A Phase 3, Multicenter, Randomized, Open-label Trial to Compare the Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Lenvatinib (E7080/MK-7902) Versus Docetaxel in Previously Treated Participants With Metastatic Non-small Cell Lung Cancer (NSCLC) and Progressive Disease (PD) After Platinum Doublet Chemotherapy and Immunotherapy (LEAP-008)
Phase: PHASE3
Conditions: Metastatic Non-Small Cell Lung Cancer
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
A Phase 3, multicenter, randomized, open-label trial to compare 
the efficacy and safety of pembrolizumab (MK-3475) in 
combination with lenvatinib (E7080/MK-7902) versus docetaxel in 
previously treated participants with metastatic non-small cell lung 
cancer (NSCLC) and progressive disease (PD) after platinum 
doublet chemotherapy and immunotherapy (LEAP-008)
NCT03976375
08-December-2023

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TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3, multicenter, randomized, open-label trial to compare the efficacy 
and safety of pembrolizumab (MK-3475) in combination with lenvatinib (E7080/MK-7902) 
versus docetaxel in previously treated participants with metastatic non-small cell lung cancer 
(NSCLC) and progressive disease (PD) after platinum doublet chemotherapy and 
immunotherapy (LEAP-008)
Protocol Number: 008-09 (E7080-G000-316)
Compound Number: MK-7902 (E7080/lenvatinib) and MK-3475 (pembrolizumab)
Sponsor Name: Merck Sharp & Dohme LLC (hereafter called 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):
NCT
Not Applicable
EU CT
2022-501439-18-00
EudraCT
2018-003791-12
JRCT
Not Applicable
WHO
Not Applicable
UTN
Not Applicable
IND
140221
Approval Date: 08 December 2023
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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 9
08-DEC-2023
The study is to be discontinued based on the 
observation that the combination of 
pembrolizumab + lenvatinib versus docetaxel
monotherapy did not meet the prespecified 
criteria for the primary endpoint of OS at the final 
analysis and the second dual primary endpoint of 
PFS at IA2.
Amendment 8
27-FEB-2023
Updated to align with the Protocol Clarification 
Letter, which specified to follow the more 
stringent contraception requirements for male and 
female participants if included in local label for 
specific country.
Amendment 7
12-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.
Additional changes were made throughout the
protocol to align with the EU CTR.
Amendment 6
28-APR-2021
To update the dose modification and toxicity 
management guidelines for irAEs. The protocol 
was amended to update the CTCAE version 
within Dose Modification and Toxicity 
Management Guidelines for irAEs and table that 
was used in this study.
Amendment 5
26-MAR-2021
To provide guidance regarding osteonecrosis of 
the jaw for participants treated with lenvatinib; 
alignment with lenvatinib program standards, 
revised informed consent language in response to 
COVID-19 for in-person visit safety 
considerations to allow documented (oral) 
consent if allowable by IRB/IEC and local Health 
Authority; updated pembrolizumab dose 
modification table.
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Document
Date of Issue
Overall Rationale
Amendment 4
27-MAY-2020
Amended to clarify and update futility analyses 
criteria, to align Section 9.1 and Section 9.7.2 of 
the SAP, to adjust DCR12 evaluation 
requirements, to provide additional guidance to 
investigators regarding dose modifications and 
overdose reporting, to include lenvatinib label 
safety updates, and to include country-specific 
requirements for enrollment.
Amendment 3
16-JAN-2020
Progressive disease (PD) during/after platinum 
doublet chemotherapy is for treatment of 
metastatic disease, therefore a clarification was 
added to the platinum doublet chemotherapy 
(inclusion criterion #3). The clarification states 
that completion of treatment with a platinum 
doublet chemotherapy as neoadjuvant, adjuvant, 
or definitive chemo-radiation treatment for early 
stage disease (Stage I-III) within 1 year of signing 
the ICF will satisfy the prior platinum doublet 
chemotherapy treatment requirement. In addition, 
an update was added to the immunotherapy 
refractory criteria (inclusion criterion #2), 
treatment with only one prior anti-PD-1/PD-L1 
immunotherapy is permitted.
Amendment 2
28-AUG-2019
Removal of the second confirmatory image for 
PD; added MUGA/ECHO at baseline for all 
participants; significant updates to the Inclusion 
and Exclusion Criteria; general template updates.
Amendment 1
04-APR-2019
Amended to update the study design.
Original Protocol
18-DEC-2018
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 09
Overall Rationale for the Amendment:
The study is to be discontinued based on the observation that the combination of pembrolizumab + lenvatinib versus docetaxel 
monotherapy did not meet the prespecified criteria for the primary endpoint of OS at the final analysis and the second dual primary 
endpoint of PFS at IA2.
Summary of Changes Table
Section Number and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 1.1, Synopsis
Clarify that the study is to be discontinued based 
on a lack of additional clinical benefit on overall 
survival of the combination of pembrolizumab 
plus lenvatinib over docetaxel monotherapy. 
Upon study termination, participants are 
discontinued and may be enrolled in an
extension study, if available.
This change addresses new data that 
recently became available. The 
combination of pembrolizumab + 
lenvatinib versus docetaxel monotherapy 
did not meet the prespecified criteria for 
the primary endpoint of OS at the final 
analysis and the second dual primary 
endpoint of PFS at IA2.
Other Changes in Amendment
Section 1.1, Synopsis
The changes specify which analyses and 
procedures will or will not continue to be 
conducted.
Refer to Section 1.1 rationale.
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Section Number and Name
Description of Change
Brief Rationale
Section 1.1, Synopsis
Table: Intervention Groups and Duration: To 
clarify that the study is to be discontinued based 
on a lack of additional clinical benefit on overall 
survival of the combination of pembrolizumab 
plus lenvatinib over docetaxel monotherapy. 
Upon study termination, participants are 
discontinued and may be enrolled in an
extension study, if available.
Refer to Section 1.1 rationale.
Section 4.4, Beginning and End-
of-Study Definition
Participants may be enrolled in an extension 
study upon discontinuation at study termination.
Refer to Section 1.1 rationale.
Section 6.1, Study Intervention(s) 
Administered
Note on study-specific investigator letter has 
been added regarding participants still receiving 
study treatment.
Refer to Section 1.1 rationale.
Section 8.2.1, Tumor Scans and 
Response Assessment
Central tumor response assessments will be 
discontinued. Imaging scans will no longer be 
submitted to the iCRO nor read by BICR.
Refer to Section 1.1 rationale.
Section 8.2.1.4, End of treatment 
and Follow-up Tumor Scans
Follow-up tumor imaging is only required for 
participants who are candidate for Second 
Course treatment.
Refer to Section 1.1 rationale.
Section 8.2.2, Patient-reported 
Outcomes
ePRO assessments will be discontinued.
Refer to Section 1.1 rationale.
Section 8.4.1, Time Period and 
Frequency for Collecting AE, 
SAE, and Other Reportable Safety 
Event Information
Text for participants who enter the separate 
Extension Study was added.
Refer to Section 1.1 rationale.
Section 8.6, Pharmacokinetics
Sample collection will be discontinued.
Refer to Section 1.1 rationale.
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Section Number and Name
Description of Change
Brief Rationale
Section 8.8, Biomarkers
Sample collection will be discontinued.
Refer to Section 1.1 rationale.
Section 8.10.3, Second Course 
Treatment
Treatment of participants with study 
interventions is clarified. Note on study-specific 
investigator letter has been added.
Refer to Section 1.1 rationale.
Throughout Document
Minor administrative, formatting, grammatical, 
and typographical changes were made 
throughout the document.
To ensure clarity and accurate 
interpretation of the intent of the protocol.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES.........................................5
1
PROTOCOL SUMMARY ............................................................................................18
1.1
Synopsis.................................................................................................................18
1.2
Schema ..................................................................................................................25
1.3
Schedule of Activities (SoA)................................................................................26
1.3.1
Initial Treatment: Pembrolizumab + Lenvatinib (Arm 1) or Lenvatinib 
Monotherapy (Arm 3)..................................................................................26
1.3.2
Initial Treatment: Docetaxel (Arm 2) ..........................................................42
1.3.3
Second Course (Arm 1 – Retreatment)........................................................49
2
INTRODUCTION..........................................................................................................53
2.1
Study Rationale....................................................................................................53
2.2
Background ..........................................................................................................55
2.2.1
Pharmaceutical and Therapeutic Background .............................................55
2.2.1.1
Inhibition of VEGFR as a Target for Cancer Treatment 
(Lenvatinib)........................................................................................55
2.2.1.2
Inhibition of PD-1 as a Target for Cancer Treatment 
(Pembrolizumab)................................................................................56
2.2.1.3
Scientific Rationale for the Combination of Pembrolizumab With 
Lenvatinib ..........................................................................................56
2.2.1.4
Rationale for Lenvatinib Monotherapy Arm .....................................57
2.2.2
Preclinical and Clinical Studies ...................................................................57
2.2.2.1
Completed Studies With Pembrolizumab and Lenvatinib.................57
2.2.3
Ongoing Clinical Studies of Pembrolizumab and Lenvatinib .....................57
2.3
Benefit/Risk Assessment......................................................................................58
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................59
4
STUDY DESIGN............................................................................................................62
4.1
Overall Design......................................................................................................62
4.2
Scientific Rationale for Study Design.................................................................64
4.2.1
Rationale for Endpoints ...............................................................................64
4.2.1.1
Efficacy Endpoints.............................................................................64
4.2.1.1.1
Primary Efficacy Endpoints.....................................................64
4.2.1.1.2
Secondary Efficacy Endpoints.................................................65
4.2.1.2
Safety Endpoints................................................................................65
4.2.1.3
Rationale for Patient-reported Outcomes...........................................65
4.2.1.3.1
EORTC QLQ-C30 ...................................................................65
4.2.1.3.2
EORTC QLQ-LC13.................................................................66
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4.2.1.3.3
EuroQoL-5D-5L (EQ-5D-5L) .................................................66
4.2.1.4
Exploratory Endpoints .......................................................................66
4.2.1.4.1
Disease Control at Week 12.....................................................66
4.2.1.4.2
Pharmacokinetic Endpoints .....................................................66
4.2.1.4.3
Health Utilities.........................................................................66
4.2.1.4.4
Genomic, Metabolic, or Proteomic Determinants of 
Response or Resistance to Treatments.....................................67
4.2.1.5
Planned Exploratory Biomarker Research.........................................67
4.2.2
Rationale for Use of Comparator.................................................................68
4.3
Justification for Dose...........................................................................................69
4.3.1
Lenvatinib ....................................................................................................69
4.3.2
Pembrolizumab ............................................................................................69
4.3.3
Maximum Dose Exposure for This Study ...................................................70
4.4
Beginning and End-of-Study Definition ............................................................70
4.4.1
Clinical Criteria for Early Study Termination .............................................71
5
STUDY POPULATION ................................................................................................72
5.1
Inclusion Criteria.................................................................................................72
5.2
Exclusion Criteria................................................................................................77
5.3
Lifestyle Considerations......................................................................................80
5.3.1
Meals and Dietary Restrictions....................................................................80
5.3.2
Pregnancy.....................................................................................................80
5.4
Screen Failures.....................................................................................................81
5.5
Participant Replacement Strategy......................................................................81
6
STUDY INTERVENTION............................................................................................82
6.1
Study Intervention(s) Administered...................................................................82
6.1.1
Medical Devices...........................................................................................84
6.2
Preparation/Handling/Storage/Accountability .................................................84
6.2.1
Dose Preparation..........................................................................................84
6.2.2
Handling, Storage, and Accountability........................................................84
6.3
Measures to Minimize Bias: Randomization and Blinding..............................85
6.3.1
Intervention Assignment..............................................................................85
6.4
Stratification.........................................................................................................85
6.4.1
Blinding........................................................................................................85
6.4.1.1
TPS Results........................................................................................86
6.5
Study Intervention Compliance..........................................................................86
6.6
Concomitant Therapy..........................................................................................86
6.6.1
Allowed Concomitant Medications .............................................................87
6.6.2
Prohibited Concomitant Medications ..........................................................87
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6.6.3
Drug Interactions .........................................................................................88
6.6.4
Rescue Medications and Supportive Care ...................................................88
6.6.4.1
Systemic Corticosteroid Use..............................................................89
6.7
Dose Modification (Escalation/Titration/Other)...............................................89
6.7.1
Concomitant Combination Therapy.............................................................89
6.7.2
Lenvatinib Dose Modification and Toxicity Management..........................90
6.7.2.1
Management of Hypertension............................................................91
6.7.2.2
Management of Proteinuria................................................................93
6.7.2.3
Management of Diarrhea ...................................................................94
6.7.2.4
Management of Hepatotoxicity..........................................................94
6.7.2.5
Management of Thromboembolic Events..........................................95
6.7.2.6
Management of PRES/RPLS.............................................................95
6.7.2.7
Management of Hypocalcemia ..........................................................95
6.7.2.8
Management of Hemorrhage .............................................................95
6.7.2.9
Management of Gastrointestinal Perforation or Fistula Formation...95
6.7.2.10
Management of QT Prolongation ......................................................96
6.7.2.11
Management of Osteonecrosis of the Jaw .........................................96
6.7.3
Pembrolizumab ............................................................................................96
6.7.3.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).......................................................................................96
6.7.3.2
Dose Modification and Toxicity Management for Infusion 
Reactions Related to Pembrolizumab..............................................101
6.7.4
Dose Modification for Overlapping Toxicities..........................................102
6.7.5
Other Allowed Dose Interruptions.............................................................103
6.7.6
Docetaxel ...................................................................................................104
6.8
Intervention After the End of the Study..........................................................104
6.9
Clinical Supplies Disclosure..............................................................................104
6.10
Standard Policies................................................................................................104
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL..........................................................................................................105
7.1
Discontinuation of Study Intervention.............................................................105
7.2
Participant Withdrawal From the Study.........................................................107
7.3
Lost to Follow-up ...............................................................................................107
8
STUDY ASSESSMENTS AND PROCEDURES......................................................108
8.1
Administrative and General Procedures .........................................................108
8.1.1
Informed Consent.......................................................................................108
8.1.1.1
General Informed Consent...............................................................108
8.1.2
Inclusion/Exclusion Criteria ......................................................................109
8.1.3
Participant Identification Card...................................................................109
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8.1.4
Medical History .........................................................................................109
8.1.5
Prior and Concomitant Medications Review.............................................110
8.1.5.1
Prior Medications.............................................................................110
8.1.5.2
Concomitant Medications................................................................110
8.1.6
Assignment of Screening Number.............................................................110
8.1.7
Assignment of Allocation Number............................................................110
8.1.8
Study Intervention Administration ............................................................111
8.1.8.1
Timing of Dose Administration.......................................................111
8.1.8.2
Compliance ......................................................................................112
8.1.9
Discontinuation and Withdrawal ...............................................................112
8.1.10
Participant Blinding/Unblinding................................................................112
8.1.11
Calibration of Equipment...........................................................................112
8.1.12
Demographics ............................................................................................112
8.1.13
Subsequent Antineoplastic Treatment .......................................................112
8.2
Efficacy Assessments .........................................................................................113
8.2.1
Tumor Imaging and Assessment of Disease..............................................113
8.2.1.1
Pretrial Imaging to Confirm Disease Progression ...........................113
8.2.1.2
Initial Tumor Imaging......................................................................114
8.2.1.3
Tumor Imaging During the Study....................................................114
8.2.1.4
End of Treatment and Follow-up Tumor Imaging...........................115
8.2.1.5
Second Course Retreatment Tumor Imaging...................................115
8.2.1.6
RECIST 1.1 Assessment of Disease................................................116
8.2.1.7
iRECIST Assessment of Disease for Immune-based Therapeutics.116
8.2.1.8
Tumor Tissue Collection..................................................................119
8.2.2
Patient-reported Outcomes.........................................................................120
8.3
Safety Assessments.............................................................................................120
8.3.1
Physical Examinations...............................................................................121
8.3.2
Vital Signs..................................................................................................121
8.3.3
Electrocardiograms ....................................................................................121
8.3.4
Echocardiograms or Multigated Acquisition Scans...................................122
8.3.5
Clinical Safety Laboratory Assessments ...................................................122
8.3.5.1
Laboratory Safety Evaluations (Hematology, Chemistry, and 
Urinalysis)........................................................................................123
8.3.5.1.1
Hematology and Clinical Chemistry......................................123
8.3.5.1.2
Urine Dipstick Testing/Urinalysis .........................................123
8.3.5.1.3
Thyroid Function Testing ......................................................123
8.3.5.2
Pregnancy Test.................................................................................124
8.3.6
Eastern Cooperative Oncology Group Performance Status.......................124
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8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events..................................................................................................................124
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................124
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....126
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.127
8.4.4
Regulatory Reporting Requirements for SAE ...........................................127
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................127
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................128
8.4.7
Events of Clinical Interest (ECIs)..............................................................128
8.5
Treatment of Overdose......................................................................................129
8.6
Pharmacokinetics...............................................................................................130
8.6.1
Blood Collection for Serum Pembrolizumab.............................................130
8.6.2
Blood Collection for Plasma Lenvatinib....................................................130
8.7
Pharmacodynamics............................................................................................130
8.8
Biomarkers .........................................................................................................130
8.8.1
Planned Genetic Analysis Sample Collection............................................131
8.9
Medical Resource Utilization and Health Economics.....................................131
8.10
Visit Requirements.............................................................................................131
8.10.1
Screening....................................................................................................132
8.10.1.1
Rescreening......................................................................................132
8.10.2
Initial Treatment.........................................................................................132
8.10.2.1
Telephone Contact or Visit..............................................................133
8.10.3
Second Course Treatment..........................................................................133
8.10.4
Discontinued Participants Continuing to be Monitored in the Study ........134
8.10.5
Posttreatment Visit.....................................................................................134
8.10.5.1
Safety Follow-up Visit.....................................................................134
8.10.5.2
Follow-up Visits...............................................................................134
8.10.5.3
Survival Follow-up Contacts ...........................................................134
8.10.6
Survival Status ...........................................................................................135
9
STATISTICAL ANALYSIS PLAN ...........................................................................136
9.1
Statistical Analysis Plan Summary...................................................................136
9.2
Responsibility for Analyses/In-house Blinding ...............................................138
9.3
Hypotheses/Estimation ......................................................................................138
9.4
Analysis Endpoints.............................................................................................138
9.4.1
Efficacy Endpoints.....................................................................................138
9.4.2
Safety Endpoints........................................................................................139
9.4.3
PRO Endpoints...........................................................................................139
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9.5
Analysis Populations..........................................................................................140
9.5.1
Efficacy Analysis Population.....................................................................140
9.5.2
Safety Analysis Population........................................................................140
9.5.3
Pharmacokinetic Analysis Population .......................................................140
9.5.4
PRO Analysis Population ..........................................................................140
9.6
Statistical Methods.............................................................................................140
9.6.1
Statistical Methods for Efficacy Analyses.................................................140
9.6.1.1
Overall Survival...............................................................................141
9.6.1.2
Progression-free Survival.................................................................141
9.6.1.3
Objective Response..........................................................................142
9.6.1.4
Duration of Response.......................................................................143
9.6.1.5
Analysis Strategy for Key Efficacy Endpoints................................144
