy not specified in this protocol
−
Note: Topical anticancer agents to treat skin lesions (eg, in situ melanoma or 
squamous cell carcinoma) are allowed, excluding skin metastasis of 
melanoma.

Other concurrent investigational drugs

Live or attenuated vaccines within 30 days and while participating in the study. Note: 
killed vaccines are allowed. 

Systemic glucocorticoids for any purpose other than those listed in Section 6.5.4.1

Radiation therapy for disease control
−
Note: Palliative radiotherapy is permitted for nontarget lesions if considered 
medically necessary by the treating physician and upon discussion with the 
Sponsor.
For participants who, in an assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management, continuation of the study intervention
and further participation in the study must be discussed and agreed upon with the Sponsor.
If participants receive additional anticancer therapies, this will be judged to represent 
evidence of PD, and study intervention will be discontinued. These participants should 
complete all end-of-treatment assessments and continue to be followed for survival during
the follow-up period.
6.5.3
Drug Interactions
NOTE: As of Amendment 007-06, lenvatinib and matching placebo have been removed 
from the study. This section is no longer applicable, but has been left unchanged for 
reference.
There are no DDI-related concomitant medication prohibitions or restrictions. 
Lenvatinib is not expected to clinically meaningfully alter exposure to CYP3A4/
P-glycoprotein (Pgp) substrates based on results from a lenvatinib drug-drug interaction 
(DDI) study with midazolam (a sensitive CYP3A and Pgp substrate). Clinical studies also 
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showed that co-administration of lenvatinib with either inducers or inhibitors of 
CYP3A4/Pgp are not of clinical concern.
No drug interaction is expected between pembrolizumab and lenvatinib because of divergent 
metabolic pathways. Pembrolizumab is a monoclonal antibody and is primarily catabolized 
like other proteins, while lenvatinib is metabolized by enzymatic (CYP3A and aldehyde 
oxidase) and nonenzymatic processes (see lenvatinib IB).
6.5.4
Rescue Medications and Supportive Care
NOTE: As of Amendment 007-06, lenvatinib and matching placebo have been removed 
from the study. This section has been updated accordingly.
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 in Section 6.6.1.
6.5.4.1
Systemic Corticosteroid Use
Systemic corticosteroids are permitted in the following situations:

To mediate potential immune-related adverse events (irAEs) as guided in Table 3.

As pre- or postmedication to prevent AEs associated with IV contrast.

Brief, limited use of systemic corticosteroids (≤7 days) are permitted where such use 
is considered SOC (eg, for chronic obstructive pulmonary disease [COPD]
exacerbation).

Replacement doses of steroids (for example, prednisone 10 mg daily) are permitted 
while on study, as is the use of local steroid injections and topical steroids.
6.6
Dose Modification
NOTE: As of Amendment 007-06, text in this section relating to dose modification and 
other allowed dose interruptions of lenvatinib/matching placebo is no longer applicable. 
This section has been updated accordingly.
6.6.1
Immune-related Events and Dose Modification (Withhold, Treat, Discontinue)
6.6.1.1
Dose Modification and Toxicity Management for Immune-related AEs 
Associated with Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
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interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation. Based on the severity of irAEs, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids.
Modification and toxicity management guidelines for irAEs associated with pembrolizumab 
monotherapy, coformulations, or IO combinations are provided in Table 3.
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Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if the 
irAEs are not controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid dose 
is not ≤10 mg/day within 12 weeks of the last treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 after 
corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
Administer corticosteroids (initial dose 
of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Monitor participants for signs and symptoms of 
pneumonitis
Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment
Add prophylactic antibiotics for opportunistic 
infections
Recurrent Grade 2 
or Grade 3 or 4 
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other therapies
Monitoring and Follow-up
Diarrhea / Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids (initial dose 
of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (ie, peritoneal signs 
and ileus)
Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis
Participants with diarrhea/colitis should be advised 
to drink liberal quantities of clear fluids. If 
sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV 
infusion.
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
AST / ALT 
Elevation or 
Increased 
Bilirubin
Grade 2
Withhold
Administer corticosteroids (initial dose 
of 0.5-1 mg/kg prednisone or 
equivalent) followed by taper
Monitor with liver function tests (consider weekly 
or more frequently until liver enzyme value 
returned to baseline or is stable)
Grade 3 or 4 
Permanently 
discontinue
Administer corticosteroids (initial dose 
of 1-2 mg/kg prednisone or 
equivalent) followed by taper
T1DM or 
Hyperglycemia
New onset T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure
Withhold a
Initiate insulin replacement therapy for 
participants with T1DM
Administer antihyperglycemic in 
participants with hyperglycemia
Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other therapies
Monitoring and Follow-up
Hypophysitis
Grade 2
Withhold
Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue a
Hyperthyroidism 
Grade 2
Continue
Treat with nonselective beta-blockers 
(eg, propranolol) or thionamides as 
appropriate
Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
Permanently 
discontinue a
Hypothyroidism
Grade 2-4
Continue
Initiate thyroid replacement hormones 
(eg, levothyroxine or liothyronine) 
per standard of care
Monitor for signs and symptoms of thyroid 
disorders
Nephritis and 
renal dysfunction
Grade 2
Withhold
Administer corticosteroids (prednisone 
1-2 mg/kg or equivalent) followed 
by taper
Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1 
Withhold
Based on severity of AE administer 
corticosteroids
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other therapies
Monitoring and Follow-up
All Other irAEs
Persistent Grade 2
Withhold
Based on severity of AE administer 
corticosteroids
Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold or 
discontinue b
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune-related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 
diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
b
Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically important irAEs 
(eg, vasculitis and sclerosing cholangitis).
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6.6.1.2
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 for pembrolizumab-associated 
infusion reactions are provided in Table 4.
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Table 4
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the investigator.
None
Grade 2
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 h
Stop Infusion.
Additional appropriate medical therapy may include but is not limited to the 
following:
-
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/h to 
50 mL/h). 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 pembrolizumab 
treatment.
Participant may be premedicated 1.5 h 
(± 30 minutes) before infusion of 
pembrolizumab with:
-
Diphenhydramine, 50 mg PO (or 
equivalent dose of antihistamine).
-
Acetaminophen, 500-1000 mg PO (or 
equivalent dose of analgesic).
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NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (eg, renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy may include but is not limited to:
-
Epinephrine**
-
IV fluids
-
Antihistamines
-
NSAIDs
-
Acetaminophen
-
Narcotics
-
Oxygen
-
Pressors
-
Corticosteroids
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be used immediately.
Participant is permanently discontinued from further pembrolizumab
treatment.
No subsequent dosing
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous; NCI = National Cancer Institute; NSAIDs = nonsteroidal anti-
inflammatory drugs; PO = by mouth.
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 CTCAE, version 4.0, at http://ctep.cancer.gov.
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6.6.2
Other Allowed Dose Interruptions 
Pembrolizumab may be interrupted for situations other than treatment-related AEs, such as 
medical/surgical events or logistical reasons not related to study therapy. Participants should 
be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the Sponsor. The reason for interruption should be documented in 
the participant's study record. Scans should not be delayed for delays in cycle treatment.
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
6.8
Clinical Supplies Disclosure
NOTE: As of Amendment 007-06, the study is unblinded and this section is no longer 
applicable.
6.9
Standard Policies
At the close of the study after unblinding, a letter is to be sent by the investigator to those 
participants who received placebo in the image of the competitor’s product to provide the 
following advice:
“You have participated in a study conducted by the Sponsor. This letter is to advise you that 
you were among those who received a look-alike capsule provided by the Sponsor to 
resemble the drug lenvatinib as much as possible. You did not receive the active drug 
lenvatinib as provided by MSD .”
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
NOTE: As of Amendment 007-06, lenvatinib and matching placebo have been removed 
from the study and participants stopped receiving those. This section has been updated 
accordingly.
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Sections 1.3 and 8.11.4
unless the participant has withdrawn from the study (Section 7.2).
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
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occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Sections 8.1.9 and 8.11.4.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:

The participant or participant’s legally acceptable representative requests to 
discontinue study intervention.

The participant interrupts study intervention administration for more than 12 weeks, 
except if agreed to by the Sponsor.

The participant has a medical condition or personal circumstance that, in the opinion 
of the investigator and/or Sponsor, places the participant at unnecessary risk from 
continued administration of the study intervention.

The participant has a confirmed positive serum pregnancy test.

The participant has intercurrent illness that prevents further administration of 
treatment.

The participant has any progression or recurrence of any malignancy or occurrence of 
another malignancy that requires active treatment. Exceptions to malignancy include 
basal cell carcinoma of the skin, squamous cell carcinoma of the skin, new 
nonulcerated primary melanoma <1 mm in depth with no nodal involvement, or 
carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone 
potentially curative therapy. Exceptions should be discussed with the Sponsor before
continuing therapy or remaining in follow-up.

The participant has unacceptable AE(s) or toxicities.

Any study intervention-related toxicity specified as a reason for permanent 
discontinuation as defined in the guidelines for dose modification due to AEs in 
Section 6.6. 
7.1.1
Second-course Treatment Phase
NOTE: As of Amendment 007-06, the Second-course Treatment Phase has been 
removed from the study.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
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If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study are outlined in Section 8.1.9. The procedures to be performed should a participant 
repeatedly fail to return for scheduled visits and/or if the study site is unable to contact the 
participant are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:

The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.

The investigator or designee must make every effort to regain contact with the 
participant at each missed visit (eg, telephone calls and/or a certified letter to the 
participant’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the participant’s medical record.

Note: A participant is not considered lost to follow-up until the last scheduled visit for 
the individual participant. The missing data for the participant will be managed via 
the prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel 
responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).

All study-related medical decisions must be made by an investigator who is a 
qualified physician.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
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
Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.