9.6.2
Statistical Methods for Safety Analyses ....................................................144
9.6.3
Statistical Methods for Patient-Reported Outcomes..................................146
9.6.4
Summaries of Baseline Characteristics......................................................147
9.7
Interim Analyses ................................................................................................147
9.7.1
Safety Interim Analyses.............................................................................147
9.7.2
Efficacy Interim Analyses..........................................................................148
9.8
Multiplicity .........................................................................................................150
9.8.1
Objective Response Rate ...........................................................................151
9.8.1.1
Objective Response Rate – Pembrolizumab + Lenvatinib Versus 
Docetaxel .........................................................................................151
9.8.1.2
Objective Response Rate – Pembrolizumab + Lenvatinib Versus 
Lenvatinib ........................................................................................152
9.8.2
Progression-free Survival...........................................................................152
9.8.3
Overall Survival.........................................................................................153
9.8.4
Safety Analyses..........................................................................................154
9.9
Sample Size and Power Calculations ...............................................................155
9.10
Subgroup Analyses.............................................................................................156
9.11
Compliance (Medication Adherence)...............................................................156
9.12
Extent of Exposure.............................................................................................156
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................157
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......157
10.1.1
Code of Conduct for Clinical Trials...........................................................157
10.1.2
Financial Disclosure...................................................................................160
10.1.3
Data Protection...........................................................................................160
10.1.3.1
Confidentiality of Data ....................................................................160
10.1.3.2
Confidentiality of Participant Records.............................................160
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10.1.3.3
Confidentiality of IRB/IEC Information..........................................161
10.1.4
Committees Structure.................................................................................161
10.1.4.1
Steering Committee .........................................................................161
10.1.4.2
Executive Oversight Committee......................................................161
10.1.4.3
External Data Monitoring Committee .............................................161
10.1.5
Publication Policy......................................................................................162
10.1.6
Compliance with Study Registration and Results Posting Requirements .162
10.1.7
Compliance with Law, Audit, and Debarment ..........................................163
10.1.8
Data Quality Assurance .............................................................................163
10.1.9
Source Documents .....................................................................................164
10.1.10
Study and Site Closure...............................................................................164
10.2
Appendix 2: Clinical Laboratory Tests............................................................166
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................168
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................168
10.3.2
Definition of AE ........................................................................................168
10.3.3
Definition of SAE ......................................................................................169
10.3.4
Additional Events Reported on the Same Manner as SAE........................170
10.3.5
Recording AE and SAE .............................................................................170
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................174
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................175
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................176
10.5.1
Definitions..................................................................................................176
10.5.2
Contraception Requirements......................................................................177
10.5.3
Pregnancy Testing......................................................................................177
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................178
10.7
Appendix 7: Country-specific Requirements..................................................179
10.7.1
Germany-specific Requirements................................................................179
10.7.2
UK-specific Requirements.........................................................................179
10.7.3
Japan-specific Requirements .....................................................................180
10.7.4
France-specific Requirements....................................................................180
10.7.5
Canada-specific Requirements...................................................................180
10.7.6
Italy-specific Requirements .......................................................................181
10.7.7
Portugal-specific Requirements.................................................................181
10.8
Appendix 8: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................182
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10.9
Appendix 9: Eastern Cooperative Oncology Group (ECOG) Performance 
Status...................................................................................................................186
10.10 Appendix 10: Abbreviations .............................................................................187
11
REFERENCES.............................................................................................................192
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values .............................................77
Table 2
Study Interventions......................................................................................83
Table 3
Dose Modification Guidelines for Lenvatinib-Related Adverse Events .....91
Table 4
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ...........................................................................97
Table 5
Dose Modification and Treatment Guidelines for Pembrolizumab 
Infusion Reactions .....................................................................................................101
Table 6
Summary of Imaging and Treatment Requirements After First 
Radiologic Evidence of Disease Progression ............................................................118
Table 7
Reporting Time Periods and Time Frames for Adverse Events and
Other Reportable Safety Events.................................................................................126
Table 8
Censoring Rules for Primary and Sensitivity Analyses of Progression-
free Survival...............................................................................................................142
Table 9
Censoring Rules for Duration of Response ...............................................143
Table 10
Analysis Strategy for Key Efficacy Variables...........................................144
Table 11
Analysis Strategy for Safety Parameters....................................................146
Table 12
Probability of Passing Single-arm Futility Analysis..................................149
Table 13
Summary of Efficacy Analysis in Interim and Final Analyses..................150
Table 14
Possible Alpha Level and Approximate ORR Difference Between 
Pembrolizumab + Lenvatinib Arm and Docetaxel Arm Required to Demonstrate 
Efficacy for ORR at Interim Analysis 1 ....................................................................151
Table 15
Possible Alpha Level and Approximate ORR Difference Between 
Pembrolizumab + Lenvatinib and Lenvatinib Required to Demonstrate Efficacy 
for ORR ....................................................................................................................152
Table 16
Efficacy Boundaries and Properties for Progression-free Survival 
Analyses ....................................................................................................................153
Table 17
Efficacy Boundaries and Properties for Overall Survival Analyses..........154
Table 18
Protocol-required Safety Laboratory Assessments....................................166
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LIST OF FIGURES
Figure 1
Initial Treatment...........................................................................................25
Figure 2
Second Course .............................................................................................25
Figure 3
Imaging and Treatment for Clinically Stable Participants Treated With 
Pembrolizumab After First Radiologic Evidence of Progressive Disease Assessed 
by the Investigator......................................................................................................119
Figure 4
Multiplicity Diagram for Type I Error Control..........................................151
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, multicenter, randomized, open-label trial to compare the efficacy 
and safety of pembrolizumab (MK-3475) in combination with lenvatinib (E7080/MK-7902) 
versus docetaxel in previously treated participants with metastatic non-small cell lung cancer 
(NSCLC) and progressive disease (PD) after platinum doublet chemotherapy and 
immunotherapy (LEAP-008)
Short Title: Pembrolizumab with Lenvatinib versus Docetaxel for Metastatic NSCLC after 
Platinum Doublet Chemotherapy and Immunotherapy
Acronym: Protocol 008
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
In participants with metastatic NSCLC and PD after platinum doublet chemotherapy and 
treatment with 1 prior anti-PD-1/PD-L1 monoclonal antibody (mAb):
Note: Progression-free survival (PFS), objective response rate (ORR), duration of response 
(DOR), and disease control rate at 12 weeks (DCR12) will be assessed per Response 
Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) modified to follow a 
maximum of 10 target lesions and a maximum of 5 target lesions per organ.
Note: Based on the data from the final safety and efficacy analysis for LEAP-008 (data cutoff 
11-AUG-2023), the combination of pembrolizumab + lenvatinib versus docetaxel 
monotherapy did not meet the prespecified criteria for the primary endpoint of overall 
survival (OS) at the final analysis and the second dual primary endpoint of PFS at IA2. 
Safety analysis will be performed at the end of the study; there will be no further analyses for 
efficacy and electronic patient-reported outcome endpoints.
Note: In alignment with the study-specific investigator letter dated 22-SEP-2023, all study 
participants still receiving study treatment should continue to receive therapy on study and 
undergo modified protocol study procedures as specified in this amendment. Participants 
currently on study treatment with lenvatinib or docetaxel can continue treatment per 
investigator’s discretion. Participants who are potential candidates for Second Course 
treatment will continue in Efficacy Follow-up. 
As of Amendment 09, participants who are still on study treatment will no longer require 
tumor response assessments by blinded independent central review (BICR) to be performed. 
Scans will no longer be submitted to the imaging Contract Research Organization. 
Participants who are still on study medication should continue tumor imaging assessment as 
assessed by investigator per protocol. Biomarker and pharmacokinetic specimen collection is 
discontinued.
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Primary Objective
Primary Endpoint
To compare pembrolizumab + lenvatinib to 
docetaxel with respect to overall survival 
(OS).
Hypothesis (H1): Pembrolizumab + 
lenvatinib prolongs OS compared with 
docetaxel.
OS, defined as the time from randomization 
to the date of death due to any cause.
To compare pembrolizumab + lenvatinib to 
docetaxel with respect to PFS per RECIST 
1.1 by blinded independent central review 
(BICR).
Hypothesis (H2): Pembrolizumab + 
lenvatinib prolongs PFS per RECIST 1.1 
based on BICR compared with docetaxel.
PFS, defined as the time from 
randomization to the first documented 
progressive disease (PD) or death due to 
any cause, whichever occurs first.
Secondary Objectives
Secondary Endpoints
To compare pembrolizumab + lenvatinib to 
docetaxel with respect to ORR per RECIST 
1.1 by BICR.
Hypothesis (H3): Pembrolizumab + 
lenvatinib results in a superior ORR per 
RECIST 1.1 based on BICR compared with 
docetaxel.
Objective response, defined as a confirmed 
complete response (CR) or partial response 
(PR).
To compare pembrolizumab + lenvatinib to 
lenvatinib monotherapy with respect to 
ORR per RECIST 1.1 by BICR.
Hypothesis (H4): Pembrolizumab + 
lenvatinib results in a superior ORR per 
RECIST 1.1 based on BICR, compared with 
lenvatinib monotherapy.
Objective response, defined as a confirmed 
complete response (CR) or partial response 
(PR).
To assess DOR with pembrolizumab + 
lenvatinib and docetaxel per RECIST 1.1 by 
BICR.
DOR, defined as the time from the first 
documented evidence of CR or PR until PD 
or death due to any cause, whichever occurs 
first, in participants demonstrating CR or 
PR.
To assess the safety and tolerability of 
treatment with pembrolizumab + lenvatinib 
versus docetaxel. To assess the safety and 
tolerability of treatment with lenvatinib 
monotherapy.
Adverse events (AEs) and discontinuations 
due to AEs.
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To compare pembrolizumab + lenvatinib to 
docetaxel with respect to the mean change 
from baseline in global health status/quality 
of life (QoL), cough, chest pain, dyspnea, 
and physical functioning.
Scores for the following scales/items:
Global health status/QoL (European 
Organization for Research and Treatment of 
Cancer [EORTC] Quality of Life 
Questionnaire Core 30 items [QLQ-C30] 
Items 29 and 30)
Cough (EORTC Quality of Life 
Questionnaire Lung Cancer Module 13 
[QLQ-LC13] Item 31)
Chest pain (EORTC QLQ-LC13 Item 40)
Dyspnea (EORTC QLQ-C30 Item 8)
Physical functioning (EORTC QLQ-C30 
Items 1 to 5)
To compare pembrolizumab + lenvatinib to 
docetaxel with respect to time to true 
deterioration (TTD) in global health 
status/QoL, cough, chest pain, dyspnea, and 
physical functioning scales.
TTD, defined as the time from baseline to 
the first onset of ≥10-point decrease from 
baseline, with confirmation by the 
subsequent visit of ≥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)
Physical functioning (EORTC QLQ-C30 
Items 1 to 5)
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Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
The treatment of metastatic Non-small cell 
lung cancer with squamous or nonsquamous 
histology
Population
Participants with metastatic NSCLC who 
have experienced PD after platinum doublet 
chemotherapy and immunotherapy (in 
combination or sequentially), without 
restriction regarding PD-L1 expression.
Study Type
Interventional
Intervention Model
Parallel
This is a multi site study.
Type of Control
Active Control Without Placebo
Study Blinding
Unblinded open-label
Blinding Roles
No blinding
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.
Number of Participants:
Approximately 405 participants will be randomized 4:4:1 to receive pembrolizumab + 
lenvatinib, docetaxel, or lenvatinib monotherapy. All participants will meet the study 
inclusion/exclusion criteria, follow the Schedule of Activities (SoA), and undergo safety 
monitoring as defined in the protocol.
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Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
Arm 1
Pembrolizumab 25 mg/mL
200 mg
IV Infusion
Q3W
Test Product
Arm 1
Lenvatinib
10 mg
4 mg
20 mg
Oral
QD
Test Product
Arm 2
Docetaxel
20 mg/ mL
75 mg/m2
IV Infusion
Q3W
Comparator
Arm 3
Lenvatinib
10 mg
4 mg
24 mg
Oral
QD
Test Product
Abbreviations: IV = intravenous; PO = oral; Q3W = every 3 weeks; QD = once daily.
Total Number of 
Intervention 
Groups/Arms
3 arms
Duration of 
Participation
Each participant will be in the study from the time the participant 
provides documented informed consent through the final contact.
The site’s study team must have reviewed and submitted images that 
are of diagnostic quality from at least 2 dates:
1) imaging prior to anti-PD-1/PD-L1 treatment or an image 
showing nadir during anti-PD-1/PD-L1 treatment; AND
2) imaging to determine that radiographic progression has occurred 
per RECIST 1.1 within 12 weeks from the last dose of an 
anti-PD-1/PD-L1 mAb.
These images will be submitted to the central imaging vendor (CIV) 
before randomization to confirm that the images are of diagnostic 
quality. The central vendor will not be confirming eligibility before 
randomization (see Section 8.2.1.1).
Both archival tissue and tissue from a newly obtained biopsy will be 
submitted to the central vendor before randomization. The archival 
tissue for PD-L1 biomarker analysis will be used for stratification. 
Participants will provide tissue for analysis from a newly obtained 
formalin-fixed sample from a recent biopsy of a tumor lesion not 
previously irradiated, and without systemic antineoplastic therapy 
between the new biopsy and initiation of study intervention (ie, study 
drug or study treatment).
Note: For participants from whom obtaining a new tumor biopsy will 
be medically inappropriate, the investigator may request an exception 
from the Sponsor’s study clinical director. The request including 
details of why the biopsy is medically inappropriate will be 
documented in a Sponsor Consultation Form.
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After a screening phase of up to 42 days, participants will be 
randomly assigned to receive pembrolizumab + lenvatinib (Arm 1), 
docetaxel (Arm 2), or lenvatinib monotherapy (Arm 3).
Each eligible participant will receive a randomization number. This 
will occur centrally using an interactive response technology (IRT) 
system.
Initial Treatment
Pembrolizumab: Participants may continue receiving pembrolizumab 
for up to 35 treatment cycles (~2 years), until PD or until a 
discontinuation criterion is met.
Lenvatinib: Participants may continue receiving lenvatinib until PD 
or until a discontinuation criterion is met.
Docetaxel: Participants may continue receiving docetaxel until PD or 
until a discontinuation criterion is met.
Treatment in the study will continue until reaching a discontinuation 
criterion (defined in Section 7.1).
Participants receiving pembrolizumab will be permitted to continue 
study treatment beyond RECIST 1.1-defined PD, as long as the 
treating investigator considers that the participant may experience 
clinical benefit with continued treatment per iRECIST, and the 
participant is clinically stable and 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.
Second Course Phase (Arm 1)
Participation in the Second Course phase is at the discretion of the 
investigator, according to the criteria in Section 8.10.3.
End of Treatment
Each participant will be followed for the occurrence of AEs, 
spontaneously reported pregnancy (Section 8.4), and survival status.
Participants who discontinue for reasons other than radiographic PD 
will have posttreatment follow-up imaging for disease status until PD 
is documented radiographically per RECIST 1.1 and verified by 
BICR, initiating a nonstudy cancer treatment, withdrawing consent, or 
becoming lost to follow-up (ie, the participant is unable to be 
contacted by the investigator).
All participants will be followed for overall survival until death, 
withdrawal of consent, lost to follow-up, or the end of the study. Note: 
Upon withdrawal of consent, the investigator will ask the participant if 
he or she may be contacted periodically for survival status; the 
participant’s response will be documented in the study chart.
The overall study ends when the last participant completes the last 
study-related contact, withdraws from the study, or is lost to follow-
up.
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The study is to be discontinued based on the observation that the 
combination of pembrolizumab + lenvatinib versus docetaxel
monotherapy did not meet the prespecified criteria for the primary 
endpoint of OS at the final analysis and the second dual primary 
endpoint of PFS at IA2. Upon study termination, participants are 
discontinued and may be enrolled in an extension study, if available.
Study Governance Committees:
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Steering Committee
Yes
Study governance considerations are outlined in Appendix 1 (Section 10.1.1).
Study Accepts Healthy Participants: No
A list of abbreviations used in this document is in Appendix 10.
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1.2
Schema
The study design is shown in Figure 1 (Initial Treatment) and Figure 2 (Second Course).
Figure 1
Initial Treatment
ALK = anaplastic lymphoma kinase gene; CNS = central nervous system; ECOG = Eastern Cooperative Oncology Group; 
EGFR = epidermal growth factor receptor; IO = anti-PD-1/PD-L1 treatment as immediate prior therapy versus not the 
immediate prior therapy NSCLC = non-small cell lung cancer; PD-1 = programmed cell death protein 1; PD-1L = 
programmed cell death ligand 1; Q3W = every 3 weeks; Q12W = every 12 weeks; QD = once daily; ROS1 = c-ros oncogene 
1; TPS = tumor proportion score.
a
Until disease progression, intolerable toxicity, investigator decision, or completion of 35 treatment cycles.
b
Until disease progression, intolerable toxicity, or investigator decision.
Figure 2
Second Course
CR = complete response; IV = intravenously; PD = progressive disease; PO = orally; PR = partial response; Q3W = every 3 
weeks; QD = once daily; RECIST = Response Evaluation Criteria in Solid Tumors Version 1.1.
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1.3
Schedule of Activities (SoA)
1.3.1
Initial Treatment: Pembrolizumab + Lenvatinib (Arm 1) or Lenvatinib Monotherapy (Arm 3)
The same activities will apply both to participants in Arm 1 and Arm 3 unless specified in the SoA.
Trial Period
Screening
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety 
FU
FU
Survival 
FU
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 
35
≥36 At D/C
30 days 
after last 
dose
Q12W
Q12W
All procedures are 
performed before 
administration of study 
intervention unless otherwise 
indicated.
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window 
(days)
-42 to -1
+3
+3
+3
±3
+3
±3
±3
±3
±3
±3
−
+7
±7
±14
Administrative and General Procedures
Informed 
consent
X
Documented informed 
consent was obtained before 
any protocol-specific 
screening procedures.
Reconsent required at time 
of progression if study 
intervention is to be 
continued.
Inclusion/
exclusion 
criteria
X
Participant 
identification 
card
X
X*
*Update with randomization 
number.
Demographics 
and medical 
history
X
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Trial Period
Screening
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety 
FU
FU
Survival 
FU
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 
35
≥36 At D/C
30 days 
after last 
dose
Q12W
Q12W
All procedures are 
performed before 
administration of study 
intervention unless otherwise 
indicated.
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window 
(days)
-42 to -1
+3
+3
+3
±3
+3
±3
±3
±3
±3
±3
−
+7
±7
±14
Prior/
concomitant 
medications
X
Record within 30 days 
before first dose of study 
intervention through 30 days 
after last dose of study 
intervention, or 90 days for 
medications for SAEs.
Prestudy 
anticancer 
therapies for 
NSCLC 
X
Study Intervention Administration
Lenvatinib 
dispensing
X
X
X
X
X
X
X
Collect and record number 
of capsules returned.
Lenvatinib PO 
QD
Given in the clinic for Day 1 
of each cycle and C1D15. 
See Section 8.1.8.1 for 
timing of lenvatinib dosing.
- Taken at home QD for all 
additional doses.
Pembrolizumab 
IV Q3W
X
X
X
X
X
X
Arm 1 only.
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Trial Period
Screening
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety 
FU
FU
Survival 
FU
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 
35
≥36 At D/C
30 days 
after last 
dose
Q12W
Q12W
All procedures are 
performed before 
administration of study 
intervention unless otherwise 
indicated.
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window 
(days)
-42 to -1
+3
+3
+3
±3
+3
±3
±3
±3
±3
±3
−
+7
±7
±14
Tumor Imaging
Tumor imaging 
(chest, 
abdomen, and 
pelvis) and 
response 
assessment 
X
X
X
Screening imaging within 30 
days before randomization.
Imaging at 6 weeks 
(+7 days) and 12 weeks (+7 
days) from date of 
randomization, and then 
Q6W (±7 days), or more 
frequently if clinically 
indicated. After 36 weeks, 
imaging Q9W (±7 days). 
After Week 54, imaging 
Q12W (±7 days).
Schedule should be followed 
regardless of treatment 
delays. If imaging was 
obtained within 4 weeks 
before D/C, a scan is not 
mandatory.
FU visits may be scheduled 
to coincide with the imaging 
schedule.
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Trial Period
Screening
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety 
FU
FU
Survival 
FU
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 
35
≥36 At D/C
30 days 
after last 
dose
Q12W
Q12W
All procedures are 
performed before 
administration of study 
intervention unless otherwise 
indicated.
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window 
(days)
-42 to -1
+3
+3
+3
±3
+3
±3
±3
±3
±3
±3
−
+7
±7
±14
Brain MRI
X
Required at screening. 
Within 30 days of 
randomization.
FU MRI is required if 
clinically indicated.
If MRI is contraindicated, or 
is medically inappropriate, 
CT with contrast is 
acceptable.
Efficacy Procedures
Subsequent 
anticancer 
therapy status
X
X
X
X
Record until death or 
termination of survival FU. 
FU information may be 
obtained at a clinic visit, by 
telephone or email, or from 
other sources.
Survival status
X
Survival FU continues after 
PD, after D/C of study 
intervention, and after the 
start of new anticancer 
treatment.
Upon Sponsor request, 
participants may be 
contacted for survival status 
at any time during the study.
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Trial Period
Screening
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety 
FU
FU
Survival 
FU
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 
35
≥36 At D/C
30 days 
after last 
dose
Q12W
Q12W
All procedures are 
performed before 
administration of study 
intervention unless otherwise 
indicated.
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window 
(days)
-42 to -1
+3
+3
+3
±3
+3
±3
±3
±3
±3
±3
−
+7
±7
±14
Clinical Procedures/Assessments
Complete 
physical 
examination
X
X
Per institutional standards.
Directed 
physical 
examination
X
X
X
X
X
X
X
X
X
X
Contact 
X
Telephone contact or visit 
(in-person or virtual) to 
assess for early toxicity.
If early toxicity is suspected, 
an unscheduled visit may 
take place before C1 D15, 
and at any time during the 
study, if deemed necessary 
by the investigator.
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
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Trial Period
Screening
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety 
FU
FU
Survival 
FU
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 
35
≥36 At D/C
30 days 
after last 
dose
Q12W
Q12W
All procedures are 
performed before 
administration of study 
intervention unless otherwise 
indicated.
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window 
(days)
-42 to -1
+3
+3
+3
±3
+3
±3
±3
±3
±3
±3
−
+7
±7
±14
Vital signs
X
X
X*
X
X*
X
X
X
X
X
X
X
*D15 visits mandatory for 
C1 and C2.
C3 and subsequent cycles, 
participants may return on 
D15 if BP monitoring is 
required.
Refer to Section 6.6.2.1 for 
hypertension management 
and BP monitoring 
guidelines.
08LX4B