Additional evaluations/testing may be deemed necessary by the investigator and or 
the Sponsor for reasons related to participant safety. In some cases, such 
evaluation/testing may be potentially sensitive in nature (eg, HIV, hepatitis C), 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.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant or their legally 
acceptable representative prior to participating in this clinical study or future biomedical 
research. If there are changes to the participant’s status during the study (eg, health or age of 
majority requirements), the investigator or medically qualified designee must ensure the 
appropriate documented informed consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the trial protocol number, trial 
protocol title, dated signature, and /agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
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If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or his/her legally acceptable representative will be asked to sign 
consent.
Specifics about the study and the study population are to be included in the study informed 
consent form. 
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator who is a qualified 
physician to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
allocation/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
8.1.4.1
General Medical History
A medical history will be obtained by the investigator or qualified designee.
Medical history will include all active conditions, drug allergies, significant medical 
procedures, and any condition diagnosed within the previous 10 years that are considered to 
be clinically important by the investigator. Any cancer, other than the cancer under study, 
will be recorded as medical history, even if diagnosed greater than 10 years before 
enrollment. Details regarding the cancer under study will be recorded separately and not 
listed as medical history. The medical history will also include an assessment of smoking 
history.
8.1.4.2
Oncologic Disease Details
The investigator or qualified designee will obtain historic and current details of the 
participant’s cancer under study. This information will include, but is not limited to, date of 
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diagnosis, stage, histology, locations of primary lesions, and location of metastases, if 
applicable.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 30 days before the first dose of study intervention. Treatment for the disease for which 
the participant has enrolled in the study will be recorded separately and not listed as a prior 
medication.
8.1.5.2
Prior Oncologic Treatment
The investigator or qualified designee will review and record all treatments for the cancer 
under study, including systemic and local treatment, vaccinations, radiation, and surgeries. 
Additional information collected on these treatments will include, but is not limited to, 
reason for discontinuation, best response, and date of progression after each treatment as 
applicable.
8.1.5.3
Concomitant Medications
NOTE: As of Amendment 007-06, the Second-course Treatment Phase has been 
removed from the study. This section has been updated accordingly.
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study. Concomitant medications will be recorded for 30 days after the last dose of 
study intervention (or 90 days if used to treat an SAE).
Any new anticancer therapy started after the participant’s discontinuation from the treatment 
period will be recorded separately. Additional information collected on this treatment will 
include, but is not limited to, best response and date of progression.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only 1 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/rescreening visit 
requirements are provided in Section 8.11.1.
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8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Study intervention should begin within 3 days of randomization.
Study intervention will be administered by the investigator and/or study staff according to the 
specifications within the Pharmacy Manual.
8.1.8.1
Timing of Dose Administration
8.1.8.1.1
Lenvatinib/Matching Placebo
NOTE: As of Amendment 007-06, lenvatinib and matching placebo have been removed 
from the study. This section is no longer applicable. 
Lenvatinib/matching placebo 20 mg (two 10-mg capsules) QD will be taken orally with 
water (with or without food) in 21-day cycles at approximately the same time each day. On 
Day 1 of each pembrolizumab cycle, lenvatinib/matching placebo will be administered 0-4 
hours after pembrolizumab. 
If a lenvatinib/matching placebo dose is missed and cannot be taken within 12 hours, then 
that dose should be skipped and the next dose should be taken at the usual time of 
administration.
For nonvisit days, lenvatinib will be taken at home.
When a participant attends a study visit, he or she will bring any unused capsules.
8.1.8.1.2
Pembrolizumab
Pembrolizumab will be administered as a 30-minute IV infusion on Day 1 of each 21-day 
cycle. Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window of 
5 minutes and +10 minutes is permitted (ie, infusion time is 30 minutes: 5 min/+10 min).
After Cycle 1 Day 1, pembrolizumab may be administered up to 3 days before or after the 
scheduled Day 1 of each subsequent cycle for administrative reasons.
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Administration of pembrolizumab will be witnessed by the investigator and/or study staff. 
The total volume of study treatment infused will be compared with the total volume prepared 
to determine compliance with each dose administered.
8.1.8.2
Lenvatinib Compliance
Lenvatinib compliance will be calculated by the Sponsor until discontinuation, based on the 
drug accountability documented by the site staff and monitored by the Sponsor/designee. The 
objective is 100% compliance, and investigators and their staff should evaluate compliance at 
each visit and take appropriate steps to optimize compliance.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA and Section 8.11.4.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the final study visit should be performed (at the time of withdrawal). Any AEs
that are present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.3.
8.1.10
Participant Blinding/Unblinding
NOTE: As of Amendment 007-06, lenvatinib and matching placebo have been removed 
from the study and the study is unblinded. Participants who remain on treatment will 
receive open-label pembrolizumab monotherapy as per protocol. 
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy/Immunogenicity Assessments
8.2.1
Tumor Scans and Assessment of Disease
NOTE: After amendment 007-06, imaging obtained on study will be submitted to the 
imaging vendor but these will not be assessed; similarly, verification of PD is no longer 
needed before treatment discontinuation. This section was updated accordingly.
Throughout this section, the term “scan” refers to any medical imaging data used to assess 
tumor burden and may include cross-sectional imaging (such as CT or MRI), or other 
methods as specified in this protocol.
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The process for scan collection and transmission to the central imaging vendor can be found 
in the Site Imaging Manual. Tumor scans are strongly preferred to be acquired by computed 
tomography (CT). For the abdomen and pelvis, contrast-enhanced MRI may be used when 
CT with iodinated contrast is contraindicated, or when mandated by local practice. The same 
scan technique regarding modality, ideally the same scanner, and the use of contrast should 
be used in a participant throughout the study to optimize the reproducibility of the assessment 
of existing and new tumor burden and improve the accuracy of the assessment of response or 
progression based on scans. Note: for the purposes of assessing tumor scans, the term 
“investigator” refers to the local investigator at the site and/or the radiological reviewer 
located at the site or at an offsite facility.
MRI is preferred for brain scans; however, CT scans will be acceptable, if MRI is medically 
contraindicated.
Bone scans may be performed to evaluate bone metastases. Any supplemental scans
performed to support a positive or negative bone scan, such as plain X-rays acquired for 
correlation, should be submitted to the central imaging vendor. 
Participant eligibility will be determined using local assessment (investigator assessment) 
based on RECIST 1.1. All scheduled scans for each participant will be submitted to the 
central imaging vendor. In addition, unscheduled scans to determine PD and scans obtained 
for other reasons, but demonstrate radiologic progression, are to be submitted to the central 
imaging vendor.
When the investigator identifies disease progression per RECIST 1.1, but elects to implement 
iRECIST, the investigator will assess for confirmation of progression by iRECIST at 
subsequent time points. Images should continue to be submitted to the central imaging 
vendor.
8.2.1.1
Initial Tumor Scans
Initial tumor scans at screening must be performed within 28 days before the date of 
randomization. The site study team must review screening scans to confirm the participant 
has measurable disease per RECIST 1.1.
The screening scans must be submitted to the central imaging vendor for retrospective 
eligibility review.
Tumor scans performed as part of routine clinical management is acceptable for use as 
screening tumor scans if it is of diagnostic quality and performed within 28 days before the 
date of randomization and can be assessed by the central imaging vendor.
If brain scan is performed to document the stability of existing metastases, an MRI scan 
should be used if possible. If MRI is medically contraindicated, CT with contrast is an 
acceptable alternative.
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8.2.1.2
Tumor Scans During the Study
The first on-study scan assessment should be performed at 9 weeks (63 days ±7 days) from 
the date of randomization. Subsequent tumor scans should be performed every 9 weeks (63 
days ±7 days) or more frequently if clinically indicated. After 54 weeks, participants who 
remain on treatment will have scans performed every 12 weeks (84 days ±7 days). Scan 
timing should follow calendar days and should not be adjusted for delays in cycle starts. 
Scans should continue to be performed until PD is identified by the investigator (unless the 
investigator elects to continue treatment and follow iRECIST), the start of new anticancer 
treatment, withdrawal of consent, death, or any other reason for discontinuation of 
pembrolizumab listed in Section 7.1 is met, whichever occurs first. All supplemental scans 
must be submitted to the central imaging vendor.
OR should be confirmed by a repeat scan assessment. Tumor scans to confirm PR or CR 
should be performed at least 4 weeks after the first indication of a response is observed. 
Participants will then return to regular scheduled scans, starting with the next scheduled time 
point. Participants who receive additional scans for confirmation do not need to undergo the 
next scheduled tumor scan if it is less than 4 weeks later; tumor scans may resume at the 
subsequent scheduled time point. Note: Response does not need to be verified in real time by 
the central imaging vendor.
Per iRECIST (Section 8.2.1.6), PD should be confirmed by the site 4 to 8 weeks after 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 PD
is confirmed by the site, provided they have met the conditions detailed in Section 8.2.1.6. 
Participants who receive confirmatory scans do not need to undergo the next scheduled 
tumor scan if it is less than 4 weeks later; tumor scans may resume at the subsequent 
scheduled time point, if clinically stable. Participants who have confirmed PD by iRECIST, 
as assessed by the site, will discontinue study intervention. Exceptions are detailed in 
Section 8.2.1.6.
8.2.1.3
End of Treatment and Follow-up Tumor Scans
For participants who discontinue study intervention, tumor scans should be performed at the 
time of treatment discontinuation (±4-week window). If previous scans were obtained within 
4 weeks before the date of discontinuation, then scans at treatment discontinuation is not 
mandatory. For participants who discontinue study intervention because of documented PD, 
this is the final required tumor scan.
After amendment 007-06, imaging obtained on study will be submitted to the imaging 
vendor but these will not be assessed; similarly, verification of PD is no longer needed 
before treatment discontinuation.
8.2.1.4
Second-course Treatment Tumor Scans
NOTE: As of Amendment 007-06, the Second-course Treatment Phase has been 
removed from this study. This section is no longer applicable.
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8.2.1.5
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used by BICR as the primary measure for assessment of tumor response
and date of PD, and as a basis for all protocol guidelines related to disease status (eg, 
discontinuation of study intervention). Although RECIST 1.1 references a maximum of 
5 target lesions in total and 2 per organ, this protocol follows a maximum of 10 target lesions 
and a maximum of 5 target lesions per organ, if clinically relevant to enable a broader 
sampling of tumor burden.
If disease progression has been assessed by the investigator, the process continues as follows:

If participant is clinically stable, continue study intervention per protocol 
-
Resume imaging per protocol schedule (≥4 weeks to next scan)
-
Send scans to imaging vendor 
-
Continue local assessment 
-
Do not change investigator assessment of progression
-
If subsequent scan(s) indicate progression, submit scan(s) to imaging vendor 

If the participant is not clinically stable, best medical practice is to be applied
Before stopping study intervention or imaging or starting new anticancer therapy in a 
participant who is clinically stable, communication with the Sponsor is required. 