PRODUCT: MK-7902
32
PROTOCOL/AMENDMENT NO.: 008-09
MK-7902-008-09 FINAL PROTOCOL
08-DEC-2023
Trial Period
Screening
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety 
FU
FU
Survival 
FU
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 
35
≥36 At D/C
30 days 
after last 
dose
Q12W
Q12W
All procedures are 
performed before 
administration of study 
intervention unless otherwise 
indicated.
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window 
(days)
-42 to -1
+3
+3
+3
±3
+3
±3
±3
±3
±3
±3
−
+7
±7
±14
12-lead ECG 
with QTcF 
determination
X
X^
X^
X*
X*
X
X
*Every 4 cycles (12 weeks) 
after C2, or at every cycle if 
clinically indicated.
^ For the first 90 subjects in 
Arm 1 assigned to have PK 
samples drawn: ECG at 
C1D1 and C2D1 should be 
performed approximately 2 
hours post-lenvatinib dose.
For high-risk patients (as 
defined in Section 8.3.3), 
conduct monitoring every 
cycle.
If lenvatinib is discontinued, 
ECGs are only required at 
the EOT and Safety Follow-
up visits.
MUGA scan or 
ECHO 
X
X
Additional LVEF 
assessments as clinically 
indicated.
08LX4B

PRODUCT: MK-7902
33
PROTOCOL/AMENDMENT NO.: 008-09
MK-7902-008-09 FINAL PROTOCOL
08-DEC-2023
Trial Period
Screening
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety 
FU
FU
Survival 
FU
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 
35
≥36 At D/C
30 days 
after last 
dose
Q12W
Q12W
All procedures are 
performed before 
administration of study 
intervention unless otherwise 
indicated.
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window 
(days)
-42 to -1
+3
+3
+3
±3
+3
±3
±3
±3
±3
±3
−
+7
±7
±14
ECOG 
performance 
status
X
X*
X
X
X
X
X
X
X
X
*Within 7 days before first 
dose of study drug on, or, 
before randomization for all 
subjects. If C1D1 is the 
same day as randomization, 
C1D1 ECOG will be used as 
the ECOG value for 
randomization/IVR.
AE/SAE 
review
X
X*
X
*Report NSAEs occurring 
within 30 days after the last 
dose of study intervention, 
regardless of initiation of 
new therapy.
Report SAEs occurring 
within 90 days after the last 
dose of study intervention, 
or within 30 days after the 
last dose of study 
intervention if new 
anticancer therapy is 
initiated.
08LX4B

PRODUCT: MK-7902
34
PROTOCOL/AMENDMENT NO.: 008-09
MK-7902-008-09 FINAL PROTOCOL
08-DEC-2023
Trial Period
Screening
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety 
FU
FU
Survival 
FU
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 
35
≥36 At D/C
30 days 
after last 
dose
Q12W
Q12W
All procedures are 
performed before 
administration of study 
intervention unless otherwise 
indicated.
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window 
(days)
-42 to -1
+3
+3
+3
±3
+3
±3
±3
±3
±3
±3
−
+7
±7
±14
Laboratory Procedures/Assessments (Local Laboratory)
Pregnancy test: 
urine or serum 
β-HCG
(WOCBP only)
X
X
X
X
X
X
X
X
X
Urine test within 24 hours or 
serum test within 72 hours 
before the first dose of study 
intervention. Additional 
urine/serum testing if 
clinically warranted and/or 
defined by local regulations 
(See Appendix 7).
Serum test required if urine 
test cannot be confirmed as 
negative.
HIV and 
hepatitis B/C
X
Only if mandated by local 
health authority (See 
Appendix 7).
Serum FSH 
(WONCBP 
only)
X
In the absence of 12 months 
of amenorrhea, confirmation 
with 2 FSH values at least 
24 hours apart in 
postmenopausal range is 
required.
08LX4B

PRODUCT: MK-7902
35
PROTOCOL/AMENDMENT NO.: 008-09
MK-7902-008-09 FINAL PROTOCOL
08-DEC-2023
Trial Period
Screening
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety 
FU
FU
Survival 
FU
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 
35
≥36 At D/C
30 days 
after last 
dose
Q12W
Q12W
All procedures are 
performed before 
administration of study 
intervention unless otherwise 
indicated.
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window 
(days)
-42 to -1
+3
+3
+3
±3
+3
±3
±3
±3
±3
±3
−
+7
±7
±14
CBC with 
differential
X
X
X
X
X
X
X
X
X
X
At screening, within 10 days 
before first dose.
After C1, within 3 days 
before dosing; every effort 
should be made to collect 
samples at the same time of 
day.
Clinical 
chemistry
X
X
X
X
X
X
X
X
X
X
Urinalysis/
Urine dipstick 
testing 
X
X
X
X
X
X
X
X
X
X
X
At screening, complete 
urinalysis is required within 
10 days before first dose and 
every 6 cycles At other 
visits, either urinalysis or 
urine dip stick are 
acceptable (refer to Section 
8.3.5.1.2).
-D15 visit is mandatory in 
C1 and C2. During C3 and 
subsequent cycles, 
participants may return for 
the D15 visit if monitoring 
is required as specified in 
Section 8.3.5.1.2.
08LX4B

PRODUCT: MK-7902
36
PROTOCOL/AMENDMENT NO.: 008-09
MK-7902-008-09 FINAL PROTOCOL
08-DEC-2023
Trial Period
Screening
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety 
FU
FU
Survival 
FU
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 
35
≥36 At D/C
30 days 
after last 
dose
Q12W
Q12W
All procedures are 
performed before 
administration of study 
intervention unless otherwise 
indicated.
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window 
(days)
-42 to -1
+3
+3
+3
±3
+3
±3
±3
±3
±3
±3
−
+7
±7
±14
PT/INR and 
aPTT/PTT
X
Within 10 days before first 
dose.
Additional testing as 
clinically indicated for 
participants taking 
anticoagulants.
T3 or FT3, 
FT4, TSH
X
X
X
X*
X*
X
Within 10 days before first 
dose.
*After screening, within 
3 days before dosing at 
every other cycle, beginning 
with C2.
Participants may be dosed 
while test results are 
pending.
FT3 is acceptable if T3 
cannot be determined.
The central laboratory may 
be used only if the local 
laboratory cannot perform 
tests.
PK/Biomarkers (Central Laboratory)
Blood for 
genetic 
analysis
X
Predose.
08LX4B

PRODUCT: MK-7902
37
PROTOCOL/AMENDMENT NO.: 008-09
MK-7902-008-09 FINAL PROTOCOL
08-DEC-2023
Trial Period
Screening
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety 
FU
FU
Survival 
FU
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 
35
≥36 At D/C
30 days 
after last 
dose
Q12W
Q12W
All procedures are 
performed before 
administration of study 
intervention unless otherwise 
indicated.
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window 
(days)
-42 to -1
+3
+3
+3
±3
+3
±3
±3
±3
±3
±3
−
+7
±7
±14
Serum for 
pembrolizumab 
PK: first 
90 participants 
in Arm 1
X
X
*X
Predose on C1D1, C2D1, 
and *C8D1.
Serum anti-
pembrolizumab 
antibodies: first 
90 participants 
in Arm 1
X
X
*X
Predose on C1D1, C2D1, 
and *C8D1.
08LX4B