Investigator judgment will determine action
Note: the reconsent addendum may be signed any time after investigator-assessed 
progression is identified, but must be signed prior to starting study intervention.
-
Obtain scans locally per original protocol schedule
-
Do not send scans to imaging vendor
For the purpose of this decision process, lack of clinical stability is defined as:

Unacceptable toxicity

Clinical signs or symptoms indicating clinically significant disease progression

Decline in performance status

Rapid disease progression or threat to vital organs or critical anatomical sites (eg, 
CNS metastasis, respiratory failure due to tumor compression, spinal cord 
compression) requiring urgent alternative medical intervention
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8.2.1.6
iRECIST Assessment of Disease
NOTE: After amendment 007-06, imaging obtained on study will be submitted to the 
imaging vendor but these will not be assessed, verification of PD is no longer needed 
before treatment discontinuation, and posttreatment imaging is no longer required.
This section has been updated accordingly.
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 [Seymour, L., et al 2017]. When 
clinically stable, participants will continue study intervention beyond RECIST 1.1 PD with 
continuous assessment of response according to the rules outlined in Appendix 6. iRECIST 
reflects some participants can have a transient tumor flare after the start of immunotherapy, 
then experience subsequent disease response. This data will be captured in the clinical 
database.
Clinical stability is defined as the following:

Absence of symptoms and signs indicating clinically significant PD

No decline in ECOG performance status

No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care
Any participant deemed clinically unstable should be discontinued from study intervention at 
site-assessed first radiologic evidence of PD and is not required to have repeat tumor scans
for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study intervention and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment. Scans should continue to be sent in to the 
central imaging vendor .
If repeat scans do not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study intervention may continue and follow the 
regular scan schedule. If PD is confirmed, participants will be discontinued from study 
intervention.
If a participant has iRECIST-confirmed radiographic progression (iCPD) as defined in 
Appendix 6, study intervention should be discontinued; however, if the participant is 
achieving a clinically meaningful benefit, an exception to continue study intervention may be 
considered following consultation with the Sponsor. In this case, if study intervention is 
continued, tumor scans should continue to be performed following the intervals as outlined in 
Section 1 and submitted to the central imaging vendor.
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A description of the adaptations and iRECIST process is provided in Appendix 6, with 
additional details in the iRECIST publication [Seymour, L., et al 2017]. A summary of scans 
and treatment requirements after first radiologic evidence of progression is provided in 
Table 5.
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Table 5
Summary of Imaging and Treatment Requirements After First Radiologic Evidence of Progression
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic evidence of PD 
by RECIST 1.1 per investigator 
assessment
Submit the imaging to BICR 
for verification.
Repeat imaging at 4 to 
8 weeks to confirm PD per 
iRECIST.
May continue study intervention at 
the discretion of the investigator 
and after obtaining participant’s 
consent.
No additional imaging 
required.
Discontinue treatment
Repeat tumor imaging 
confirms PD (iCPD) by 
iRECIST per investigator 
assessment
No additional imaging 
required.
Discontinue treatment (exception is 
possible upon consultation with 
Sponsor).
No additional imaging 
required.
Not applicable
Repeat tumor imaging shows 
iUPD by iRECIST per 
investigator assessment
Repeat imaging at 4 to 
8 weeks to confirm PD.
Continue study intervention at the 
investigator’s discretion.
No additional imaging 
required.
Discontinue treatment
Repeat tumor imaging shows 
iSD, iPR, or iCR by iRECIST 
per investigator assessment.
Continue regularly scheduled 
imaging assessments.
Continue study intervention at the 
investigator’s discretion.
No additional imaging 
required.
Discontinue treatment
Abbreviations: iCPD = iRECIST-confirmed progressive disease; iCR = iRECIST complete response; iRECIST = adjusted Response Evaluation Criteria in Solid Tumors 1.1 for 
immune-based therapeutics; iSD = iRECIST stable disease; iUPD = iRECIST unconfirmed progressive disease; PD = progressive disease; RECIST 1.1 = Response Evaluation 
Criteria in Solid Tumors, version 1.1; VOP = verification of progression.
Note: If PD has been centrally verified, further management is performed by the site, based on iRECIST. Any further imaging should still be submitted to the central imaging 
vendor, but no rapid review will occur. If RECIST 1.1 PD has not been centrally verified, ideally the site should continue treatment. Whether or not treatment continues, imaging 
should be collected and submitted to the central imaging vendor with VOP request until RECIST 1.1 PD is verified by BICR.
As of amendment 007-06, imaging obtained on study will be submitted to the imaging vendor but these will not be assessed for verification of progression. This table was 
updated accordingly.
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8.2.1.7
Tumor Tissue Collection for PD-L1 Status
Participation in this study will be dependent upon supplying tumor tissue for PD-L1 testing 
from locations not radiated before biopsy; formalin-fixed specimens after the participant has 
been diagnosed with metastatic disease will be preferred for determination of PD-L1 status 
before randomization. Biopsies obtained before receipt of adjuvant/neoadjuvant 
chemotherapy will be permitted if recent biopsy is not feasible.
All participants should submit either a newly obtained core or excisional biopsy or archival 
tissue (fine-needle aspiration is not adequate for both archival and new tissue samples) to a 
central laboratory for characterization of PD-L1 status before treatment allocation.
A fine-needle aspirate, frozen sample, plastic-embedded sample, cell block, clot, bone, bone 
marrow, cytologic specimen, decalcified or formalin-fixed sample that was frozen at any 
point will not be acceptable for analysis.
Note: Submission of formalin-fixed paraffin-embedded tumor tissue sample blocks are 
preferred; if submitting unstained slides, the slides should be freshly cut and submitted to the 
testing laboratory within 14 days from the site slide section date; otherwise, a new specimen 
will be requested.
If the sample is determined to be nonevaluable before testing by the central laboratory, a new 
sample should be submitted if available.
The central vendor PD-L1 TPS results of participants will be blinded to the investigator. The 
Sponsor acknowledges that because of the commercial availability of PD-L1 testing assays, it 
is possible that the investigator may know a participant’s TPS before screening. This risk is 
seen as acceptable, as the treatment interventions are hypothesized to provide benefit 
regardless of TPS.
8.2.2
Patient-reported Outcomes
NOTE: As of Amendment 007-06, PROs will no longer be collected. This section is no 
longer applicable.
The EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-5L questionnaires will be 
administered by trained site personnel and completed electronically by participants in the 
following order: EORTC QLQ-C30, EORTC QLQ-LC13, and lastly EQ-5D-5L. The 
questionnaires should be administered before dosing at every cycle through Cycle 17, then 
every other cycle through Cycle 35 (eg, Cycles 1-17, 19, 21, 23, 25, 27, 29, 31, 33, and 35), 
at the Treatment Discontinuation Visit, and at the 30-day Safety Follow-up Visit.
If the Treatment Discontinuation Visit occurs 30 days from the last dose of study 
intervention, at the time of the mandatory Safety Follow-up Visit, the electronic 
patient-reported outcomes (ePROs) do not need to be repeated.
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It is best practice and strongly recommended that the ePROs are administered to randomized 
participants before drug administration, AE evaluation, and disease status notification. If the 
participant does not complete the ePROs at a scheduled time point, the MISS_MODE form 
must be completed to capture the reason the assessment was not performed.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
The investigator or qualified designee will perform a complete physical examination during 
the screening period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical examination are described in the SoA (Section 1.3). 
After the first dose of study treatment, new clinically significant abnormal findings should be 
recorded as AEs.
For cycles that do not require a full physical examination per the SoA (Section 1.3), the 
investigator or qualified designee will perform a directed physical examination as clinically 
indicated before study treatment administration. New clinically significant abnormal findings 
should be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
NOTE: As of Amendment 007-06, lenvatinib and matching placebo have been removed 
from the study. Repeat BP measurements for monitoring participants receiving 
lenvatinib are no longer required. This section has been updated accordingly.
The investigator or qualified designee will take vital signs at screening, before the 
administration of each dose of study treatment and during the follow-up period, as specified 
in the SoA (Section 1.3). Vital signs include temperature, heart rate, respiratory rate, weight, 
and blood pressure. Height will be measured at Visit 1 only.
8.3.3
Electrocardiograms
NOTE: As of Amendment 007-06, lenvatinib and matching placebo have been removed 
from the study. Additional ECG measurements for monitoring participants receiving 
lenvatinib are no longer required. This section has been updated accordingly.
Electrocardiograms (ECGs) will be obtained as designated in the SoA (Section 1.3). 
Complete, standardized, 12-lead ECG recordings that permit all 12 leads to be displayed on a 
single page with an accompanying lead II rhythm strip below the customary 3 × 4 lead 
format are to be used. In addition to a rhythm strip, a minimum of 3 full complexes should be 
recorded from each lead simultaneously. Participants must be in the recumbent position for a 
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period of 5 minutes prior to the ECG. The Fridericia correction method for calculating QTc 
will be used.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see 
Appendix 3) and the eCRF Entry Guidelines. In these instances, the AE corresponding to the 
ECG abnormality will be recorded on the appropriate case report form (CRF).
8.3.4
Echocardiograms or Multigated Acquisition Scans
A MUGA scan (using a technetium-based tracer) or an ECHO will be performed to assess 
LVEF as designated in the SoA (Section 1.3). Additional assessments may be performed as 
clinically indicated.
MUGA scans or ECHOs should be performed locally in accordance with the institution’s 
standard practice. MUGA scans are the preferred modality. However, whichever modality is 
used for an individual participant at baseline should be repeated for all subsequent LVEF 
assessments for that participant.
LVEF, as assessed by the institution, will be entered in the electronic case report form 
(eCRF). Investigator assessment will be based on institutional reports.
8.3.5
Clinical Safety Laboratory Assessments
8.3.5.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.

The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected 
for the participant's condition.

CBC with differential and clinical chemistry results must be reviewed before 
administration of study intervention. Electrolytes such as potassium, calcium, and 
magnesium should be monitored and abnormalities, when considered clinically 
significant, should be corrected in all participants before starting study intervention.

All protocol-required laboratory assessments, as defined in Appendix 2, 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 
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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 
intervention, every attempt should be made to perform repeat assessments until the 
values return to normal or baseline or if a new baseline is established as determined 
by the investigator.
8.3.5.2
Pregnancy Test
All women who are being considered for participation in the study, and who are not 
surgically sterilized or postmenopausal, must be tested for pregnancy within 24 hours of the 
first dose of study intervention. If a urine test is positive or not evaluable, a serum test will be 
required. Participants must be excluded/discontinued from the study in the event of a positive 
test result. Repeated pregnancy test (such as monthly testing) may be conducted if required 
by local regulations.
8.4
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 3. 
Progression of the cancer under study is not considered an AE as described in Section 8.4.6 
and Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent but before intervention allocation/randomization must be 
reported by the investigator if the participant is receiving placebo run-in or other run-in 
treatment, if the event cause the participant to be excluded from the study, or is the result of a 
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protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, or a procedure.

All AEs from the time of intervention allocation/randomization through 30 days 
following cessation of study intervention must be reported by the investigator.

All AEs meeting serious criteria, from the time of intervention 
allocation/randomization through 90 days following cessation of study intervention or 
30 days following cessation of study intervention if the participant initiates new 
anticancer therapy, whichever is earlier, must be reported by the investigator.

All pregnancies and exposure during breastfeeding, from the time of treatment 
allocation/randomization through 120 days following pembrolizumab/placebo or 30 
days following cessation of lenvatinib/placebo, whichever occurs last, must be 
reported by the investigator. If the participant initiates new anticancer therapy 
following discontinuation of study intervention, the time period for reporting 
pregnancies and exposure during breastfeeding is reduced to 30 days following 
cessation of study intervention.
Exception: A positive pregnancy test at the time of initial screening is not a reportable 
event unless the participant has received study intervention.

Additionally, any SAE brought to the attention of an investigator at any time outside 
the time period specified above must be reported immediately to the Sponsor if the 
event is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 6.
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Table 6
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time Period:
After the Protocol-
specified Follow-up Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
Nonserious Adverse 
Event (NSAE) 
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse Event 
(SAE) including Cancer 
and Overdose
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all SAEs, 
cancer, overdose 
associated with 
pembrolizumab and 
overdose associated 
with lenvatinib with 
an AE
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/
Lactation Exposure
Report if:
- participant has 
been exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout 
or run-in treatment 
including placebo 
run-in)
Exception: A 
positive pregnancy 
test at the time of 
initial screening is 
not a reportable 
event.
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
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events 
including pregnancy and exposure during breastfeeding, events of clinical interest (ECIs), 
cancer, and overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for 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
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
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8.4.6
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 
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. 
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor. 
Events of clinical interest for this study include: 
1.
An overdose of pembrolizumab, as defined in Section 8.5, that is not associated with 
clinical symptoms or abnormal laboratory results.
2.
Any dose over the prescribed dose of lenvatinib associated with an AE.
3.
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 Study 
File Binder (or equivalent).
8.5
Treatment of Overdose
NOTE: After amendment 007-06, lenvatinib and matching placebo were discontinued.
This section was left unchanged for reference.
For purposes of this study, an overdose will be defined as any dose exceeding the prescribed 
dose as follows:

Pembrolizumab: ≥5 times the protocol-specified dose.

Lenvatinib: any dose above the protocol-specified dose if associated with an adverse 
event.
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There is no specific antidote for an overdose of lenvatinib. Due to its high degree of plasma 
protein binding, lenvatinib is not expected to be dialyzable. Adverse reactions in patients 
receiving single doses of lenvatinib as high as 40 mg were similar to those in clinical studies 
at the recommended dose for differentiated thyroid cancer and RCC. 
No specific information is available on the treatment of overdose of pembrolizumab or 
lenvatinib. In the event of overdose, the participant should be observed closely for signs of 
toxicity. Appropriate supportive treatment should be provided if clinically indicated.
All reports of pembrolizumab overdose with and without an AE and all reports of lenvatinib 
overdose with an AE must be reported by the investigator within 24 hours to the Sponsor 
either by electronic media or paper. 
Reports of pembrolizumab overdose without any associated clinical symptoms or abnormal 
laboratory results, should be reported using the terminology “accidental or intentional 
overdose without adverse effect.”
8.6
Pharmacokinetics
As of Protocol Amendment 05, the Sponsor has determined that there is sufficient 
pembrolizumab/lenvatinib PK data in NSCLC participants. Consequently, no further PK 
samples for pembrolizumab and lenvatinib or ADA samples for pembrolizumab will be 
collected. 
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Planned Genetic Analysis Sample Collection
Samples are to be collected for planned analysis of associations between genetic variants in 
germline/tumor DNA and drug response. If a documented law or regulation prohibits (or 
local IRB/IEC does not approve) sample collection for these purposes, then such samples are
not be collected at the corresponding sites.
8.9
 
 
 
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8.10
Medical Resource Utilization and Health Economics
All-cause hospitalizations and emergency room visits must be reported in the eCRF, from the 
time of treatment randomization through 90 days after cessation of study intervention, or 
30 days after cessation of study intervention, if the participant initiates new anticancer 
therapy, whichever is earlier.
8.11
Visit Requirements
NOTE: As of Amendment 007-06, the Second-course Treatment Phase has been 
removed from the study. The following subsections have been updated accordingly.
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.
Unscheduled visits are permitted at any time during the course of the study.
8.11.1
Screening
Documented informed consent must be provided before performing any protocol-specific
procedure. Results of a test performed before the participant signs the ICF 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 28 days before the
first dose of study intervention except for the following:

Laboratory tests are to be performed per the SoA (Section 1.3).

Evaluation of ECOG is to be performed at screening, within 7 days before Cycle 1
but before randomization.

For WOCBP, a urine or serum pregnancy test will be performed within 24 hours
before the first dose of study intervention. If urine pregnancy results cannot be
confirmed as negative, a serum pregnancy test will be required (performed by the
local study site laboratory).
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria.
Results from assessments during the initial screening period are acceptable in lieu of a repeat
screening test if performed within the specified time frame and the corresponding
inclusion/exclusion criteria are met. Participants who are rescreened will retain their original
screening number.
8.11.2
Initial Treatment Phase
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.1.
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8.11.3
Second-course Treatment Phase
NOTE: As of Amendment 007-06, the Second-course Treatment Phase has been 
removed from the study.
8.11.4
Discontinued Participants Continuing to be Monitored in the Study
The Discontinuation Visit should occur at the time study intervention is discontinued for any 
reason. If the Discontinuation Visit occurs 30 days from the last dose of study intervention, at 
the time of the mandatory Safety Follow-up Visit, the Discontinuation Visit procedures and 
any additional safety follow-up procedures should be performed.
Visit requirements are outlined in the SoA. Additional details regarding participant 
withdrawal and discontinuation are presented in Section 8.1.9.
8.11.5
Poststudy
8.11.5.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visits should be conducted approximately 30 days after the 
last dose of study intervention or before the initiation of a new anticancer treatment, 
whichever comes first.
8.11.5.2
Efficacy Follow-up Visits
NOTE: After amendment 007-06, imaging obtained on study will be submitted to the 
imaging vendor but these will not be assessed, verification of PD is no longer needed 
before treatment discontinuation, and posttreatment imaging is no longer required.
Participants who complete the protocol-required cycles of study intervention or who 
discontinue study intervention for a reason other than PD will move into Efficacy Follow-up 
Phase and should be assessed as outlined in the SoA (Section 1.3) to monitor disease status. 
Every effort should be made to collect information regarding disease status until the start of 
new anticancer therapy, PD, death, or end of study. Information regarding poststudy 
anticancer treatment will be collected if new treatment is initiated. Participants who 
completed all efficacy assessments and/or will not have further efficacy assessments must 
enter Survival Follow-up Phase.
8.11.5.3
Survival Follow-up Assessments
Participants who experience confirmed PD or start a new anticancer therapy will move into 
the Survival Follow-Up Phase and should be contacted by telephone approximately every 
12 weeks (or more often as required) to assess survival status until death, withdrawal of 
consent, or the end of the study, whichever occurs first. Participants may be contacted for 
survival status at any time during the course of the study. 
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9
STATISTICAL ANALYSIS PLAN
NOTE: Data from an interim safety and futility eDMC for LEAP-007 (data cutoff: 19-
MAY-2021) indicated that the study met the prespecified nonbinding futility criteria for 
OS for the combination of lenvatinib plus pembrolizumab compared with placebo plus 
pembrolizumab. This futility analysis was requested at a previous eDMC meeting and 
conducted as described in the sSAP. Based upon these data and the recommendation of 
the eDMC, Amendment 007-06 was implemented to unblind the study and remove 
lenvatinib and matching placebo from the treatment arms. The prespecified interim 
and final analyses of the study described in the statistical analysis plan (SAP) will not be 
performed. Selected analyses of safety and ePRO endpoints will be performed at the 
end of the study; there will be no further analyses of efficacy endpoints.
This section outlines the statistical analysis strategy and procedures for the study. As of 
Amendment 007-06, the study has been unblinded. Changes made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, that occurred 
prior to study unblinding were documented in previous protocol amendment(s) (consistent 
with International Council for Harmonisation [ICH] of Technical Requirements for 
Pharmaceuticals for Human Use Guideline E9). Changes to exploratory or other 
nonconfirmatory analyses made after the protocol has been finalized, but before
unblinding/final database lock, will be documented in a supplemental statistical analysis plan 
(sSAP) and referenced in the clinical study report (CSR) for the study. Post hoc exploratory 
analyses will be clearly identified in the CSR. Separate analysis plans (ie, separate 
documents from the sSAP) will be developed to detail PK and biomarker analyses. The 
ePRO analysis plan will be included in the sSAP.
9.1
Statistical Analysis Plan Summary
Key elements of the SAP are summarized below. The comprehensive plan is provided in 
Sections 9.2 through 9.12. As of Amendment 007-06, the prespecified interim and final 
analyses of the study described in SAP will not be performed. Selected analyses of 
safety and ePRO endpoints will be performed at the end of the study; there will be no 
further analyses of efficacy endpoints. The SAP summary has been updated 
accordingly.
Study Design Overview
Phase 3 study of pembrolizumab plus lenvatinib vs pembrolizumab plus placebo 
for 1L treatment of metastatic NSCLC in participants whose tumors express 
PD-L1 (TPS ≥1%)
Treatment Assignment
Approximately 620 participants will be randomized in a 1:1 ratio between 
2 treatment arms: (1) pembrolizumab + lenvatinib and (2) pembrolizumab +
placebo.
Stratification factors are as follows:

Geographic region (East Asia vs non-East Asia)

ECOG PS (0 vs 1)

TPS (1%-49% vs ≥50%)
As of Amendment 007-06, the study is unblinded and all ongoing participants 
will continue treatment with open-label pembrolizumab monotherapy.
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Analysis Populations
Efficacy: Intention-to-Treat (ITT)
Safety: All Participants as Treated (APaT)
Primary Endpoints

PFS per RECIST 1.1 based on BICR

OS
Secondary Endpoints

OR per RECIST 1.1 based on BICR

Safety and tolerability

Change from baseline in Global health status/QoL, cough, chest pain, dyspnea
and physical functioning scores

Time to True Deterioration (TTD) in global health status/QoL, cough, chest 
pain, dyspnea, and physical functioning 

TTD in the composite endpoint of cough, chest pain, or dyspnea items
Statistical Methods for
Key Efficacy Analyses
As of Amendment 007-06, the prespecified interim and final analyses of the 
study will not be performed. There will be no further analyses of efficacy 
endpoints.
The primary hypotheses will be evaluated by comparing pembrolizumab + 
lenvatinib to pembrolizumab + placebo in PFS and OS using a stratified log-rank 
test and in ORR using the stratified Miettinen and Nurminen method [Miettinen, 
O. and Nurminen, M. 1985]. The HR will be estimated using a stratified Cox 
regression model. Event rates over time will be estimated within each treatment 
group using the Kaplan-Meier method. The difference in ORR will be estimated 
using the stratified Miettinen and Nurminen method with strata weighting by 
sample size.
Statistical Methods for
Key Safety Analyses
The analysis of safety results will follow a tiered approach. The tiers differ with
respect to the analyses that will be performed. There are no events of interest that 
warrant elevation to Tier 1 events in this study. Tier 2 parameters will be assessed 
via point estimates with 95% CIs provided for between-group comparisons; only 
point estimates by treatment group are provided for Tier 3 safety parameters. The 
95% CIs for the between-treatment differences in percentages will be provided 
using the Miettinen and Nurminen method.
Interim Analyses
As of Amendment 007-06, no interim analyses of the study will be performed.
Multiplicity
As of Amendment 007-06, no interim or final analyses of the study will be 
performed.
Sample Size and Power
As of Amendment 007-06, no interim or final analyses of the study will be 
performed.
The planned sample size is approximately 620 participants. For PFS, based on 416 
events, the study has 86.5% power to detect a HR of 0.7 (pembrolizumab +
lenvatinib vs pembrolizumab + placebo) at α=0.55% (1-sided). For OS, based on 
388 events, the study has 90% power to detect a HR of 0.71 (pembrolizumab +
lenvatinib vs pembrolizumab + placebo) at α=1.95% (1-sided).
China Extension Study
As of Amendment 007-06, enrollment in the Extension Study in China has 
been stopped.
China participants randomized during the global study phase will be included in 
all global study analyses (efficacy and safety). China participants randomized 
during the China extension phase will be excluded from all global study analyses. 
China participants randomized during global and extension phases will both be 
included in any China-specific analyses.   
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9.2
Responsibility for Analyses/In-house Blinding
Note: As of Amendment 007-06, the study is unblinded to the Sponsor, the 
investigational sites, and the participants. This section has been updated accordingly.
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study was conducted as a double-blind study under in-house blinding procedures until 
after the eDMC recommended study unblinding. 
The Sponsor generated the randomized allocation schedule(s) for study intervention
assignment. Blinding issues related to the planned interim analyses are described in Section 
9.7, but are no longer applicable as of Amendment 007-06.
Extension Study in China
For all participants in China, including participants randomized in the global study and the 
extension study, statistician(s)/programmers were blinded to participant level treatment 
randomization and this information had been clearly documented.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below.
9.4.1
Efficacy Endpoints
9.4.1.1
Primary Endpoints
PFS: the time from randomization to the first documented PD per RECIST 1.1, adjusted to 
follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, based 
on BICR or death due to any cause, whichever occurs first. See Section 9.6.1 for the 
definition of censoring.
OS: the time from randomization to death due to any cause.
9.4.1.2
Secondary Endpoints
OR: a confirmed CR or PR per RECIST 1.1, adjusted to follow a maximum of 10 target 
lesions and a maximum of 5 target lesions per organ, based on BICR.
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9.4.1.3
 
9.4.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, SAEs, fatal AEs, laboratory tests, and vital signs. Furthermore, specific events will be 
collected and designated as ECIs as described in Section 8.4.7.
9.4.3
Patient-reported Outcome Endpoints
The following secondary PRO endpoints will be evaluated as described in Section 4.2.1.3
and analyzed as described in Section 9.6.3:
Change from baseline in

Global Health Status/QoL scale (QLQ-C30 items 29-30)

Single-item symptom scales: cough (QLQ-LC13 item 31), chest pain (QLQ-LC13 
item 40), and dyspnea (QLQ-C30 item 8)

Physical functioning scale (QLQ-C30 items 1-5)
Time to true deterioration (TTD) in 

Global Health Status/QoL scale (QLQ-C30 items 29-30)

Single-item symptom scales: cough (QLQ-LC13 item 31), chest pain (QLQ-LC13 
item 40), and dyspnea (QLQ-C30 item 8)

Physical functioning scale (QLQ-C30 items 1-5)