PRODUCT: MK-7902
38
PROTOCOL/AMENDMENT NO.: 008-09
MK-7902-008-09 FINAL PROTOCOL
08-DEC-2023
Trial Period
Screening
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety 
FU
FU
Survival 
FU
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 
35
≥36 At D/C
30 days 
after last 
dose
Q12W
Q12W
All procedures are 
performed before 
administration of study 
intervention unless otherwise 
indicated.
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window 
(days)
-42 to -1
+3
+3
+3
±3
+3
±3
±3
±3
±3
±3
−
+7
±7
±14
Plasma for 
lenvatinib PK: 
first 90 
participants in 
Arm 1
X
X
X
C1D1: postdose at any time 
from 0.5 to 4 hours and from 
6 to 10 hours postdose 
(2 samples).
C1D15: predose within 
2 hours of lenvatinib dosing 
and then at any time from 2 
to 12 hours postdose 
(2 samples).
C2D1: predose within 
2 hours of lenvatinib dosing 
and then at any time from 
0.5 to 4 hours and from 6 to 
10 hours postdose 
(3 samples).
Note: No PK samples if 
lenvatinib dosing is on hold 
for any reason.
Blood for 
plasma 
biomarker 
analyses 
(Arm 1 and 
Arm 3)
X
X
X
X
X*
X
Predose.
*D1 of every 3 cycles after 
C5.
08LX4B

PRODUCT: MK-7902
39
PROTOCOL/AMENDMENT NO.: 008-09
MK-7902-008-09 FINAL PROTOCOL
08-DEC-2023
Trial Period
Screening
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety 
FU
FU
Survival 
FU
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 
35
≥36 At D/C
30 days 
after last 
dose
Q12W
Q12W
All procedures are 
performed before 
administration of study 
intervention unless otherwise 
indicated.
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window 
(days)
-42 to -1
+3
+3
+3
±3
+3
±3
±3
±3
±3
±3
−
+7
±7
±14
Blood for 
serum 
biomarker 
analyses 
(Arm 1 and 
Arm 3)
X
X
X
X
X
X
Predose.
Blood for RNA 
analysis 
(Arm 1 and 
Arm 3)
X
X
X
X
X
Predose.
Blood for 
circulating 
tumor nucleic 
acids (Arm 1 
and Arm 3)
X
X
X
X
X*
X
Predose.
*D1 of every 3 cycles after 
C5.
Tumor Tissue Collection
Archival tumor 
tissue 
X
To central laboratory before 
randomization for PD-L1 
analysis and stratification. 
See Section 8.2.1.8 for 
window for obtaining tissue.
08LX4B

PRODUCT: MK-7902
40
PROTOCOL/AMENDMENT NO.: 008-09
MK-7902-008-09 FINAL PROTOCOL
08-DEC-2023
Trial Period
Screening
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety 
FU
FU
Survival 
FU
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 
35
≥36 At D/C
30 days 
after last 
dose
Q12W
Q12W
All procedures are 
performed before 
administration of study 
intervention unless otherwise 
indicated.
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window 
(days)
-42 to -1
+3
+3
+3
±3
+3
±3
±3
±3
±3
±3
−
+7
±7
±14
Newly 
obtained tissue 
biopsy
X
To central laboratory before 
randomization.
No anticancer treatment 
between biopsy and 
randomization.
See Section 8.2.1.8 for 
window for obtaining tissue.
EGFR, ALK, 
and ROS1 
molecular 
status
X
Not required in squamous 
NSCLC.
Tumor tissue may be sent to 
central laboratory for 
molecular testing if status is 
unknown and cannot be 
determined locally.
08LX4B

PRODUCT: MK-7902
41
PROTOCOL/AMENDMENT NO.: 008-09
MK-7902-008-09 FINAL PROTOCOL
08-DEC-2023
Trial Period
Screening
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety 
FU
FU
Survival 
FU
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 
35
≥36 At D/C
30 days 
after last 
dose
Q12W
Q12W
All procedures are 
performed before 
administration of study 
intervention unless otherwise 
indicated.
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window 
(days)
-42 to -1
+3
+3
+3
±3
+3
±3
±3
±3
±3
±3
−
+7
±7
±14
Patient-Reported Outcomes 
EORTC 
QLQ-C30
X
X
X
X
X
X*
X
X
Administer questionnaires 
before any procedures in the 
order in this table.
*Obtain at every cycle 
through C17, then at every 
other cycle until EOT.
If the EOT visit takes place 
≥30 days after the last dose 
of study intervention and is 
combined with the 30-day 
safety FU visit, PRO 
assessments only need to be 
performed at that visit.
EORTC 
QLQ-LC13
X
X
X
X
X
X*
X
X
EQ-5D-5L
X
X
X
X
X
X*
X
X
Abbreviations: AE = adverse event; ALK = anaplastic lymphoma kinase gene; aPTT = activated partial thromboplastin time; BP = blood pressure; β-HCG = β human chorionic 
gonadotropin; CBC = complete blood count; CT = computed tomography; CXDY= Cycle X Day Y; D/C = discontinuation; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; EGFR = epidermal growth factor receptor gene; ECHO = echocardiogram; EORTC = European Organization for Research and Treatment of 
Cancer; EOT = end of treatment; EQ-5D-5L = European Quality of Life Five-Dimensional Five-Level Scale Questionnaire; FSH = follicle-stimulating hormone; FT3 = free 
triiodothyronine; FT4 = free thyroxine; FU = follow-up; HIV = human immunodeficiency virus; INR = international normalized ratio; IV = intravenous; IVR = Interactive 
Voice Response; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; MUGA = multigated acquisition; NSCLC = non-small cell lung cancer; 
PD = progressive disease; PD-L1 = programmed cell death ligand 1; PK = pharmacokinetics; PO = oral; PT = prothrombin time; PRO = patient-reported outcome; Q3W = 
every 3 weeks; Q6W = every 6 weeks; Q9W = every 9 weeks; Q12W = every 12 weeks; QD = once daily; QLQ-C30 = Quality of Life Questionnaire Core 30 items; QLQ-
LC13 = Quality of Life Questionnaire Lung Cancer Module 13; QTcF = QT interval corrected with Fridericia’s formula; RNA = ribonucleic acid; ROS1 = c-ros oncogene 1; 
SAE = serious adverse event; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WOCBP = women of childbearing potential; WONCBP = women of 
non-childbearing potential.
08LX4B

PRODUCT: MK-7902
42
PROTOCOL/AMENDMENT NO.: 008-09
MK-7902-008-09 FINAL PROTOCOL
08-DEC-2023
1.3.2
Initial Treatment: Docetaxel (Arm 2)
Trial Period
Screening
Treatment Cycle = 21 days
Posttreatment
Notes
EOT
Safety 
FU
FU
Survival 
FU
Visit 
Timing/Cycle 
Number
1
2
3
4
5
6 and 
beyond
At 
D/C
30 days 
after last 
dose
Q12W
Q12W
All procedures are performed before 
administration of study intervention 
unless otherwise indicated.
Cycle Day
1
1
1
1
1
1
Scheduling 
Window 
(days)
-42 to -1
+3
±3
±3
±3
±3
±3
−
+7
±7
±14
Administrative and General Procedures
Informed 
consent
X
Documented informed consent was 
obtained before any protocol-specific 
screening procedures.
Reconsent required at time of progression 
if study intervention is to be continued.
Inclusion/ 
exclusion 
criteria
X
Participant 
identification 
card
X
X*
*Update with randomization number.
Demographics 
and medical 
history
X
Prior/ 
concomitant 
medications
X
Record within 30 days before first dose 
of study intervention through 30 days 
after last dose of study intervention, or 90 
days for medications for SAEs.
Prestudy 
anticancer 
therapies for 
NSCLC
X
08LX4B

PRODUCT: MK-7902
43
PROTOCOL/AMENDMENT NO.: 008-09
MK-7902-008-09 FINAL PROTOCOL
08-DEC-2023
Trial Period
Screening
Treatment Cycle = 21 days
Posttreatment
Notes
EOT
Safety 
FU
FU
Survival 
FU
Visit 
Timing/Cycle 
Number
1
2
3
4
5
6 and 
beyond
At 
D/C
30 days 
after last 
dose
Q12W
Q12W
All procedures are performed before 
administration of study intervention 
unless otherwise indicated.
Cycle Day
1
1
1
1
1
1
Scheduling 
Window 
(days)
-42 to -1
+3
±3
±3
±3
±3
±3
−
+7
±7
±14
Study Intervention Administration
Docetaxel
IV Q3W
X
X
X
X
X
X
Tumor Imaging
Tumor 
imaging 
(chest, 
abdomen, and 
pelvis) and 
response 
assessment
X
X
X
Screening imaging within 30 days before 
randomization.
Imaging at 6 weeks (+7 days) and 
12 weeks (+7 days) from date of 
randomization, and then Q6W (±7 days), 
or more frequently if clinically indicated. 
After 36 weeks, imaging Q9W (±7 days). 
After Week 54, imaging Q12W (±7 
days).
Schedule should be followed regardless 
of treatment delays. If imaging was 
obtained within 4 weeks before D/C, a 
scan is not mandatory.
FU visits may be scheduled to coincide 
with the imaging schedule.
Brain MRI
X
Required at screening. Within 30 days of 
randomization.
FU MRI is required if clinically 
indicated.
If MRI is contraindicated, or is medically 
inappropriate, CT with contrast is 
acceptable.
08LX4B

PRODUCT: MK-7902
44
PROTOCOL/AMENDMENT NO.: 008-09
MK-7902-008-09 FINAL PROTOCOL
08-DEC-2023
Trial Period
Screening
Treatment Cycle = 21 days
Posttreatment
Notes
EOT
Safety 
FU
FU
Survival 
FU
Visit 
Timing/Cycle 
Number
1
2
3
4
5
6 and 
beyond
At 
D/C
30 days 
after last 
dose
Q12W
Q12W
All procedures are performed before 
administration of study intervention 
unless otherwise indicated.
Cycle Day
1
1
1
1
1
1
Scheduling 
Window 
(days)
-42 to -1
+3
±3
±3
±3
±3
±3
−
+7
±7
±14
Efficacy Procedures
Subsequent 
anticancer 
therapy status
X
X
X
X
Record until death or termination of 
survival FU. FU information may be 
obtained at a clinic visit, by telephone or 
email, or from other sources.
Survival 
status
X
Survival FU continues after PD, after 
D/C of study intervention, and after the 
start of new anticancer treatment.
Upon Sponsor request, participants may 
be contacted for survival status at any 
time during the study.
Clinical Procedures/Assessments
Complete 
physical 
examination
X
X
Per institutional standards.
Directed 
physical 
examination
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
Calculate BSA.
Vital signs
X
X
X
X
X
X
X
X
X
12-lead ECG 
with QTcF 
determination
X
MUGA scan 
or ECHO 
X
Additional LVEF assessments as 
clinically indicated.
08LX4B

PRODUCT: MK-7902
45
PROTOCOL/AMENDMENT NO.: 008-09
MK-7902-008-09 FINAL PROTOCOL
08-DEC-2023
Trial Period
Screening
Treatment Cycle = 21 days
Posttreatment
Notes
EOT
Safety 
FU
FU
Survival 
FU
Visit 
Timing/Cycle 
Number
1
2
3
4
5
6 and 
beyond
At 
D/C
30 days 
after last 
dose
Q12W
Q12W
All procedures are performed before 
administration of study intervention 
unless otherwise indicated.
Cycle Day
1
1
1
1
1
1
Scheduling 
Window 
(days)
-42 to -1
+3
±3
±3
±3
±3
±3
−
+7
±7
±14
ECOG 
performance 
status
X
X*
X
X
X
X
X
X
X
*Within 7 days before first dose of study 
drug and before randomization for all 
subjects. If C1D1 is the same day as 
randomization, C1D1 ECOG will be used 
as the ECOG value for enrollment/IVR.
AE/SAE 
review
X
X*
X
*Report NSAEs occurring within 30 days 
after the last dose of study intervention, 
regardless of initiation of new therapy.
Report SAEs occurring within 90 days 
after the last dose of study intervention, 
or within 30 days after the last dose of 
study intervention if new anticancer 
therapy is initiated.
Laboratory Procedures/Assessments (Local Laboratory)
Pregnancy 
test: urine or 
serum β-HCG 
(WOCBP 
only)
X
X
X
X
X
X
X
X
Urine test within 24 hours or serum test 
within 72 hours before the first dose of 
study intervention. Additional 
urine/serum testing if clinically warranted 
and/or defined by local regulations 
(Appendix 7).
Serum test required if urine test cannot be 
confirmed as negative.
HIV and 
hepatitis B/C
X
Only if mandated by local health 
authority (Appendix 7).
Serum FSH 
(WONCBP 
only)
X
In the absence of 12 months of 
amenorrhea, confirmation with 2 FSH 
values at least 24 hours apart in 
postmenopausal range is required.
08LX4B