Composite symptom endpoint: cough (QLQ-LC13 item 31), chest pain (QLQ-LC13 
item 40), or dyspnea (QLQ-C30 item 8)
The TTD in global health status/QoL, cough, chest pain, dyspnea, and physical functioning is 
defined as the time from baseline to the first onset of a 10 or more points deterioration from 
baseline with confirmation by the subsequent visit of a 10 or more points deterioration from 
baseline. The TTD in the composite endpoint of cough, chest pain, or dyspnea is defined as 
the time to first onset of 10 or more points deterioration from baseline in any one of 3 scale 
items with confirmation by the subsequent visit of 10 points or more deterioration from 
baseline in the same scale as the first onset. The EQ-5D-5L will be evaluated as an 
exploratory endpoint. These analyses and other supportive PRO analyses will be described in 
the sSAP.
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9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The analyses of the primary efficacy endpoints are based on the ITT population. All 
randomized participants will be included in this population. Participants will be analyzed in 
the treatment group to which they are randomized. Details on the approach to handling 
missing data are provided in Section 9.6.
Extension Study in China
NOTE: As of Amendment 007-06, enrollment in the Extension Study in China has been 
stopped. This section has been updated accordingly.
The participants in China who were randomized in the extension study will not be included 
in the above global study primary efficacy analysis population. The ITT participants in China, 
including all participants in China randomized in the global study and the extension study, 
will be analyzed. 
9.5.2
Safety Analysis Populations
Safety analyses will be conducted in the APaT population, which consists of all randomized
participants who received at least 1 dose of study intervention. Participants will be included 
in the treatment group corresponding to the study intervention they actually received for the 
analysis of safety data using the APaT population. This will be the treatment group to which 
they were randomized, except for participants who take incorrect study intervention for the 
entire treatment period; such participants will be included in the treatment group 
corresponding to the study intervention actually received. Any participant who receives the 
incorrect study intervention for 1 cycle, but receives the randomized treatment for all other 
cycles, will be analyzed according to the randomized treatment group, and a narrative will be 
provided for any events that occur during the cycle for which the participant is incorrectly 
dosed.
At least 1 laboratory, vital sign, or ECG measurement obtained after at least 1 dose of study 
intervention is required for inclusion in the analysis of the respective safety parameter. To 
assess change from baseline, a baseline measurement is also required.
Extension Study in China
The participants in China who were randomized and treated in the extension study will not be 
included in the above global study primary safety analysis population. The APaT participants 
in China, including all randomized participants in China (in the global study and extension 
study) who received at least 1 dose of study treatment, will be analyzed.
9.5.3
Patient-reported Outcome Analysis Population
The analyses of PRO endpoints will be based on the PRO full analysis set (FAS) population 
following the ITT principle and ICH E9 guidelines. The PRO FAS population consists of all 
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randomized participants who have received at least 1 dose of study intervention and have 
completed at least 1 PRO assessment.
9.5.4
Pharmacokinetic Analysis Population
The population of PK analysis set includes all the participants who have received at least 
1 dose of study intervention with documented dosing history in the lenvatinib +
pembrolizumab arm and have measurable plasma levels of lenvatinib or serum levels of 
pembrolizumab.
9.6
Statistical Methods
NOTE: As of Amendment 007-06, the prespecified interim and final analyses of the 
study will not be performed. Selected analyses of safety and ePRO endpoints will be 
performed at end of study; there will be no further analyses of efficacy endpoints. The 
subsections below are retained for reference.
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary efficacy
objectives. Methods related to exploratory objectives will be described in the sSAP. Efficacy 
results that will be deemed to be statistically significant after consideration of the Type I 
error control strategy are described in Section 9.8. Nominal p values will be computed for 
other efficacy analyses, but should be interpreted with caution because of potential issues of 
multiplicity.
The stratification factors used for randomization (see Section 6.3.2) will be applied to all 
stratified analyses, in particular, the stratified log-rank test, stratified Cox model, and 
stratified Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985]. If there 
are small strata, for the purpose of analysis, strata will be combined to ensure sufficient 
number of participants, responses and events in each stratum. Details regarding the pooling 
strategy will be prespecified in the sSAP prior to the database lock for the first analysis when 
each applicable endpoint will be analyzed, and decisions regarding the pooling will be based 
on a blinded review of response and event counts by stratum.
The efficacy analyses for OR, DOR and PFS will include responses and documented 
progression events that occur prior to Second-course treatment.
A summary of the primary analysis strategy for the key efficacy endpoints is provided in 
Table 7.
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Table 7
Analysis Methods for Key Efficacy Endpoints
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Analyses:
PFS (RECIST 1.1)
by BICR
Testing: stratified log-rank test
Estimation: Stratified Cox model 
with Efron's tie-handling method 
ITT
Censored according to rules in
Table 8
OS
Testing: stratified log-rank test
Estimation: Stratified Cox model 
with Efron's tie-handling method
ITT
Censored at last known alive date
Secondary Analyses:
ORR (RECIST 1.1) 
by BICR
Testing and estimation:
stratified Miettinen and 
Nurminen method
ITT
Participants with missing data are 
considered nonresponders
Abbreviations: BICR = blinded independent central review; ITT = intention-to-treat; ORR = objective response
rate; OS = overall survival; PFS = progression-free survival; RECIST 1.1 = Response Evaluation Criteria in 
Solid Tumors.
The strategy to address multiplicity issues with regard to multiple endpoints and interim 
analyses is described in Section 9.7, Interim Analyses, and in Section 9.8, Multiplicity.
9.6.1.1
Progression-free Survival
The nonparametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. The hypotheses of treatment difference in PFS will be tested by the 
stratified log-rank test. A stratified Cox proportional hazard model with Efron's method of tie 
handling will be used to estimate the magnitude of the treatment difference (ie, HR) between 
the treatment arms. The HR and its 95% CI from the stratified Cox model with Efron's 
method of tie handling and with a single treatment covariate will be reported.
Since PD is assessed periodically, PD can occur any time in the time interval between the last 
assessment where PD was not documented and the assessment when PD is documented. For 
the primary analysis, for the participants who have PD, the true date of PD will be 
approximated by the date of the first assessment at which PD is objectively documented per 
RECIST 1.1 by the BICR vendor, regardless of discontinuation of study drug. Additional
analyses will be performed for PFS per iRECIST.
To evaluate the robustness of the PFS endpoint per RECIST 1.1 via BICR by the imaging 
vendor, 1 primary and 2 sensitivity analyses with a different set of censoring rules will be 
performed. For the primary analysis, if the events (PD or death) are after more than 1 missed 
disease assessment, the data are censored at the last disease assessment before missing visits. 
Also, data after new anticancer therapy are censored at the last disease assessment before the 
initiation of new anticancer therapy. The first sensitivity analysis follows ITT principles (ie, 
PDs/deaths are counted as events regardless of missed study visits or initiation of new 
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anticancer therapy). The second sensitivity analysis considers discontinuation of treatment or 
initiation of an anticancer treatment after discontinuation of study-specified treatments, 
whichever occurs later, to be a PD event for participants without documented PD or death. If 
a participant meets multiple criteria for censoring, the censoring criterion that occurs earliest 
will be applied. The censoring rules for primary and sensitivity analyses are summarized in 
Table 8.
Table 8
Censoring Rules for Primary and Sensitivity Analyses of Progression-free 
Survival
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
No PD and no death; new 
anticancer treatment is not 
initiated
Censored at last disease 
assessment
Censored at last 
disease assessment
Progressed at treatment 
discontinuation for reasons 
other than CR; otherwise,
censored at last disease 
assessment if still on study 
intervention or completed 
study intervention
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 or death documented 
after ≤1 missed disease 
assessment and before new 
anticancer therapy
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
Censored at last disease 
assessment before the
earlier date of 
≥2 consecutive missed 
disease assessment and 
new anticancer therapy
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or death
Abbreviation: CR = complete response; PD = progressive disease.
9.6.1.2
Overall Survival
The nonparametric Kaplan-Meier method will be used to estimate the survival curves. The 
treatment difference in survival will be assessed by the stratified log-rank test (based on the 
stratification factors defined in Section 6.3.2). A stratified Cox proportional hazard model 
with Efron's method of tie handling will be used to assess the magnitude of the treatment 
difference (ie, the HR). The HR and its 95% CI from the stratified Cox model with a single 
treatment covariate will be reported. The stratification factors used for randomization 
(Section 6.3.2) will be applied to both the stratified log-rank test and the stratified Cox 
model. Participants without documented death at the time of analysis will be censored at the 
date of last known contact. The analysis using the restricted mean survival time method may 
be conducted for OS to account for the possible nonproportional hazards effect.
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9.6.1.3
Objective Response Rate
The stratified Miettinen and Nurminen method will be used for comparison of ORR between 
the treatment groups. The difference in ORR and its 95% CI from the stratified Miettinen and 
Nurminen method with strata weighting by sample size will be provided.
9.6.1.4
Duration of Response
For participants who demonstrate CR or PR, DOR is defined as the time from first 
documented evidence of CR or PR until PD or death due to any cause, whichever occurs 
first.
The nonparametric Kaplan-Meier method will be used to summarize the DOR. The median
and range of DOR will be provided.
Censoring rules for DOR are summarized in Table 9.
Table 9
Censoring Rules for Duration of Response
Situation
Date of Progression or Censoring
Outcome
No PD or death, no new anticancer 
therapy initiated
Last adequate disease assessment
Censor
(nonevent)
No PD or death, new anticancer 
therapy initiated
Last adequate disease assessment before new 
anticancer therapy initiated
Censor
(nonevent)
Death or PD immediately after ≥2 
consecutive missed disease 
assessments or after new anticancer 
therapy, if any
Earlier date of last adequate disease assessment 
before ≥2 missed adequate disease assessments 
and new anticancer therapy, if any
Censor
(nonevent)
Death or PD after ≤1 missed disease 
assessments and before new 
anticancer therapy, if any
PD or death
End of response
(event)
Abbreviation: PD = progressive disease.
Note: A missed disease assessment includes any assessment that is not obtained or is considered inadequate for 
evaluation of response.
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, vital signs, and ECG measurements.
The analysis of safety results will follow a tiered approach (Table 10). The tiers differ with 
respect to the analyses that will be performed. AEs (specific terms as well as system organ 
class terms) and events that meet predefined limits of change in laboratory, vital signs, and 
ECG parameters are either prespecified as “Tier 1” endpoints or will be classified as 
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belonging to “Tier 2” or “Tier 3,” based on observed proportions of participants with an 
event.
Tier 1 Events
Safety parameters or AEs of special interest that are identified a priori constitute “Tier 1” 
safety endpoints that will be subject to inferential testing for statistical significance. AEs that 
are immune-mediated or potentially immune-mediated are well documented and will be 
evaluated separately; however, these events have been characterized consistently throughout 
the pembrolizumab clinical development program, and determination of statistical 
significance is not expected to add value to the safety evaluation. Similarly, the combination 
of pembrolizumab and lenvatinib has not been associated with any new safety signals. 
Finally, there are no known AEs associated with participants with NSCLC for which 
determination of a p value is expected to impact the safety assessment. Therefore, there are 
no Tier 1 events for this protocol.
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events using the Miettinen and Nurminen method, an 
unconditional, asymptotic method [Miettinen, O. and Nurminen, M. 1985].
Membership in Tier 2 requires that at least 10% of participants in any treatment group exhibit 
the event; all other AEs and predefined limits of change will belong to Tier 3. The threshold 
of at least 10% of participants was chosen for Tier 2 events because the population 
randomized in this study are in critical conditions and usually experience various AEs of 
similar types regardless of treatment; events reported less frequently than 10% of participants 
would obscure the assessment of the overall safety profile and add little to the interpretation 
of potentially meaningful treatment differences. In addition, Grade 3 to 5 AEs (≥5% of 
participants in one of the treatment groups) and SAEs (≥5% of participants in one of the 
treatment groups) will be considered Tier 2 endpoints. Because many 95% CIs may be 
provided without adjustment for multiplicity, the CIs should be regarded as a helpful 
descriptive measure to be used in safety review, not a formal method for assessing the 
statistical significance of the between-group differences.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment group are provided for Tier 3 safety parameters.
Continuous Safety Measures
For continuous measures such as changes from baseline in laboratory, vital signs, and ECG 
parameters, summary statistics for baseline, on-treatment, and change from baseline values 
will be provided by treatment group in table format.
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Table 10
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
95% CI for
Treatment
Comparison
Descriptive
Statistics
Tier 2
Any AE (≥10% of participants in one of the treatment groups)
X
X
Any Grade 3 to 5 AE (≥5% of participants in one of the 
treatment groups)
X
X
Any serious AE (≥5% of participants in one of the treatment 
groups)
X
X
Tier 3
Any AE
X
Change from baseline results (laboratory test toxicity grade)
X
Abbreviations: AE = adverse event; CI = confidence interval; X = results will be provided.
9.6.3
Statistical Methods for Patient-reported Outcome Analyses
Mean change from baseline
The time point for the mean change from baseline will be determined based on blinded data 
review prior to the database lock for any PRO analysis and documented in the sSAP.
To assess the treatment effects on the PRO score change from baseline in the PRO endpoints 
defined in Section 9.4.3, a constrained longitudinal data analysis (cLDA) model proposed by 
Liang and Zeger [Liang, Kung-Yee and Zeger, Scott L. 2000] will be applied, with the PRO 
score as the response variable, and treatment, time, the treatment by time interaction, and 
stratification factors used for randomization (See Section 6.3.2) as covariates. The treatment 
difference in terms of least square (LS) mean change from baseline will be estimated from 
this model together with 95% CI. Model-based LS mean with 95% CI will be provided by 
treatment group for PRO scores at baseline and postbaseline time point.
Time to Deterioration (TTD)
For the TTD endpoints defined in Section 9.4.3, the Kaplan-Meier method will be used to 
estimate the TTD curve for each treatment group. The estimate of median time to 
deterioration and its 95% CI will be obtained from the Kaplan-Meier estimates. The 
treatment difference in TTD will be assessed by the stratified log-rank test. A stratified Cox 
proportional hazard model with Efron’s method of tie handling and with a single treatment 
covariate will be used to assess the magnitude of the treatment difference (ie, HR). The HR 
and its 95% CI will be reported. The same stratification factors used for the stratified PFS 
and OS analyses will be used as the stratification factors in both the stratified log-rank test 
and the stratified Cox model.  
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9.6.4
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis 
tests will be performed on these characteristics. The number and percentage of participants 
screened and randomized and the primary reason for screening failure and discontinuation 
will be displayed. Demographic variables, baseline characteristics, primary and secondary 
diagnoses, and prior and concomitant therapies will be summarized by treatment, either by 
descriptive statistics or categorical tables.
9.7
Interim Analyses
NOTE: As of Amendment 007-06, no interim analyses of the study will be performed. 
This section is no longer applicable.
9.7.1
Safety Interim Analyses
The DMC conducted regular safety monitoring. The timing of the safety monitoring was
specified in the DMC charter. No further analysis is warranted.
9.8
Multiplicity
NOTE: As of Amendment 007-06, no interim or final analyses of the study will be 
performed. This section is no longer applicable.
9.9
Sample Size and Power Calculations
NOTE: As of Amendment 007-06, no interim or final analyses of the study will be 
performed. This section is retained for reference.
The study will randomize 620 participants in a 1:1 ratio into the pembrolizumab + lenvatinib
and pembrolizumab + placebo arms. PFS and OS are primary endpoints for the study, with 
OR as the secondary endpoint.
For the PFS endpoint, based on a target number of 416 events at the final PFS analysis, the 
study has approximately 86.5% power to detect an HR of 0.7 at the initially allocated
α=0.0055 (1-sided).
For the OS endpoint, based on a target number of 388 events and one interim analysis at 
approximately 78% of the target number of events, the study has approximately 90% power 
to detect an HR of 0.71 at the initially allocated α=0.0195 (1-sided).
Based on KEYNOTE-042 data, the above sample size and power calculations for PFS and 
OS assume the following:
PFS follows a piecewise exponential distribution, with a median of 5 months up to 6.5 
months and then a median of 12 months thereafter for the control group.
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OS follows an exponential distribution, with a median of 16.7 months for the control group.
Enrollment period is approximately 21.7 months.
Annual drop-out rate is 20% and 2% for PFS and OS, respectively.
Follow-up period is approximately 8.8 and 18.5 months for PFS and OS, respectively, after 
the last participant is randomized.
The sample size and power calculations were performed in R (package “gsDesign”) and 
EAST 6.4.
Extension Study in China
As of amendment 007-06, enrollment in the Extension Study in China has been stopped.
In order to evaluate the consistency of efficacy and safety in the subpopulation in China 
compared with the global population, following completion of global study enrollment, 
participants in China will continue to be randomized in a 1:1 ratio into the pembrolizumab + 
lenvatinib arm and pembrolizumab + placebo arm until the planned sample size of 
approximately 120 participants in China is reached. Participants in China randomized after 
completion of enrollment in the global study will not be included in the analysis of the global 
study.
9.10
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
between-group treatment effect for OS, PFS, and OR (with a nominal 95% CI) will be 
estimated and plotted by treatment group within each category of the following subgroup
variables:

Geographic region (East Asia, non-East Asia)

ECOG performance status (0, 1)

Predominant tumor histology (squamous, nonsquamous)

TPS (1%-49%, ≥50%)

Age category (<65, ≥65 years)

Sex (female, male)

Race (white, nonwhite)

Smoking status (never, former/current smoker)
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
Brain metastasis at baseline (presence, absence)

Liver metastasis at baseline (presence, absence)
The consistency of the treatment effect will be assessed using descriptive statistics for each 
category of the subgroup variables listed above. If the number of participants in a category of 
a subgroup variable is less than 10% of the ITT population, the subgroup analysis will not be 
performed for this category of the subgroup variable, and this subgroup variable will not be 
displayed in the forest plot. The subgroup analyses for PFS and OS will be conducted using 
unstratified Cox model, and the subgroup analyses for OR will be conducted using 
unstratified Miettinen and Nurminen method.
9.11
Compliance (Medication Adherence)
Drug accountability data for study intervention will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
9.12
Extent of Exposure
Extent of exposure for a participant is defined as number of cycles in which the participant 
receives the study intervention. Summary statistics will be provided on extent of exposure for 
the APaT population.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
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 (eg, contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, 
efficacy, and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. 
Alternatively, MSD may conduct outcomes research trials, trials to assess or validate various endpoint 
measures, or trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and 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 
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potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing, in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, 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.
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MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
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 that 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.
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10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked 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.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Steering Committee
This study will be conducted in consultation with a Steering Committee. The Steering 
Committee is composed of the following:

Sponsor personnel

Eisai personnel

Investigators participating in the study

Consulting therapeutic area and clinical study experts
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The Steering Committee will provide guidance on the operational aspects of the study and 
provide input with respect to study design, interpretation of results, and subsequent 
peer-reviewed scientific publications.
Specific details regarding responsibilities and governance of the Steering Committee will be 
described in a separate charter.
10.1.4.2
Executive Oversight Committee
The EOC is composed of members of Sponsor Senior Management. The EOC will receive 
and decide upon any recommendations made by the DMC or Steering Committee regarding 
the study.
10.1.4.3
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7, Interim 
Analysis) 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 OR external 
collaborating organization protocol team; meeting facilitation; the study governance 
structure; and requirements for and proper documentation of DMC reports, minutes, and 
recommendations will be described in the DMC charter that is reviewed and approved by all 
the DMC members.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
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Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
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 study 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.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of GCP); and all applicable federal, state and local laws, rules and 
regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Studies.
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. 
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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.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
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.
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10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
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10.2
Appendix 2: Clinical Laboratory Tests

The laboratory tests detailed in Table 11 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 if determined 
necessary by the investigator or required by local regulations.

Pregnancy testing requirements for study inclusion are described in Section 5.1 and 
Section 8.3.5.2.

Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at monthly intervals during intervention.

Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the end of relevant systemic exposure and correspond with the time 
frame for female participant contraception in Section 5.1, Inclusion Criteria.

Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the participant’s participation in the study.
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Table 11
Protocol-Required Safety Laboratory Assessments
Hematology
Comprehensive
Chemistry Panel
Urinalysis
Other
Hematocrit
Albumin
Blood
FSHa
Hemoglobin
Alkaline phosphatase
Glucose
Pregnancy test (highly 
sensitive serum or urine)
human chorionic 
gonadotropin (hCG)b
Platelet count
ALT
Protein
PT/INR and aPTT/PTT
RBC
WBC count with 
differential (absolute or 
percentage):
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
AST
Specific gravity
Total T3 (or FT3), total T4 
(or FT4), and TSHc,d
CO2 or bicarbonatee
Microscopic 
examination, if 
abnormal results 
are noted
HIV testingf
Calcium
Hepatitis B and C testingf,g
Chloride
Blood for genetic analysis
Creatinine
Glucose
Magnesium
Phosphorus
Potassium
Blood for serum 
biomarkers
Sodium
Blood for RNA analysis
Total bilirubin
Blood for circulating tumor 
nucleic acids
Direct bilirubinh
Blood for plasma 
biomarkers
Total protein
BUN or ureai
Amylase
Lipase
Abbreviations: ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; 
AST = aspartate aminotransferase; BUN = blood urea nitrogen; C1D1 = Cycle 1 Day 1; CO2 = carbon 
dioxide; FSH = follicle-stimulating hormone; FT3 = free triiodothyronine; FT4 = free thyroxine; 
HIV = human immunodeficiency virus; INR = international normalized ratio; PT = prothrombin time; 
PTT = partial thromboplastin time; RBC = red blood cells; SOC = standard of care; T3 = triiodothyronine; 
T4 = thyroxine; TSH = thyroid-stimulating hormone; WBC = white blood cell; WOCBP = women of 
childbearing potential.
a
As needed, FSH to be performed at screening to confirm postmenopausal status.
b
Perform on WOCBP only 24 hours before first dose. Pregnancy tests must be repeated before every 
cycle.
c
T3 is preferred; if not available, free T3 may be tested.
d
Participants may be dosed in subsequent cycles after C1D1 while thyroid function tests are pending.
e
Bicarbonate only if available as SOC in the region.
f
If mandated by local health authority.
g
Hepatitis B surface antigen (HBsAg) or hepatitis B virus (HBV)-DNA. Hepatitis C virus (HCV)-RNA 
(qualitative) or HCV antibody.
h
If total bilirubin is elevated above the upper limit of normal.
i
BUN or urea (one or the other should be collected per institutional standard).
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.

NOTE: For purposes of AE definition, study intervention (also referred to as 
Sponsor’s product) includes any pharmaceutical product, biological product, vaccine, 
diagnostic agent, or protocol specified procedure whether investigational or marketed
(including placebo, active comparator product, or run-in intervention), manufactured 
by, licensed by, provided by, or distributed by the Sponsor for human use in this 
study.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
Note: Congenital disorders (eg, present from birth) not detected or diagnosed prior to 
study intervention administration do not qualify for reporting as AE.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.

For all reports of overdose (whether accidental or intentional) with an associated AE, 
the AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported 
using the terminology “accidental or intentional overdose without adverse effect.”
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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 8.4.6 for protocol-specific exceptions.
10.3.2
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 participant’s 
medical history.
d. Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
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
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect

In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events

Medical or scientific judgment should be exercised in deciding whether SAE
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.

Is a new cancer (that is not a condition of the study)

Is associated with an overdose of pembrolizumab
10.3.4
Recording AE and SAE
AE and SAE recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.

The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
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
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.

There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity

An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
1.
The investigator will make an assessment of intensity for each AE and SAE (and 
other reportable safety event) according to the NCI Common Terminology for 
Adverse Events (CTCAE), version 4. Any AE that changes CTCAE grade over the 
course of a given episode will have each change of grade recorded on the AE 
CRFs/worksheets.
−
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.
−
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental 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
1.
Did the Sponsor’s product cause the AE?
2.
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 
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assessing the likelihood of a relationship between the test product and the AE based 
upon the available information.
3.
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the 
Sponsor’s product caused the AE:
−
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment 
(pill count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
−
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE 
compatible with a drug-induced effect (applies to studies with investigational 
medicinal product)?
−
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors.
−
Dechallenge: Was the Sponsor’s product discontinued or 
dose/exposure/frequency reduced?
−
If yes, did the AE resolve or improve?
−
If yes, this is a positive dechallenge.
−
If no, this is a negative dechallenge.
−
(Note: This criterion is not applicable if: (1) the AE resulted in death or 
permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; (3) the study is a single-dose drug study; or (4) 
Sponsor’s product(s) is/are only used 1 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 1 time.)
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NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
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.
4.
Consistency with study intervention profile: Is the clinical/pathological 
presentation of the AE consistent with previous knowledge regarding the Sponsor’s 
product or drug class pharmacology or toxicology?
5.
The assessment of relationship will be reported on the case report forms/worksheets 
by an investigator who is a qualified physician according to his/her best clinical 
judgment, including consideration of the above elements.
6.
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
−
Yes, there is a reasonable possibility of Sponsor’s product relationship:
−
There is evidence of exposure to the Sponsor’s product. The temporal 
sequence of the AE onset relative to the administration of the Sponsor’s 
product is reasonable. The AE is more likely explained by the Sponsor’s 
product than by another cause.
−
No, there is not a reasonable possibility of Sponsor's product relationship:
−
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)
7.
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.
8.
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.
9.
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.
10.
The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements.
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11.
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.
10.3.5
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).
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
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF

If the EDC tool is not operational, facsimile transmission or secure 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 Study File Binder (or equivalent).
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
This section is not applicable.
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:

Premenarchal

Premenopausal female with 1 of the following:
−
Documented hysterectomy
−
Documented bilateral salpingectomy
−
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note:  Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.