PRODUCT: MK-7902
46
PROTOCOL/AMENDMENT NO.: 008-09
MK-7902-008-09 FINAL PROTOCOL
08-DEC-2023
Trial Period
Screening
Treatment Cycle = 21 days
Posttreatment
Notes
EOT
Safety 
FU
FU
Survival 
FU
Visit 
Timing/Cycle 
Number
1
2
3
4
5
6 and 
beyond
At 
D/C
30 days 
after last 
dose
Q12W
Q12W
All procedures are performed before 
administration of study intervention 
unless otherwise indicated.
Cycle Day
1
1
1
1
1
1
Scheduling 
Window 
(days)
-42 to -1
+3
±3
±3
±3
±3
±3
−
+7
±7
±14
CBC with 
differential
X
X
X
At screening, within 10 days before first 
dose.
After C1, within 3 days before dosing; 
every effort should be made to collect 
samples at the same time of day.
Clinical 
chemistry
X
X
X
Urinalysis
X
X*
X
X
At screening, within 10 days before first 
dose.
*At C6 and then every 6 cycles within 3 
days before D1.
PT/INR and 
aPTT/PTT
X
At screening, within 10 days before first 
dose.
T3 or FT3, 
FT4, TSH
X
Biomarkers (Central Laboratory)
Blood for 
genetic 
analysis
X
Predose.
Blood for 
plasma 
biomarker 
analyses
X
X
X
X
X*
X
Predose.
*D1 of every 3 cycles after C5.
Blood for 
serum 
biomarker 
analyses
X
X
X
X
X
Predose.
Blood for 
RNA analysis
X
X
X
X
X
Predose.
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Trial Period
Screening
Treatment Cycle = 21 days
Posttreatment
Notes
EOT
Safety 
FU
FU
Survival 
FU
Visit 
Timing/Cycle 
Number
1
2
3
4
5
6 and 
beyond
At 
D/C
30 days 
after last 
dose
Q12W
Q12W
All procedures are performed before 
administration of study intervention 
unless otherwise indicated.
Cycle Day
1
1
1
1
1
1
Scheduling 
Window 
(days)
-42 to -1
+3
±3
±3
±3
±3
±3
−
+7
±7
±14
Blood for 
circulating 
tumor nucleic 
acids
X
X
X
X
X*
X
Predose.
*D1 of every 3 cycles after C5.
Tumor Tissue Collection
Archival 
tumor tissue
X
To central laboratory before 
randomization for PD-L1 analysis and 
stratification.
See Section 8.2.1.8 for window for 
obtaining tissue.
Newly 
obtained 
tissue biopsy
X
To central laboratory before 
randomization.
No anticancer treatment between biopsy 
and randomization.
See Section 8.2.1.8 for window for 
obtaining tissue.
EGFR, ALK, 
and ROS1 
molecular 
status
X
Not required in squamous NSCLC.
Tumor tissue may be sent to central 
laboratory for molecular testing if status 
is unknown and cannot be determined 
locally.
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Trial Period
Screening
Treatment Cycle = 21 days
Posttreatment
Notes
EOT
Safety 
FU
FU
Survival 
FU
Visit 
Timing/Cycle 
Number
1
2
3
4
5
6 and 
beyond
At 
D/C
30 days 
after last 
dose
Q12W
Q12W
All procedures are performed before 
administration of study intervention 
unless otherwise indicated.
Cycle Day
1
1
1
1
1
1
Scheduling 
Window 
(days)
-42 to -1
+3
±3
±3
±3
±3
±3
−
+7
±7
±14
Patient-Reported Outcomes
EORTC 
QLQ-C30
X
X
X
X
X
X*
X
X
Administer questionnaires before any 
procedures in the order in this table.
*Obtain at every cycle through C17, then 
at every other cycle until EOT.
If the EOT visit takes place ≥30 days 
after the last dose of study intervention 
and is combined with the 30-day safety 
FU visit, PRO assessments only need to 
be performed at that visit.
EORTC 
QLQ-LC13
X
X
X
X
X
X*
X
X
EQ-5D-5L
X
X
X
X
X
X*
X
X
Abbreviations: AE = adverse event; ALK = anaplastic lymphoma kinase gene; aPTT = activated partial thromboplastin time; β-HCG = β human chorionic gonadotropin; 
BSA = body surface area; CBC = complete blood count; CT = computed tomography; CXDY= Cycle X Day Y; D/C = discontinuation; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor gene; ECHO = echocardiogram; EORTC = European Organization for Research and 
Treatment of Cancer; EOT = end of treatment; EQ-5D-5L = European Quality of Life Five-Dimensional Five-Level Scale Questionnaire; FSH = follicle-stimulating hormone; 
FT3 = free triiodothyronine; FT4 = free thyroxine; FU = follow-up; HIV = human immunodeficiency virus; INR = international normalized ratio; IVR = Interactive Voice 
Response; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; MUGA = multigated acquisition; NSAE = nonserious adverse event; NSCLC = non-
small cell lung cancer; PD = progressive disease; PD-L1 = programmed cell death ligand 1; PK = pharmacokinetics; PT = prothrombin time; PRO = patient-reported outcome; 
Q3W = every 3 weeks; Q6W = every 6 weeks; Q9W = every 9 weeks; Q12W = every 12 weeks; QD = once daily; QLQ-C30 = Quality of Life Questionnaire Core 30 items; 
QLQ-LC13 = Quality of Life Questionnaire Lung Cancer Module 13; QTcF = QT interval corrected with Fridericia’s formula; RNA = ribonucleic acid; ROS1 = c-ros oncogene 
1; SAE = serious adverse event; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WOCBP = women of childbearing potential; WONCBP = women 
of non-childbearing potential.
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1.3.3
Second Course (Arm 1 – Retreatment)
Trial Period
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety
Follow-upa
Follow-
upb
Survival 
Follow-
up
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 
17
≥18
At 
D/C
30 days 
after last 
dose
Q12W
Q12W
All procedures are performed before 
administration of study intervention 
unless otherwise indicated.
Scheduling 
Window (days)
-
±3
±3
±3
±3
±3
±3
−
+7
±7
±14
Administrative and General Procedures
Inclusion/exclusion 
criteria
X
All safety parameters listed in the inclusion 
criteria, and none listed in the exclusion 
criteria, are met.
Eligibility criteria
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
Record within 30 days before first dose of 
study intervention through 30 days after 
last dose of study intervention, or 90 days 
for medications for SAEs.
Study Intervention Administration
Lenvatinib 
dispensing
X
X
X
X
X
X
X
Collect and record number of capsules 
returned.
Lenvatinib PO QD 
at dose level last 
received
X
X
X
X
X
X
X
The decision to continue lenvatinib will be 
at the discretion of the investigator.
If continued, the first dose will be given in 
the clinic just after the pembrolizumab 
infusion.
If pembrolizumab is discontinued, 
lenvatinib will be given in the clinic on D1 
of each cycle and taken at home on all 
other days.
Lenvatinib treatment will continue until a 
discontinuation criterion is met.
Pembrolizumab IV 
Q3W
X
X
X
X
X
X
Eligible participants may receive up to 
17 additional treatment cycles of 
pembrolizumab.
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Trial Period
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety
Follow-upa
Follow-
upb
Survival 
Follow-
up
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 
17
≥18
At 
D/C
30 days 
after last 
dose
Q12W
Q12W
All procedures are performed before 
administration of study intervention 
unless otherwise indicated.
Scheduling 
Window (days)
-
±3
±3
±3
±3
±3
±3
−
+7
±7
±14
Efficacy Procedures
Tumor imaging 
(chest, abdomen, 
and pelvis) and 
response 
assessment
X
X
X*
Baseline imaging is the scan showing PD 
that indicates treatment is necessary. 
Perform within 30 days before C1.
Q12W (±7 days) from C1. This schedule 
should be followed regardless of treatment 
delays. If imaging was obtained within 
4 weeks before D/C, a scan at D/C is not 
mandatory.
*FU visits may be scheduled to coincide 
with the imaging schedule.
Efficacy Procedures
Subsequent 
anticancer therapy 
status
X
X
X
X
Record until death or termination of 
survival FU. FU information may be 
obtained at a clinic visit or by telephone, 
email, or other sources.
Survival status
X
Survival FU continues after PD, after 
discontinuation of study intervention, and 
after the start of new anticancer treatment.
Upon Sponsor request, participants may be 
contacted for survival status at any time 
during the study.
Clinical Procedures/Assessments
Complete physical 
examination
X
X
Per institutional standards.
Directed physical 
examination
X
X
X
X
X
X
X
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Trial Period
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety
Follow-upa
Follow-
upb
Survival 
Follow-
up
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 
17
≥18
At 
D/C
30 days 
after last 
dose
Q12W
Q12W
All procedures are performed before 
administration of study intervention 
unless otherwise indicated.
Scheduling 
Window (days)
-
±3
±3
±3
±3
±3
±3
−
+7
±7
±14
Vital signs; weight
X
X
X
X
X
X
X
X
X
Refer to Section 6.6.2.1 for hypertension 
management and BP monitoring 
guidelines.
12-lead ECG with 
QTcF 
determination
X
X
X*
X*
X
X
*Every 4 cycles (12 weeks) after C2.
For high-risk patients (as defined in 
Section 8.3.3), conduct monitoring every 
cycle.
If lenvatinib is discontinued, ECGs are 
only required at the EOT and Safety 
Follow-up visits.
ECOG 
performance status
X*
X
X
X
X
X
X
X
*Within 7 days prior to C1.
AE/SAE review
X*
X
Report NSAEs occurring within 30 days 
after the last dose of study intervention, 
regardless of initiation of new therapy.
*Report SAEs occurring within 90 days 
after the last dose of study intervention, or 
within 30 days after the last dose of study 
intervention if a new anticancer therapy is 
initiated.
Laboratory Procedures/Assessments (Local Laboratory)
Pregnancy test: 
urine or serum β-
HCG
(WOCBP only)
X
X
X
X
X
X
X
X
X
Urine test within 24 hours or serum test 
within 72 hours before C1.
Additional urine/serum testing if clinically 
warranted and/or as defined by local 
regulations (see Appendix 7).
Serum test required if urine test cannot be 
confirmed as negative.
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Trial Period
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety
Follow-upa
Follow-
upb
Survival 
Follow-
up
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 
17
≥18
At 
D/C
30 days 
after last 
dose
Q12W
Q12W
All procedures are performed before 
administration of study intervention 
unless otherwise indicated.
Scheduling 
Window (days)
-
±3
±3
±3
±3
±3
±3
−
+7
±7
±14
CBC with 
differential
X
X
X
X
X
X
X
X
X
Within 10 days before C1. After C1, within 
3 days before dosing; every effort should 
be made to collect samples at the same 
time of day.
Clinical chemistry
X
X
X
X
X
X
X
X
X
Urinalysis/
Urine dipstick 
testing 
(participants taking 
lenvatinib)
X
X
X
X
X
X
X
X
X
Complete urinalysis is required within 10 
days of C1 and every 6 cycles during 
pembrolizumab treatment. At other visits, 
either urinalysis or urine dip stick are 
acceptable while taking lenvatinib (refer to 
Section 8.3.5.1.2).
PT/INR and 
aPTT/PTT 
X
Additional testing as clinically indicated 
for participants taking anticoagulants.
T3 or FT3, FT4, 
and TSH 
X
X
X
X*
X*
X
Within 10 days before C1.
*After C1, within 3 days before dosing at 
every other cycle, beginning with C2.
Participants may be dosed while test results 
are pending.
FT3 is acceptable if T3 cannot be 
determined.
The central laboratory may be used only if 
the local laboratory cannot perform these 
tests.
Abbreviations: AE = adverse event; aPTT = activated partial thromboplastin time; β-HCG = beta human chorionic gonadotropin; BP = blood pressure; CBC = complete blood count; 
CXDY = Cycle X Day Y; D/C = discontinuation; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; FT3 = free triiodothyronine; FT4 = free 
thyroxine; FU = follow-up; INR = international normalized ratio; IV = intravenous; NSAE = nonserious adverse event; PD = progressive disease; PO = oral; PT = prothrombin time; PTT = partial 
thromboplastin time; Q3W = every 3 weeks; Q12W = every 12 weeks; QD = once daily; QTc = QT interval corrected with Fridericia’s formula; SAE = serious adverse event;T3 = triiodothyronine; 
T4 = thyroxine; TSH = thyroid-stimulating hormone; W = weeks; WOCBP = women of childbearing potential.
a If the discontinuation visit is ≥30 days from the last dose of study intervention, the 30-day safety FU visit is not required.
b For participants discontinuing treatment for reasons other than PD, FU visits and imaging will continue until PD or initiation of new anticancer therapy. Participants discontinuing treatment with PD 
will proceed directly to survival FU.
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2
INTRODUCTION
Lenvatinib (also known as E7080 or MK-7902; hereafter referred to as lenvatinib) 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.
2.1
Study Rationale
The global incidence of lung cancer was 1.8 million cases 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, and 5% neuroendocrine, and the rest is not 
otherwise specified [Sulpher, J. A., et al 2013].
Approximately 70% of patients with NSCLC have advanced disease not amenable to surgical 
resection at the time of diagnosis. The 5-year relative survival for patients with any lung 
cancer overall, and metastatic lung cancer specifically, has been reported to be 17.7% and 
4.3%, respectively [National Cancer Institute 2016].
The therapeutic landscape in metastatic NSCLC has dramatically changed with approvals of 
immunotherapy agents in both treatment-naïve and previously treated cancer, irrespective of 
histology. In previously treated patients with advanced NSCLC, immune-checkpoint 
inhibitors targeting the programmed cell death protein 1 (PD-1)/programmed cell death 
ligand 1 (PD-L1) pathway (pembrolizumab, nivolumab, and atezolizumab) have proven 
benefits for survival over the standard chemotherapy, docetaxel [Borghaei, H., et al 2015] 
[Brahmer, J., et al 2015] [Herbst, R. S., et al 2016] [Rittmeyer, A., et al 2017].
The results from the KEYNOTE-001 and KEYNOTE-010 studies demonstrated that 
pembrolizumab provided substantial, clinically meaningful benefits in OS, progression-free 
survival (PFS), and objective response rate (ORR) in patients with NSCLC whose disease 
progressed after platinum-containing chemotherapy and whose tumor cells expressed PD-L1. 
Based on these 2 studies, pembrolizumab monotherapy is approved for the treatment of 
patients with metastatic NSCLC whose tumors express PD-L1 (tumor proportion score [TPS] 
≥1%), with PD during or after platinum-containing chemotherapy. In addition, the National 
Comprehensive Cancer Network Guidelines recommend immune-checkpoint inhibitors as 
the preferred agent for subsequent therapy in patients with metastatic NSCLC based on 
improved survival rates, longer duration of response, and fewer AEs compared with 
cytotoxic chemotherapy [National Comprehensive Cancer Network 2018].
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The results from KEYNOTE-024 established pembrolizumab monotherapy as first-line (1L) 
therapy for patients whose tumors have TPS ≥50% and no EGFR or ALK genomic 
aberrations. Approximately 30% of patients with newly diagnosed advanced NSCLC highly 
express PD-L1 to TPS ≥50% [Reck, M., et al 2016]. Additionally, KEYNOTE-042 compared 
pembrolizumab monotherapy to standard of care (SOC) platinum-based chemotherapy in 
previously untreated participants with advanced or metastatic NSCLC whose tumors 
expressed PD-L1 with TPS ≥1%. The study confirmed the OS treatment effect of 
pembrolizumab monotherapy observed in participants with TPS ≥50% NSCLC in 
KEYNOTE-024, and it extended these benefits to a broader population with TPS ≥1% 
NSCLC.
Two recently completed studies, KEYNOTE-189 and KEYNOTE-407, demonstrated a 