Postmenopausal female
−
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.
◦
A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or HRT. However, in the absence of 12 months of amenorrhea, 
confirmation with 2 FSH measurements in the postmenopausal range is 
required.
◦
Females on HRT and whose menopausal status is in doubt will be required to 
use one of the nonhormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.

Progestogen-only subdermal contraceptive implantb

Intrauterine hormone-releasing system (IUS)c

Intrauterine device (IUD)

Bilateral tubal occlusion

Azoospermic partner (Vasectomized or secondary to medical cause)

This is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used. A 
spermatogenesis cycle is approximately 90 days.
Note:  Documentation of azoospermia can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview.
Sexual Abstinence 

Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study and the preferred and usual lifestyle of the 
participant.
a.
Contraceptive use by men or women should be consistent with local regulations 
regarding the use of contraceptive methods for participants of clinical studies.
b. If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) 
guidelines, acceptable contraceptive implants are limited to those which inhibit 
ovulation.
c.
IUS is a progestin-releasing IUD.
Note: The following are not acceptable methods of contraception:
−
Periodic abstinence (calendar, symptothermal, postovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea 
method (LAM).
−
Male condom with cap, diaphragm, or sponge with spermicide.
−
Male and female condom should not be used together (due to risk of failure 
with friction).
10.5.3
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test. Refer to Section 8.3.5.2 and Appendix 2 for further details.
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A urine pregnancy test will be obtained per the SoA (Section 1.3). Additional urine/serum 
testing may be performed if clinically warranted and/or as defined by local regulations. If a 
urine pregnancy test cannot be confirmed as negative, a serum pregnancy test is required.
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10.6
Appendix 6: Description of the iRECIST Process for Assessment of Disease 
Progression
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 to guide decisions about changes in management.
Assessment at Screening and Before RECIST 1.1 Progression
Until radiographic PD based on RECIST 1.1, there is no distinct iRECIST assessment.
Assessment and Decision at RECIST 1.1 Progression
For participants who show radiological PD by RECIST 1.1, the investigator will decide 
whether to continue a participant on study intervention until repeat scans are obtained, as 
described in Section 8.2.1.6.
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

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 nontarget lesion(s) identified at baseline

Development of new lesion(s)
iRECIST defines new response categories, including iUPD (unconfirmed PD) and iCPD 
(confirmed PD). For purposes of iRECIST assessment, the first visit showing PD according 
to RECIST 1.1 will be assigned a visit (overall) response of iUPD, regardless of which 
factors caused the PD.
At this visit, target and nontarget lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or nonmeasurable, 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 – Nontarget.
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Assessment at the Confirmatory Imaging
On the confirmatory imaging, the participant will be classified as PD confirmed (with an 
overall response of iCPD), or as showing persistent unconfirmed PD (with an overall 
response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of PD
PD is considered confirmed, and the overall response will be iCPD, if ANY of the following 
occur:

Any of the factors that were the basis for the iUPD at the previous visit show 
worsening
−
For target lesions, worsening is a further increase in the sum of diameters of 
≥5 mm, compared with any prior iUPD time point
−
For nontarget lesions, worsening is any significant growth in lesions overall, 
compared with a prior iUPD time point; this does not have to meet the 
“unequivocal” standard of RECIST 1.1
−
For new lesions, worsening is any of these:
◦
An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD 
time point 
◦
Visible growth of new nontarget lesions 
◦
The appearance of additional new lesions

Any new factor appears that would have triggered PD by RECIST 1.1
Persistent iUPD
PD is considered not confirmed, and the overall response remains iUPD, if:

None of the PD-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, and iCR.
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Resolution of iUPD
PD is considered not confirmed, and the overall response becomes iSD, iPR, or iCR, if:

None of the PD-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 pseudoprogression, 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 intervention may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
intervention.
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit, an exception to continue study
intervention may be considered following consultation with the Sponsor. In this case, if study 
intervention is continued, tumor imaging should continue to be performed following the 
intervals as outlined in the SoA (Section 1.3).
Detection of Progression at Visits After Pseudo-progression Resolves
After resolution of pseudoprogression (ie, achievement of iSD, iPR, iCR, iUPD is indicated 
by any of the following events):

Target lesions
−
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from 
nadir) either for the first time, or after resolution of previous 
pseudoprogression. The nadir is always the smallest sum of diameters seen 
during the entire trial, either before or after an instance of pseudoprogression.

Nontarget lesions
−
If nontarget lesions have never shown unequivocal PD, their doing so for the 
first time results in iUPD.
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−
If nontarget lesions have shown previous unequivocal PD, and this PD has not 
resolved, iUPD results from any significant further growth of nontarget 
lesions, taken as a whole.

New lesions
−
New lesions appear for the first time
−
Additional new lesions appear
−
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
−
Previously identified nontarget lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. PD must 
be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
1 exception: if new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve 
to iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication [Seymour, L., et 
al 2017].
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Japan-specific Requirements
For the assistance to early diagnosis of pneumonitis/interstitial lung disease (ILD) in study 
participants, the following items, such as pulse oximetry monitoring (peripheral capillary 
oxygen saturation [SpO2]), C-reactive protein (CRP), Krebs von den Lungen-6 (KL-6), and 
surfactant protein-D (SP-D), will be measured in this study. These items should be measured 
as follows:

SpO2 at the timing of vital sign assessment

CRP, KL-6, and SP-D at screening*, predose on Day 1 of every cycle, end of 
treatment, and the Safety Follow-up Visit (30 days after last dose)
*Should be measured at the timing of clinical laboratory tests (such as 
hematology/chemistry).
If pneumonitis/ILD occurs regardless of causality with study intervention, an independent 
ILD evaluation committee will conduct adjudication of cases of the pneumonitis/ILD. For 
this purpose, relevant data, such as chest imaging (from the baseline to the recovery of 
pneumonitis/ILD) will be submitted to MSD K.K.
10.7.2
France-specific Requirements
Treatment with pembrolizumab should be permanently discontinued in cases of confirmed 
Stevens-Johnson syndrome or toxic epidermal necrolysis.
10.7.3
Canada-specific Requirements 
See Section 6.6.1 Immune-related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Treatment with pembrolizumab should be permanently discontinued in cases of confirmed 
Stevens-Johnson syndrome or toxic epidermal necrolysis.
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
1L
first-line
ADA
antidrug antibody
ADL
activities of daily living
AE
adverse event
AJCC
American Joint Committee on Cancer
ALK
anaplastic lymphoma kinase
APaT
All Participants as Treated
BICR
blinded independent central review
CI
confidence interval
CL
clearance
COPD
chronic obstructive pulmonary disease
CR
complete response
CRF
case report form
CRP
C-reactive protein
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTFG
Clinical Trial Facilitation Group
CVA
cerebrovascular accident
DILI
drug-induced liver injury
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DOR
duration of response
ECG
electrocardiogram
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data collection
EGFR
epidermal growth factor receptor
EMA
European Medicines Agency
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Abbreviation
Expanded Term
EOC
Executive Oversight Committee
EORTC
European Organization for Research and Treatment of Cancer
ePRO
electronic patient-reported outcome
EQ-5D-5L
EuroQoL-5D-5L
FAS
Full Analysis Set
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FGF
fibroblast growth factor
FGFR
fibroblast growth factor receptor
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
hazard ratio
HRQoL
health-related quality of life
HRT
hormone replacement therapy
IA
interim analysis
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
iCPD
confirmed PD
iCR
confirmed CR
IEC
Independent Ethics Committee
irAE
immune-related adverse event
iPR
confirmed PR
IRB
Institutional Review Board
iRECIST
adjusted RECIST 1.1 for Immune-based Therapeutics
iSD
confirmed SD
ITT
Intention to Treat
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Abbreviation
Expanded Term
IUD
intrauterine device
iUPD
unconfirmed PD
IUS
intrauterine hormone-releasing system
IV
intravenous
KL-6
Krebs von den Lungen-6
LEAP
lenvatinib and pembrolizumab
LVEF
left ventricular ejection fraction
mAb
monoclonal antibody
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
MUGA
multigated acquisition scan
NCI
National Cancer Institute
NSCLC
non–small cell lung cancer
OR
objective response
ORR
objective response rate
OS
overall survival
PD
progressive disease
PD-1
programmed cell death protein
PDGFR
platelet-derived growth factor receptor
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PFS
progression-free survival
Pgp
P-glycoprotein
PK
pharmacokinetic
PopPK
population pharmacokinetics
PR
partial response
PRES
posterior reversible encephalopathy syndrome
PRO
patient-reported outcomes
Q3W
every 3 weeks
QD
once daily
QLQ-LC13
Quality of Life Questionnaire and Lung Cancer Module 13
QoL
quality of life
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Abbreviation
Expanded Term
RCC
renal cell carcinoma
RECIST 1.1
Response Evaluation Criteria in Solid Tumors 1.1
RNA
ribonucleic acid
RP2D
recommended Phase 2 dose
RPLS
reversible posterior leukoencephalopathy syndrome
RTKi
receptor tyrosine kinase inhibitor
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SoA
schedule of activities
SOC
standard of care
SP-D
surfactant protein-D
SpO2
peripheral capillary oxygen saturation
sSAP
supplemental statistical analysis plan
TAM
tumor-associated macrophage
TB
tuberculosis
TPS
tumor proportion score
TTD
time to true deterioration
UPCR
urine protein-to-creatinine ratio
V
volume of distribution
VEGF
vascular endothelial growth factor
VEGFR
vascular endothelial growth factor receptor
WOCBP
woman/women of childbearing potential
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PRODUCT:  MK-7902 (E7080/lenvatinib) and MK-3475 (pembrolizumab)
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11
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