statistically significant and clinically meaningful improvement in OS, PFS, and ORR with 
pembrolizumab in combination with platinum doublet chemotherapy compared with 
chemotherapy alone in nonsquamous and squamous NSCLC, irrespective of PD-L1 tumor 
expression [Gandhi, L., et al 2018] [Paz-Ares, L., et al 2018].
Lenvatinib is a multi-receptor tyrosine kinase inhibitor that inhibits the kinase activities of 
VEGF and its family of receptors (VEGFRs 1-3). Lenvatinib also inhibits other receptor 
tyrosine kinases that have been implicated in pathogenic angiogenesis, tumor growth, and 
cancer progression.
Lenvatinib has been studied as both monotherapy and in combination with chemotherapy for 
the treatment of advanced NSCLC. For monotherapy, a randomized Phase 2 study (E7080-
703), 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 treatment. 
Median OS was 34.8 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 DCR was 42.7% for lenvatinib and 19.6% for placebo. Grade 3 and/or 
4 AEs occurred in 69% of lenvatinib recipients, and in 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].
Based on these results, an open-label, Phase 1b/2 study (Study 111/KEYNOTE 146) to 
assess the safety and preliminary antitumor activity of the combination of lenvatinib plus 
pembrolizumab in participants with selected solid tumors was initiated (see Section 2.2.3 
Ongoing Clinical Studies).
There is a large unmet medical need for safe and effective therapy for patients who have PD 
after platinum doublet chemotherapy and acquired resistance to immunotherapy. Although 
immunotherapy is a true paradigm shift in 1L and second-line (2L) treatment of patients with 
metastatic NSCLC, it is plausible that pembrolizumab in combination with lenvatinib could 
lead to a greater depth of response and an increase in OS. The current study is designed to 
further evaluate the safety and efficacy of combination therapy with pembrolizumab + 
lenvatinib versus docetaxel. The outcomes for patients in this study would be further 
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improved if the safety profile of pembrolizumab + lenvatinib remains acceptable and is 
shown to improve outcomes compared with docetaxel; therefore, this study could support 
regulatory approval of the combination in this population.
While docetaxel is an accepted 2L SOC treatment for patients with NSCLC, the ORR is 
approximately 5% to 10%, median PFS is approximately 3 months, and median OS is 
approximately 7.5 months [Fossella, F. V., et al 2000] [Shepherd, F. A., et al 2000] [Hanna, 
N., et al 2004]. Improvements in OS are needed, since no patient with progressive NSCLC is 
cured.
2.2
Background
2.2.1
Pharmaceutical and Therapeutic Background
2.2.1.1
Inhibition of VEGFR as a Target for Cancer Treatment (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 
known kinase inhibitors in clinical use, lenvatinib is one of the only inhibitors currently 
labeled with 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 [Yamamoto, Y., et al 2014]. In cell-based 
assays, lenvatinib inhibited VEGF-derived and FGF-derived tube formation of human 
umbilical vein endothelial cell (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 (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 
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either monotherapy or in combination with other anticancer drugs. Refer to the Investigator’s 
Brochure (IB) [IB Edition 15-Eisai 2018] for detailed background information on lenvatinib.
2.2.1.2
Inhibition of PD-1 as a Target for Cancer Treatment (Pembrolizumab)
Pembrolizumab is a potent humanized immunoglobulin G4 monoclonal antibody (mAb) with 
high specificity of binding to the PD-1 receptor, thus inhibiting its interaction with PD-L1 
and programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, 
pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an intravenous (IV) immunotherapy for advanced malignancies. Keytruda® (pembrolizumab) 
is indicated for the treatment of patients across a number of indications, including NSCLC. 
For more details on specific indications refer to the IB [IB Edition 16 2018] and the approved 
product label [U.S. Prescribing Information 2018].
2.2.1.3
Scientific Rationale for the Combination of 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/PD-L1 signal inhibitors. The effect of 
combining lenvatinib with an anti-human PD-1 humanized mAb was investigated in 4 
murine tumor isograft models, which showed significant tumor growth inhibition compared 
to 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 to that of the respective 
monotherapy groups [Kato, Y., et al 2019]. All treatments were well tolerated and severe 
body weight loss was not observed.
For this reason, an open-label, Phase 1b/2 study (Study E7080-A001-111 [Study 111]) to 
assess the safety and preliminary antitumor activity of the combination of lenvatinib plus 
pembrolizumab in participants with selected solid tumors was initiated. Phase 1b of this 
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study determined the maximum tolerated dose (MTD) and recommended Phase 2 dose 
(RP2D) of lenvatinib as 20 mg QD in combination with 200 mg of pembrolizumab IV every 
3 weeks (Q3W). The safety and efficacy of the combination at the lenvatinib RP2D is being 
assessed in the Phase 2 portion of the study that includes 6 cohorts (ie, NSCLC, renal cell 
carcinoma [RCC], endometrial cancer, urothelial carcinoma, melanoma, and squamous cell 
carcinoma of the head and neck).
2.2.1.4
Rationale for Lenvatinib Monotherapy Arm
A randomized lenvatinib arm (Arm 3) was added to the study design to assess the 
contribution of lenvatinib in the overall treatment effect of the combination of 
pembrolizumab + lenvatinib.
2.2.2
Preclinical and Clinical Studies
2.2.2.1
Completed Studies With Pembrolizumab and Lenvatinib
Refer to the respective IBs for pembrolizumab [IB Edition 15 2017] and lenvatinib [IB 
Edition 15-Eisai 2018] for additional preclinical and clinical study data for pembrolizumab 
and lenvatinib.
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 
undergoing studies in patients with different types of solid tumors, including NSCLC, in 
combination with other therapies including PD-1 targeted therapies. Full lists of ongoing 
studies are in the respective IBs for pembrolizumab and lenvatinib.
Study 111/KEYNOTE-146
Study 111/KEYNOTE-146 is a multicenter, open-label, Phase 1b/2 clinical trial being 
conducted to evaluate the efficacy and safety of lenvatinib in combination with 
pembrolizumab. Phase 1b of this study determined the MTD and RP2D of lenvatinib as 
20 mg QD in combination with 200 mg of pembrolizumab IV Q3W. The safety and efficacy 
of the combination at the lenvatinib RP2D is being assessed in the Phase 2 portion of the 
study that includes 6 cohorts (ie, NSCLC, renal cell carcinoma [RCC], endometrial cancer, 
urothelial carcinoma, melanoma, and squamous cell carcinoma of the head and neck).
As of 01-MAR-2018, a total of 21 participants with metastatic NSCLC were enrolled in the 
Phase 2 portion of Study 111/KEYNOTE-146. Participants in the Phase 2 portion of the 
study received lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously 
once every 3 weeks. ORR after 24 weeks of treatment was 33.3%. The best overall response 
(BOR) was complete response (CR) in 1 participant (4.8%), partial response (PR) in 
6 (28.6%), stable disease(SD) in 10 (47.6%), and PD in 2 (9.5%). In 2 participants the BOR 
was unknown or not evaluable. Median PFS was 5.9 months. Grade 3 and Grade 4 treatment-
related AEs occurred in 11 participants (52.4%). The most common Grade 3 treatment-
related AEs were hypertension (19%), fatigue (14%), diarrhea (14%), proteinuria (10%), and 
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arthralgia (10%). There was 1 death (exsanguination) considered possibly treatment-related
[Brose, M., et al 2018].
Based on Study 111/KEYNOTE-146, lenvatinib 20 mg QD in combination with 
pembrolizumab 200 mg IV Q3W was the dose selected for this Phase 3 study.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
With the approval of immune-checkpoint inhibitors targeting the PD-1/PD-L1 pathway as a 
1L therapy for NSCLC, there is an unmet medical need for safe and efficacious 2L + therapy 
in patients whose disease has progressed with 1L treatment. The existing data suggest that 
inhibiting angiogenesis in combination with PD-1 blockade is a promising therapeutic 
strategy, and the benefit/risk assessment for patients in this study is favorable, making the 
combination of pembrolizumab + lenvatinib a promising 2L+ therapeutic option in patients 
with metastatic squamous or nonsquamous NSCLC and no EGFR or ALK tumor genome 
aberrations, regardless of PD-L1 expression.
Additional details regarding specific benefits and risks for participants in this study are in the 
accompanying IBs and ICFs.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
In participants with metastatic NSCLC and PD after platinum doublet chemotherapy and 
treatment with 1 prior anti-PD-1/PD-L1 monoclonal antibody (mAb):
Note: Progression-free survival (PFS), objective response rate (ORR), duration of response 
(DOR), and disease control rate at 12 weeks (DCR12) will be assessed per Response 
Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) modified to follow a 
maximum of 10 target lesions and a maximum of 5 target lesions per organ.
Primary Objective
Primary Endpoint
To compare pembrolizumab + lenvatinib to 
docetaxel with respect to overall survival 
(OS).
Hypothesis (H1): Pembrolizumab + 
lenvatinib prolongs OS compared with 
docetaxel.
OS, defined as the time from randomization 
to the date of death due to any cause.
To compare pembrolizumab + lenvatinib to 
docetaxel with respect to PFS per RECIST 
1.1 by blinded independent central review 
(BICR).
Hypothesis (H2): Pembrolizumab + 
lenvatinib prolongs PFS per RECIST 1.1 
based on BICR compared with docetaxel.
PFS, defined as the time from 
randomization to the first documented 
progressive disease (PD) or death due to 
any cause, whichever occurs first.
Secondary Objectives
Secondary Endpoints
To compare pembrolizumab + lenvatinib to 
docetaxel with respect to ORR per RECIST 
1.1 by BICR.
Hypothesis (H3): Pembrolizumab + 
lenvatinib results in a superior ORR per 
RECIST 1.1 based on BICR compared with 
docetaxel.
Objective response, defined as a confirmed 
complete response (CR) or partial response 
(PR).
To compare pembrolizumab + lenvatinib to 
lenvatinib monotherapy with respect to 
ORR per RECIST 1.1 by BICR.
Hypothesis (H4): Pembrolizumab + 
lenvatinib results in a superior ORR per 
RECIST 1.1 based on BICR, compared with 
lenvatinib monotherapy.
Objective response, defined as a confirmed 
complete response (CR) or partial response 
(PR).
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To assess DOR with pembrolizumab + 
lenvatinib and docetaxel per RECIST 1.1 by 
BICR.
DOR, defined as the time from the first 
documented evidence of CR or PR until PD 
or death due to any cause, whichever occurs 
first, in participants demonstrating CR or 
PR.
To assess the safety and tolerability of 
treatment with pembrolizumab + lenvatinib 
versus docetaxel. To assess the safety and 
tolerability of treatment with lenvatinib 
monotherapy.
Adverse events (AEs) and discontinuations 
due to AEs.
To compare pembrolizumab + lenvatinib to 
docetaxel with respect to the mean change 
from baseline in global health status/quality 
of life (QoL), cough, chest pain, dyspnea, 
and physical functioning.
Scores for the following scales/items:
Global health status/QoL (European 
Organization for Research and Treatment of 
Cancer [EORTC] Quality of Life 
Questionnaire Core 30 items [QLQ-C30] 
Items 29 and 30)
Cough (EORTC Quality of Life 
Questionnaire Lung Cancer Module 13 
[QLQ-LC13] Item 31)
Chest pain (EORTC QLQ-LC13 Item 40)
Dyspnea (EORTC QLQ-C30 Item 8)
Physical functioning (EORTC QLQ-C30 
Items 1 to 5)
To compare pembrolizumab + lenvatinib to 
docetaxel with respect to time to true 
deterioration (TTD) in global health 
status/QoL, cough, chest pain, dyspnea, and 
physical functioning scales.
TTD, defined as the time from baseline to 
the first onset of ≥10-point decrease from 
baseline, with confirmation by the 
subsequent visit of ≥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)
Physical functioning (EORTC QLQ-C30 
Items 1 to 5)
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
To assess DCR12 with pembrolizumab + 
lenvatinib per RECIST 1.1 by BICR.
Disease control at 12 weeks, defined as CR, 
PR, or stable disease (SD) at 12 weeks.
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To assess ORR with lenvatinib 
monotherapy versus docetaxel per RECIST 
1.1 by BICR.
Objective response, defined as a confirmed 
complete response (CR) or partial response 
(PR).
To assess OS and PFS with pembrolizumab 
+ lenvatinib versus lenvatinib monotherapy, 
and lenvatinib monotherapy versus 
docetaxel per RECIST 1.1 by BICR.
OS, defined as the time from randomization 
to the date of death due to any cause.
PFS, defined as the time from 
randomization to the first documented 
progressive disease (PD) or death due to 
any cause, whichever occurs first.
To evaluate and compare participants’ 
health status as assessed using the European 
Quality of Life 5-Dimension 5-Level 
(EuroQoL EQ-5D-5L) questionnaire, to 
generate utility scores for use in economic 
models (pembrolizumab + lenvatinib versus 
docetaxel).
Health utilities, assessed using the EuroQoL 
EQ-5D-5L.
Objective: To assess the pharmacokinetics 
(PK) of lenvatinib when coadministered 
with pembrolizumab.
Plasma concentration of lenvatinib versus 
time.
Objective: To identify molecular (genomic, 
metabolic, and/or proteomic) biomarkers 
that may be indicative of clinical 
response/resistance, safety, and/or the 
mechanism of action of pembrolizumab 
and/or lenvatinib and/or docetaxel.
Genomic, metabolic, or proteomic 
determinants of response or resistance to 
treatments, using blood and/or tumor tissue.
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4
STUDY DESIGN
4.1
Overall Design
This is a randomized, open-label, multi-site, active-controlled study of pembrolizumab + 
lenvatinib versus docetaxel. The efficacy of lenvatinib (24 mg QD) will also be compared to 
both pembrolizumab + lenvatinib and docetaxel. Participants with metastatic NSCLC and PD
after platinum doublet chemotherapy and treatment with one prior anti-PD-1/PDL1 mAb 
(either sequentially or in combination with chemotherapy) will be enrolled in the study. 
Staging for metastatic NSCLC will be based on the American Joint Committee on Cancer 
(AJCC) Staging Manual, version 8 or current version. This study will be conducted in 
participants with measurable disease and in whom EGFR-, ALK-, or ROS1-targeted therapy 
is not indicated.
Participants will provide archival tumor tissue obtained any time from initial diagnosis of 
NSCLC and prior to receiving immunotherapy (anti-PD-1/PD-L1) for determination of PD-
L1 expression and study stratification. Participants will be stratified by:

Anti-PD-1/PD-L1 mAb (immediate prior therapy versus not the immediate prior 
therapy)

PD-L1 TPS (<50% versus ≥50%)

ECOG performance status (0 versus 1)
Additionally, a newly obtained tumor tissue biopsy, obtained after immunotherapy (anti-PD-
1/PD-L1) and before randomization is required. No systemic anticancer therapy may be 
administered between the biopsy and initiation of study treatment intervention.
Participants will also provide prestudy imaging scans to a CIV to confirm that they are of 
acceptable diagnostic quality to document PD before randomization. The site’s study team 
must have reviewed and submitted images that are of diagnostic quality from at least 2 dates, 
to determine that radiographic progression has occurred per RECIST 1.1 within 12 weeks 
(84 days) of the last dose of treatment with an anti-PD-1/PD-L1 mAb. The central vendor 
will not be confirming eligibility before randomization.
Initial Treatment
Participants will be randomized 4:4:1 to:

Pembrolizumab + lenvatinib (Arm 1)

Docetaxel (Arm 2)

Lenvatinib monotherapy (Arm 3)
All participants will receive a randomization number.
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No treatment crossover is planned for the study.
Overall, approximately 405 participants will be randomized, including 180 participants each
in Arm 1 and Arm 2, and approximately 45 participants in Arm 3.
The study design is shown in Figure 1 (Initial Treatment) and Figure 2 (Second Course).
A single-arm futility analysis will be conducted after 18 participants have been randomized 
to pembrolizumab + lenvatinib (Arm 1) and have been followed up for 20 weeks.
Futility rules are specified in Section 9.7.2.
Participants will be evaluated with radiographic imaging to assess response to study 
intervention every 6 weeks from randomization through 36 weeks, every 9 weeks through 
54 weeks, and subsequently every 12 weeks until confirmed PD or initiation of a new 
anticancer regimen. All imaging obtained during the study will be submitted to the CIV for 
BICR, which will assess the images using RECIST 1.1 (Section 4.2.1.1.2) for determination 
of PFS and ORR. The tumor imaging showing site-assessed PD should be submitted 
immediately for verification by BICR before study intervention discontinuation.
Treatment-based decisions may use site-assessed iRECIST as described in Section 8.2.1.7, 
which allows participants with initial site-assessed PD to continue study intervention until 
PD is confirmed by the site 4 to 8 weeks later.
Survival follow-up will continue after PD, discontinuation of study intervention, and the start 
of new anticancer treatment. In addition, upon Sponsor request, participants may be 
contacted for survival status at any time during the study.
AE monitoring will be ongoing throughout the study. AEs will be graded in severity 
according to the guidelines outlined in the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), version 4.0.
Treatment with pembrolizumab will continue for up to 35 treatment cycles, or until a 
discontinuation criterion is met (see Section 7.1). Treatment with pembrolizumab may be 
discontinued for participants with a confirmed CR who have received at least 6 months (8 
cycles) of pembrolizumab.
Treatment with docetaxel may continue until a discontinuation criterion (see Section 7.1) is 
met.
Treatment with lenvatinib may continue until a discontinuation criterion (see Section 7.1) is 
met.
Participants receiving pembrolizumab will be permitted to continue study treatment beyond 
RECIST 1.1-defined PD, as long as the treating investigator considers that the participant 
may experience clinical benefit with continued treatment per iRECIST, and the participant is 
clinically stable and 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.
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Second Course
Participants who stop pembrolizumab after receiving 35 treatment cycles of pembrolizumab 
or participants who stop study intervention after attaining a confirmed CR may be eligible for 
up to 17 additional treatment cycles of pembrolizumab upon experiencing BICR-verified PD. 
This retreatment is termed the Second Course and is only available if the study remains open 
and the participant meets the criteria in Section 8.10.3. The decision of whether to continue 
lenvatinib during the Second Course will be at the discretion of the investigator, unless 
lenvatinib was discontinued due to a toxicity. If continued, participants will be retreated at 
the same dose and frequency as when they last received the combination of pembrolizumab 
and lenvatinib. Radiographic imaging to assess response to study intervention will be 
performed every 12 weeks.
The study will be conducted in conformance with Good Clinical Practice (GCP).
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This study is being conducted to evaluate the efficacy and safety of pembrolizumab + 
lenvatinib in metastatic NSCLC. Lenvatinib (20 mg QD) will be evaluated in combination 
with the standard dose of pembrolizumab (200 mg Q3W). The study is open-label because of 
different infusion times for each treatment and predosing medication in the docetaxel arm. If 
the safety profile is acceptable and this combination improves outcomes, the study could 
support the regulatory approval of pembrolizumab + lenvatinib in patients with metastatic 
NSCLC previously exposed to an anti-PD-1/PD-L1 mAb. The efficacy and safety of 
lenvatinib monotherapy will be evaluated.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
4.2.1.1.1
Primary Efficacy Endpoints
This study has dual primary endpoints: OS and PFS.
OS has been recognized as the gold standard for demonstration of superiority of a new 
antineoplastic therapy in randomized clinical studies.
PFS is an acceptable measure of clinical benefit for a late-stage study that demonstrates 
superiority of a new antineoplastic therapy, especially if the magnitude of the effect is large 
and the therapy has an acceptable benefit/risk profile. The use of BICR and RECIST 1.1 to 
assess PFS is typically considered acceptable by regulatory authorities. Images will be read 
by a CIV blinded to study intervention assignment to minimize bias in response assessments. 
In addition, the final determination of radiologic progression will be based on the central 
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assessment of progression, rather than on a local site assessment. The CIV will verify 
progression by RECIST 1.1 in real time.
4.2.1.1.2
Secondary Efficacy Endpoints
In an exploratory analysis in patients with metastatic NSCLC treated with a PD-1 inhibitor,
there was a correlation between objective response and OS; therefore, objective response and 
DOR per RECIST 1.1 as assessed by BICR are considered preliminary evidence of efficacy. 
As ancillary markers of efficacy, they are also chosen to be secondary endpoints in the study.
Additional secondary endpoints in this study include safety endpoints and patient-reported 
outcomes (PROs) (Sections 4.2.1.2. and 4.2.1.3).
RECIST 1.1 will be used by the BICR when assessing images for efficacy measures and by 
the 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 a modification to RECIST 1.1 to allow a maximum of 10 target lesions in total 
and 5 per organ.
For details of assessing efficacy endpoints using RECIST 1.1, see Appendix 8.
4.2.1.2
Safety Endpoints
Safety parameters frequently used for evaluating investigational-systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of AEs/SAEs, and changes in vital signs and laboratory values. AEs 
will be assessed as defined by CTCAE, Version 4.0.
4.2.1.3
Rationale for Patient-reported Outcomes
Symptomatic improvement is considered a clinical benefit and is accepted by health 
authorities. As part of the analyses for this study, participants will provide information 
regarding their health-related QoL via the EORTC QLQ-C30, EORTC QLQ-LC13, and 
EuroQoL-5D-5L (EQ-5D-5L) 5L questionnaires. The EORTC QLQ-C30 and EQ-5D-5L
PROs are not pure efficacy or safety endpoints because they are affected by both PD and 
treatment tolerability.
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].
4.2.1.3.1
EORTC QLQ-C30
EORTC QLQ-C30 is the most widely used cancer-specific health-related QoL instrument,
which contains 30 items and measures 5 functional dimensions (physical, role, emotional, 
cognitive, and social), 3 symptom items (fatigue, nausea/vomiting, and pain), and 6 single 
items (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), 
and includes a global health and QoL scale [Aaronson, N. K., et al 1993]. EORTC QLQ-C30 
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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
EORTC 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.
4.2.1.3.3
EuroQoL-5D-5L (EQ-5D-5L)
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome and will 
provide data for developing health utilities to be used in health economic analyses [Rabin, R. 
and de Charro, F. 2001]. The 5 health state dimensions in the EQ-5D-5L are 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
Exploratory Endpoints
4.2.1.4.1
Disease Control at Week 12
The exploratory endpoint, disease control at Week 12 per RECIST 1.1 as assessed by BICR, 
will be used in the futility analysis as well as objective response. It is considered as a 
preliminary evidence of efficacy at an earlier stage of the study.
4.2.1.4.2
Pharmacokinetic Endpoints
Standard PK parameters of clearance and volume of distribution at steady state are planned to 
be calculated for lenvatinib in this study, 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, explore the exposure/response relationship for lenvatinib antitumor activity, 
evaluate the effect of extrinsic and intrinsic factors in support of the proposed dosing 
regimen, and evaluate safety in the proposed participant population.
PK evaluations will be performed for the first 90 participants in Arm 1.
4.2.1.4.3
Health Utilities
The EQ-5D-5L, and data for developing health utilities, are described in Section 4.2.1.3.3.
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4.2.1.4.4
Genomic, Metabolic, or Proteomic Determinants of Response or 
Resistance to Treatments
Genomic, metabolic, and proteomic determinants of response or resistance to treatments are 
described in Section 4.2.1.5.
4.2.1.5
Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents. 
However, the mechanism of action of these exciting new therapies, including novel 
combinations with antiangiogenesis therapy, is not completely understood and much remains 
to be learned regarding how best to leverage these new drugs in treating patients. Thus, to aid 
future patients, it is important to investigate the determinants of response or resistance to 
cancer immunotherapy and other treatments administered, as well as determinants of AEs in 
the course of our clinical studies. These efforts may identify novel predictive/PD biomarkers 
and generate information that may better guide single agent and combination therapy with 
immuno-oncology drugs. To identify novel biomarkers, biospecimens (ie, blood components, 
tumor material) will be collected to support analyses of cellular components (eg, protein, 
DNA, RNA, metabolites) and other circulating molecules. Investigations may include but are 
not limited to:
Germline (blood) genetic analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing)
This research may evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
predict efficacy or AEs, the data might inform optimal use of therapies in the patient 
population. Furthermore, it is important to evaluate germline DNA variation across the 
genome in order to interpret tumor-specific DNA mutations.
Genetic (DNA) analyses from tumor
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (ie, mutations, methylation 
status, microsatellite instability) contributing towards the development/progression of cancer 
and/or driving response to therapy. Key molecular changes of interest to immuno-oncology 
drug development include the mutational burden of tumors and the clonality of T-cells in the 
tumor microenvironment. Increased mutational burden (sometimes referred to as a ‘hyper-
mutated’ state) may generate neo-antigen presentation in the tumor microenvironment. To 
conduct this type of research, it is important to identify tumor-specific mutations that occur 
across all genes in the tumor genome. Evaluation of molecular targets and signaling 
pathways including angiogenesis- or and growth factor related signaling pathways related to 
pembrolizumab and lenvatinib may also be explored. Thus, genome-wide approaches may be 
used for this effort. Note that in order to understand tumor-specific mutations, it is necessary 
to compare the tumor genome with the germline genome. Circulating tumor DNA and/or 
RNA may also be evaluated from blood samples.
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Tumor and blood RNA analyses
Both genome-wide and targeted messenger RNA (mRNA) expression profiling and 
sequencing in tumor tissue and in blood may be performed to define gene signatures that 
correlate to clinical response to treatment with pembrolizumab or other immunotherapies. 
Pembrolizumab induces a response in tumors that likely reflects an inflamed/immune 
phenotype. Specific immune-related gene sets (ie, those capturing interferon-gamma 
transcriptional pathways) may be evaluated and new signatures may be identified. Individual 
genes related to the immune system and growth factor signaling pathways (eg, VEGF and 
FGF) may also be evaluated. MicroRNA profiling may also be pursued as well as exosomal 
profiling.
Proteomics and immunohistochemistry (IHC) using blood or tumor
Tumor and blood samples from this study may undergo proteomic analyses (eg, PD-L1 IHC). 
PD-L1 protein level in tumor sections, assessed by IHC, has been shown to correlate with 
response to pembrolizumab in patients with NSCLC, and an in vitro diagnostic (IVD) device 
has been developed for use with pembrolizumab in NSCLC. Preliminary data indicates that 
this association may also be true in additional cancer types (ie, triple negative breast cancer, 
head and neck, and gastric). Additional tumor or blood-derived proteins may also correlate 
with response to pembrolizumab and lenvatinib combination therapy. Therefore, tumor tissue 
may be subjected to proteomic analyses using a variety of platforms that could include but
are not limited to immunoassays and liquid chromatography/mass spectrometry. This 
approach could identify novel protein biomarkers that could aid in patient selection for 
pembrolizumab (MK-3475) and lenvatinib combination therapy.
Other blood-derived biomarkers
In addition to expression on the tumor tissue, PD-L1, circulating cytokines and angiogenic 
factors, and other tumor derived proteins can be shed from tumor and released into the blood. 
Assays such as enzyme-linked immunoassay (ELISA) measure such proteins in serum. 
Correlation of expression with response to pembrolizumab and lenvatinib combination 
therapy may identify new approaches for predictive biomarkers in blood, representing a 
major advance from today’s reliance on assessing tumor biomarkers. This research would 
serve to develop such assays for future clinical use.
Other molecular changes of interest include the subtype of T-cells in the tumor 
microenvironment. The T-cell repertoire from tumor tissue and blood components may be 
evaluated.
Genomic, metabolic, or proteomic determinants of response or resistance to treatment will be 
identified, and exploratory biomarker research will be conducted.
4.2.2
Rationale for Use of Comparator
Docetaxel is approved as 2L therapy for locally advanced or metastatic NSCLC after 
platinum therapy failure and is the most commonly prescribed 2L agent.
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4.3
Justification for Dose
4.3.1
Lenvatinib
The dosing regimen for lenvatinib in combination with pembrolizumab was selected based 
on the results of Phase 1b/2 Study 111/KEYNOTE-146, whose primary endpoints were the 
MTD and RP2D of lenvatinib in combination with pembrolizumab 200 mg Q3W. Thirteen 
participants, including 3 receiving lenvatinib 24 mg/day + pembrolizumab 200 mg Q3W and 
10 receiving lenvatinib 20 mg/day + pembrolizumab 200 mg Q3W, were enrolled in the 
Phase 1b study. Eight of these 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 Q3W; 1 participant had Grade 3 arthralgia, and another had Grade 3 
fatigue. Accordingly, this dose was defined as the toxic dose. No DLTs were reported in 
the10 participants who received lenvatinib 20 mg/day + pembrolizumab 200 mg Q3W. All 
participants experienced at least 1 treatment-emergent AE (TEAE). TEAEs necessitating 
dose modification included increased liver function tests (LFTs), fatigue, hypertension, 
arthralgia, decreased appetite, dehydration, diarrhea, hyponatremia, noncardiac chest pain, 
palmar-plantar erythrodysesthesia, proteinuria, maculopapular rash, and rhabdomyolysis. 
Based on review of all clinical data from these 13 participants, the MTD and RP2D were 
determined to be 20 mg lenvatinib QD with a fixed dose of 200 mg pembrolizumab Q3W.
Based on the promising antitumor efficacy and tolerable safety profile in both the 
endometrial cancer and RCC expansion cohorts in 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.
The safety and efficacy of the combination of pembrolizumab and lenvatinib at the lenvatinib 
RP2D is being assessed in the Phase 2 portion of this study that includes 6 cohorts (NSCLC, 
RCC, endometrial cancer, urothelial carcinoma, melanoma, and squamous cell carcinoma of 
the head and neck).
The dose selected for the lenvatinib monotherapy arm, 24 mg QD, is based on Study 
E7080-703, and is the recommended dose in locally recurrent or metastatic, progressive, 
radioactive iodine-refractory differentiated thyroid cancer.
4.3.2
Pembrolizumab
The planned dose of pembrolizumab for this study is 200 mg Q3W. The rationale for use of a 
fixed pembrolizumab dose in participants with solid tumors was based on:

Similar efficacy and safety of pembrolizumab at doses of 2 mg/kg Q3W, 10 mg/kg 
Q3W, or 10 mg/kg every 2 weeks (Q2W) in participants with melanoma and NSCLC.

Flat exposure-response relationships for pembrolizumab for both efficacy and safety 
in the dose range of 2 mg/kg Q3W to 10 mg/kg Q3W.
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
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 200 mg Q3W pembrolizumab as an appropriate fixed dose was based on 
simulations using the PopPK model of pembrolizumab, showing that a fixed dose of 200 mg 
Q3W would:

Provide similar control of PK variability as does weight-based dosing, with considerable 
overlap in the distribution of exposures from the 200 mg Q3W fixed dose and the 
2 mg/kg Q3W dose.

Maintain individual participant exposures in the exposure range associated with maximal 
efficacy response 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 relationship, including OS 
at 200 mg Q3W across multiple indications. Additionally, a fixed dose regimen simplified 
dosing, to be more convenient for physicians and to reduce potential for dosing errors. A 
fixed dosing scheme also reduced complexity in the logistic chain at treatment facilities and 
reduced wastage.
4.3.3
Maximum Dose Exposure for This Study
The maximum dose/exposure of pembrolizumab allowed in this study is 200 mg IV Q3W for 
up to 2 years (35 treatment cycles) of initial treatment (Section 8.10.2), and for up to 1 year 
(17 treatment cycles) of Second Course treatment (Section 8.10.3). The maximum dose of 
lenvatinib is 20 mg PO QD in Arm 1 and 24 mg PO QD in Arm 3. The maximum dose of 
docetaxel is 75 mg/m2 IV. Lenvatinib and docetaxel may be continued until a discontinuation 
criterion (eg, PD) is met (Section 7.1).
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative 
[Appendix 7, Section 10.7.1]) provides documented informed consent. The overall study 
ends when the last participant completes the last study-related contact, withdraws consent, or 
is lost to follow-up (Section 7.3). For purposes of analysis and reporting, the overall study 
ends when the Sponsor receives the last laboratory test result or at the time of final contact 
with the last participant, whichever comes last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
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Upon study termination, participants are discontinued and may be enrolled in an extension 
study, if available.
4.4.1
Clinical Criteria for Early Study Termination
The prespecified stopping rules are detailed in Section 9.7.2.
In addition, the study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio for the study population 
as a whole is unacceptable. Moreover, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP and/or 
other applicable regulatory requirements, procedure-related problems, or the number of 
discontinuations for administrative reasons is too high.
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5
STUDY POPULATION
Male or female participants with metastatic NSCLC and PD after platinum doublet 
chemotherapy and an anti-PD-1/PD-L1 mAb (either concomitantly or sequentially) who are 
at least 18 years of age may be enrolled into the study.
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
An individual is eligible for inclusion in the study if the individual meets all of the following 
criteria:
Type of Participant and Disease Characteristics
1. Have a histologically or cytologically confirmed diagnosis of metastatic squamous or 
nonsquamous NSCLC (Stage IV: M1a, M1b, M1c, AJCC Staging Manual, version 8).
Note: Mixed tumors will be characterized by the predominant cell type. If small cell 
elements are present, the participant is ineligible.
2. Have PD on treatment with one prior anti-PD-1/PD-L1 mAb administered either as 
monotherapy or in combination with other checkpoint inhibitors or other therapies. Anti-
PD-1/PD-L1 treatment progression is defined by meeting ALL of the following criteria:
Treatment with at least 2 doses of an anti-PD-1/PD-L1 mAb.
PD after an anti-PD-1/PD-L1 mAb as defined by RECIST v1.1: Evidence of PD is 
defined as:
1) imaging prior to anti-PD-1/PD-L1 treatment or image showing nadir during 
anti-PD-1/PD-L1 treatment; AND
2) imaging to determine that radiographic progression has occurred per RECIST 
1.1 within 12 weeks (84 days) from the last dose of an anti-PD-1/PD-L1 mAb.
Note: Retreatment with the same anti-PD-L1/PD-L1 mAb is acceptable in the overall
course of treatment.
Note: The CIV must have received these scans and have confirmed with the site that the
images are of acceptable diagnostic quality prior to treatment allocation in this study. The 
CIV will not be confirming disease progression prior to treatment allocation. The image 
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showing progression may be the baseline tumor image for the trial, if collected during the 
30-day screening window.
3. Have PD during/after platinum doublet chemotherapy for metastatic disease.
Note: A platinum-containing doublet is defined as a platinum-based cytotoxic systemic 
agent administered in the same cycle as another cytotoxic systemic chemotherapeutic 
agent.
Note: Completion of treatment with a platinum-containing doublet as neo-adjuvant or 
adjuvant therapy or as part of definitive chemo-radiation treatment for early stage disease 
(Stage I-III) within 1 year of providing documented informed consent will satisfy the 
prior platinum doublet chemotherapy treatment requirement.
Note: Eligible participants will have PD after an anti-PD-1/PD-L1 therapy AND 
platinum doublet chemotherapy (sequentially or concomitantly). The prestudy images 
submitted to the CIV will be images of PD on treatment with an anti-PD-1/PD-L1 mAb, 
and NOT images associated with PD on platinum doublet chemotherapy given 
sequentially.
4. Have confirmation that EGFR-, ALK-, or ROS1-directed therapy is not indicated as 
primary therapy (documentation of absence of tumor-activating EGFR mutations [eg, 
DEL19 or L858R], and absence of ALK and ROS1 gene rearrangements OR presence of a 
K-ras mutation).
Note: If the participant’s tumor is known to have a predominantly squamous histology, 
molecular testing for EGFR mutations and ALK and ROS1 translocations will not be 
required, as this testing is not part of current diagnostic guidelines.
Note: Participants who have failed directed therapy are not eligible for the study.
5. Have submitted prestudy imaging that confirmed evidence of PD based on investigator 
review of at least 2 images per RECIST 1.1, following initiation of an anti-PD-1/PD-L1 
mAb.
Note: These images will be submitted to the CIV for confirmation that they are of 
acceptable diagnostic quality. The CIV must have received these images and confirmed 
that they are of acceptable diagnostic quality before randomization.
6. Have measurable disease based on RECIST 1.1 as determined by the local site 
assessment.
Have at least 1 measurable lesion by CT or MRI per RECIST 1.1.
Note: Lesions that appear measurable but are 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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7. Have provided tumor tissue for PD-L1 biomarker analysis from an archival sample 
(defined as: from initial diagnosis of NSCLC and prior to receiving immunotherapy [anti-
PD-1/PD-L1], from the primary lesion or a metastatic lesion).
Note: The tissue sample must be received and evaluated by the central vendor before 
randomization for stratification in the study. Formalin-fixed, paraffin-embedded (FFPE) 
tissue blocks are preferred to slides. Fine-needle aspirates are not acceptable.
Note: As of 16-JUN-2021, the archival tissue sample and evaluation may be from a 
previous MSD study that the subject was enrolled in (ie, MK-3475-024, -042, -189, -407, 
-654, and -715) where the sample was evaluated by the same central laboratory.
8. Have provided prior to randomization tissue from a newly obtained formalin-fixed 
sample from a new biopsy (defined as: after completion of immunotherapy [anti-PD-
1/PD-L1] and before receiving a randomization number) of a tumor lesion not previously 
irradiated.
Note: No systemic anticancer therapy may be administered between the newly 
obtained PD-L1 biopsy and initiation of study intervention. The tissue sample must 
be shipped to the central vendor before randomization. FFPE tissue blocks are preferred 
to slides. Fine-needle aspirates are not acceptable.
Note: For participants from whom obtaining a new tumor biopsy would be medically 
inappropriate, the investigator may request an exception from the Sponsor’s study clinical 
director. If there is agreement, a waiver will be granted.
Demographics
9. Be ≥18 years of age on the day of providing documented informed consent.
10. Have ECOG performance status of 0 or 1 within 7 days before the first dose of study 
intervention but before randomization.
11. Have a life expectancy of at least 3 months.
Male Participants
12. Male participants receiving pembrolizumab ± lenvatinib or lenvatinib are eligible to 
participate if they agree to the following during the intervention period or 7 days after the 
last dose of lenvatinib:
Male participants randomized to docetaxel are eligible to participate if they agree to the 
following during the intervention period and for at least 90 days after the last dose of 
docetaxel:

Refrain from donating sperm
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•
PLUS either:

Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent.
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 WOCBP who is not currently 
pregnant.
•
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile-
vaginal penetration.

Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. If the 
contraception requirements in the local label for any of the study interventions are
more stringent than the requirements above, the local label requirements are to be 
followed.
Note: Upon 7 days after lenvatinib is stopped, if the participant is on pembrolizumab only, 
no male contraception measures are needed.
Female Participants
13. A female participant is eligible to participate if she is not pregnant or breastfeeding and at 
least 1 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 is abstinent from heterosexual 
intercourse as her preferred and usual lifestyle (abstinent on a long-term and 
persistent basis), as described in Appendix 5 during the intervention period and for at 
least 120 days after the last dose of pembrolizumab or 30 days after the last dose of 
lenvatinib, whichever occurs last; and agrees not to donate eggs (ova, oocytes) to 
others or freeze/store these for her own use for the purpose of reproduction during 
this period. The investigator should evaluate the potential for contraceptive method 
failure (ie, noncompliance, recently initiated) in relationship to the first dose of study 
intervention.
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
A WOCBP randomized to docetaxel is eligible to participate if she is using a 
contraceptive method that is highly effective with low user dependency or is abstinent 
from heterosexual intercourse as her preferred and usual lifestyle and agrees not to 
donate or freeze/store eggs during the intervention period and for at least 30 days 
after the last dose of docetaxel.

A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as 
required by local regulations [see Appendix 7]) within 24 hours for urine or within 
72 hours for serum before the first dose of study intervention.

If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.

Additional requirements for pregnancy testing during and after study intervention are 
in Appendix 2.

The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk of inclusion of a woman with an early 
undetected pregnancy.

Contraceptive use by females 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 are
more stringent than the requirement above, the local label requirements are to be 
followed.
Informed Consent
14. Have provided (or legally acceptable representative [see Appendix 7, Section 10.7.1]) 
documented informed consent for the study.
Medical History and Laboratory Values
15. 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 before randomization.
Note: Participants must not have a history of uncontrolled or poorly controlled 
hypertension, defined as ≥150/90 mm Hg for >4 weeks despite standard medical 
management.
16. If participant received major surgery or radiation therapy of >30 Gy, they have recovered 
from the toxicity and/or complications from the intervention.
17. Have adequate organ function as defined in Table 1. Specimens must be collected within 
10 days before the start of study intervention.
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Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematologic
Absolute neutrophil count 
≥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 be used in place of creatinine or CrCl)
≤1.5 × ULN OR ≥30 mL/min for participants with 
creatinine >1.5 × institutional ULN
Hepatic
Total bilirubin
≤1.5 × ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with liver 
metastases)
Coagulation
INR or PT
aPTT
≤1.5 × ULN unless the participant is receiving 
anticoagulants, as long as PT or aPTT is within the 
therapeutic range for intended use of anticoagulants
Abbreviations: ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); 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 (see Appendix 7) and guidelines for administration of specific 
chemotherapies.
a
This criterion must be met without erythropoietin dependency and without packed red blood cell transfusion within 
the last 2 weeks.
b
CrCl should be calculated per the institutional standard.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant meets any of the following 
criteria:
Prior/Concomitant Therapy
1. Has received docetaxel as monotherapy or in combination with other therapies.
2. Has received lenvatinib as monotherapy or in combination with an anti-PD-1/PD-L1 
mAb.
3. Has received radiotherapy within 2 weeks before the first dose of study intervention or 
has received lung radiation therapy >30 Gy within 6 months before the first dose of study 
intervention.
Note: Participants must have recovered to Grade 1 or less from all radiation-related 
toxicities, must not require corticosteroids, and must not have had radiation pneumonitis.
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4. Has received a live vaccine within 30 days before the first dose of study intervention.
Note: Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–
Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are 
generally killed virus vaccines and are allowed; however, intranasal influenza vaccines 
(eg, FluMist®) are live attenuated vaccines and are not allowed.
Medical Conditions
5. 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.
6. Has radiographic evidence of intratumoral cavitation, encasement, or invasion of a major 
blood vessel. Additionally, the degree of proximity to major blood vessels should be 
considered for exclusion because of the potential risk of severe hemorrhage associated 
with tumor shrinkage/necrosis after 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.
7. Has clinically significant cardiovascular impairment within 12 months of the first dose of 
study intervention, such as history of congestive heart failure greater than New York 
Heart Association Class II, unstable angina, myocardial infarction or cerebrovascular 
accident/transient ischemic attack (TIA)/stroke, cardiac revascularization, or cardiac 
arrhythmia associated with hemodynamic instability.
Note: Medically controlled arrhythmia that is stable with medication is permitted.
8. Has a history of a gastrointestinal condition or procedure that, in the opinion of the 
investigator, may affect oral study intervention absorption.
9. Has a pre-existing ≥Grade 3 gastrointestinal or non-gastrointestinal fistula.
10. Is a WOCBP who has a positive urine pregnancy test within 24 hours or a positive serum 
pregnancy test within 72 hours before randomization (see Appendix 5).
Note: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required. If 24 hours have elapsed between the screening urine (or 72 hours 
for a screening serum 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/Concurrent Clinical Study Experience
11. Is currently participating in a clinical trial and receiving study therapy or participated in a 
study of an investigational agent within 4 weeks of the first dose of study intervention.
Note: Participants who have entered the survival follow-up phase (due to PD) in an 
investigational study with a PD-1/PD-L1 inhibitor may participate in this study if it has 
been >4 weeks since the last dose of treatment and the participant meets the entry criteria 
for the study.
Note: The 4-week window should also be applied to the last dose of antineoplastic 
investigational agent or last use of an investigational device with antineoplastic intent.
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Note: Participants must have resolution of toxic effect(s) of the most recent therapy (eg, 
chemotherapy) to Grade 1 or less (except alopecia). If participants underwent major 
surgery within 3 weeks prior to the first dose of study intervention, they must have 
recovered from any toxicity and/or complications from the intervention. Adequate wound 
healing after major surgery must be assessed clinically, independent of time elapsed for 
eligibility.
Diagnostic Assessments
12. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 
(exceeding 10 mg of prednisone or equivalent daily) or any other form of 
immunosuppressive therapy within 7 days before the first dose of study intervention.
13. Has a known history of an additional malignancy, except if the participant has undergone 
potentially curative therapy with no evidence of disease recurrence for 3 years since 
initiation of that therapy.
Note: The requirement for no evidence of disease for 3 years does not apply to the 
NSCLC for which a participant is enrolled in the study. This 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.
14. Has known active central nervous system metastases and/or carcinomatous meningitis.
Note: Participants with previously treated brain metastases may be enrolled in the study 
provided they are radiologically stable (ie, without evidence of progression for at least 4 
weeks by repeat imaging [repeat imaging should be performed during study screening]), 
are clinically stable, and are without requirement for steroid treatment for at least 14 days 
before the first dose of study intervention.
15. Has severe hypersensitivity (Grade ≥3) to pembrolizumab and/or any of its excipients.
16. Has a sensitivity to any of the excipients contained in lenvatinib.
17. Has a sensitivity to any of the excipients contained in docetaxel.
18. Has an active autoimmune disease that has required systemic treatment in the past 2 years 
(ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs).
Note: Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency) is not considered a form of 
systemic treatment and is allowed.
19. Has a history of (noninfectious) pneumonitis that required systemic steroids or current 
pneumonitis/interstitial lung disease.
20. Has an active infection requiring systemic therapy.
21. Has a known history of human immunodeficiency virus (HIV) infection.
Note: No HIV testing is required unless mandated by the local health authority (see 
Appendix 7).
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22. Has a known history of hepatitis B (defined as hepatitis B surface antigen [HbsAg])
reactive or known active hepatitis C virus (HCV) (defined as HCV RNA [qualitative] is 
detected) infection.
Note: No testing for hepatitis B and hepatitis C is required unless mandated by the local 
health authority (see Appendix 7).
23. Has active tuberculosis.
24. 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 
participation 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.
25. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
26. Has a left ventricular ejection fraction (LVEF) below the institutional normal range, as 
determined by multigated acquisition (MUGA) or echocardiogram (ECHO).
27. Has QT interval corrected with Fridericia’s formula (QTcF) prolongation to >480 ms.
28. Participants with proteinuria ≥2+ (≥100 mg/dL) on urine dipstick testing/urinalysis will 
undergo 24-hour urine collection for quantitative assessment of proteinuria. Participants
with urine protein ≥1 g/24 h will be ineligible.
Other Exclusions
29. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through at least 120 days 
after the last dose of pembrolizumab or lenvatinib, or 90 days (for male participants) and 
30 days (for female participants) after the last dose of docetaxel.
Note: If the contraception requirements in the local label for any of the study 
interventions are more stringent than the requirements above, the local label requirements 
are to be followed.
30. Has had an allogeneic tissue/solid organ transplant.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
5.3.2
Pregnancy
If a participant inadvertently becomes pregnant while receiving study intervention, she will 
be immediately discontinued from study intervention. The site will contact the participant at 
least monthly and document her 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 
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or life-threatening complication in 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.
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.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (pembrolizumab, lenvatinib, and docetaxel) 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.
Note: In alignment with the study-specific investigator letter dated 22-SEP-2023, all study 
participants still receiving study treatment should continue to receive therapy on study and 
undergo modified protocol study procedures as specified in this amendment. Participants 
currently on study treatment with lenvatinib or docetaxel can continue treatment per 
investigator’s discretion. Participants who are potential candidates for Second Course 
treatment will continue in Efficacy Follow-up.
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Table 2
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Arm 1
Experimental Pembrolizumab Drug
Solution
25 mg/mL
200 mg
IV Infusion
Q3W
Test 
Product
IMP
Central
Arm 1
Experimental Lenvatinib
Drug
Capsule
10 mg
4 mg
20 mg
Oral
QD
Test 
Product
IMP
Central
Arm 2
Active 
Comparator
Docetaxel
Drug
Solution
20 mg/ mL
75 mg/m2 IV Infusion
Q3W
Comparator IMP
Provided 
centrally 
by the 
Sponsor 
or locally 
by the 
study 
site, sub-
sidearm, 
or 
designee
Arm 3
Experimental Lenvatinib
Drug
Capsule
10 mg
4 mg
24 mg
Oral
QD
Test 
Product
IMP
Central
EEA=European Economic Area; IMP=investigational medicinal product; IV=intravenous; NA=not applicable; NIMP/AxMP=noninvestigational/auxiliary medicinal product; 
Q3W=every 3 weeks; QD=once daily.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences
with respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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All supplies indicated in Table 2 will be provided per the “Sourcing” column depending on 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.1.1
Medical Devices
Not applicable.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details of the preparation, storage, and administration of pembrolizumab are provided in the 
Pharmacy Manual.
Lenvatinib is provided as capsules for oral administration and does not require preparation. If 
a lenvatinib dose is missed and cannot be taken within 12 hours of the scheduled dosing 
time, the participant should skip this dose and take the next dose at the scheduled time 
the next day.
Docetaxel will be prepared and administered as per the approved local product label.
Docetaxel 75 mg/m2 will be administered as an IV infusion over 1 hour Q3W. All 
participants randomized to docetaxel should be premedicated with oral or injectable steroids 
for 3 days starting 1 day prior to docetaxel administration to reduce the risk of fluid retention 
and the severity of hypersensitivity reactions (or according to the approved product label). 
Additional premedications may be administered as per standard practice.
See the Pharmacy Manual for additional information.
The rationale for selection of doses to be used in this study is in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
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The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention allocation/randomization will occur centrally using an IRT system. There are 3
study intervention arms. Participants will be assigned randomly in a 4:4:1 ratio to the 
pembrolizumab + lenvatinib arm, docetaxel arm, or the lenvatinib monotherapy arm, they 
will receive a randomization number.
6.4
Stratification
Stratification factors are as follows:
•
Anti-PD-1/PD-L1 mAb (immediate prior therapy versus not the immediate prior therapy)
•
PD-L1 TPS (<50% versus ≥50%)
•
ECOG performance status (0 versus 1)
6.4.1
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered for an individual participant.
Although the trial is an open-label study, with analyses or summaries generated by study 
intervention assignment, access to the information on actual study intervention received will 
be limited and documented.
The treatment-level results of the interim analyses will not be shared with the investigator 
before completion of the study.
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6.4.1.1
TPS Results
Individual PD-L1 status will not be disclosed to the sites and study participants. Analyses by 
PD-L1 biomarker status will be limited and documented.
If TPS score is nonevaluable, the participant will be stratified into the <50% group.
6.5
Study Intervention Compliance
Interruptions from the protocol-specified treatment plan for >28 days for lenvatinib or >12 
weeks for pembrolizumab or docetaxel require consultation between the investigator and the 
Sponsor and written documentation of the collaborative decision on participant management.
6.6
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 
that is specifically prohibited, discontinuation from study intervention may be required. The 
investigator should discuss any questions regarding this with the Sponsor. 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.
Medication considered necessary for the participant’s health and not expected to interfere 
with the evaluation of or interact with the study intervention may be continued during the 
study. Palliative and supportive care is permitted during the study for underlying medical 
conditions and symptom management. Surgery or radiotherapy for tumor control is not 
permitted during the study.
All prior and concomitant medications (including over-the-counter medications) received 
within 30 days before the first dose of study intervention and during the course of the study 
(starting at the date of documented informed consent) until 30 days after the last dose of 
study intervention at the Safety Follow-up visit (or 90 days after the last dose of study 
intervention if used to treat an SAE) should be recorded on the appropriate electronic case 
report form (eCRF). The investigator will record the AE for which the concomitant 
medication/therapy was administered on the appropriate eCRF. If the concomitant 
medication/therapy is being administered for a medical condition present at the time of entry 
into the study, the investigator will record the medical condition on the appropriate eCRF.
After the Safety Follow-up visit, record all medications taken for SAEs and events of clinical 
interest (ECIs) as defined in Section 10.3.
Note: Information on all prior anticancer agents will be collected and recorded on
the eCRF during the Screening Visit (eg, 1L, 2L, 3L, etc.).
If a participant enters the Second Course, all concomitant medications received within 
30 days before the first dose of Second Course treatment should be recorded. After the 
Second Course Safety Follow-up visit, record all medications received for SAEs and ECIs as 
defined in Section 10.3.
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Additionally, all diagnostic, therapeutic, or surgical procedures relating to malignancy should
be recorded.
6.6.1
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. Anti-emetic or any other prophylaxis should be 
considered in accordance with institutional guidelines.
The following concomitant medications are also allowed:

Premedication and postmedication for docetaxel administration

Hormone replacement therapy

Thyroid hormone suppressive therapy

Anticoagulants, including low molecular weight heparin, warfarin, anti-Xa agents

Anti-inflammatory agents

Bisphosphonates or denosumab

Antihypertensive therapy (including additional antihypertensive treatment as appropriate 
if BP increases once the participant is enrolled)
Note: Any additional procedural or participant-specific particularities should be 
discussed with the investigator and the Sponsor.
6.6.2
Prohibited Concomitant Medications
Participants are prohibited from receiving the following therapies during the screening and 
treatment periods of this study:

Concurrent anticancer therapies such as chemotherapy, targeted therapies, antitumor 
interventions (surgical resection, surgical tumor debulking, 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 vaccines within 30 days before the first dose of study intervention and while 
participating in the study (see exclusion criterion 4 for examples).
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
Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
immune-related AE (Section 6.6.3.1), as premedication or postmedication for docetaxel, 
as premedication before CT scanning in participants with contrast allergy, or for 
exacerbations of chronic obstructive pulmonary disease requiring steroids for recovery. 
Replacement doses of steroids (eg, prednisone 10 mg daily) are permitted during the 
study. Note: Inhaled steroids are allowed for management of asthma or seasonal 
allergies. See Section 6.5.4.1 for additional information.

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 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 in the 
follow-up period.
6.6.3
Drug Interactions
There are no DDI-related concomitant medication prohibitions or restrictions.
Lenvatinib is not expected to produce a clinically meaningful alteration in 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 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 their 
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 non-enzymatic processes (lenvatinib IB).
6.6.4
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.
For participants receiving pembrolizumab plus lenvatinib, suggested supportive care 
measures for the management of AEs with potential immunologic etiology are outlined in 
Table 4 in Section 6.6.3.1 along with the dose modification guidelines in Table 3 in Section 
6.6.2.
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Where appropriate, these guidelines include the use of oral or IV corticosteroids, as well as
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids. Note that several courses of steroid tapering may be necessary, as symptoms 
may worsen when the steroid dose is decreased. For each disorder, attempts should be made 
to rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied when 
the investigator determines the events to be related to pembrolizumab or lenvatinib.
Note: If, after the evaluation of an event, it is determined not to be related to 
pembrolizumab or lenvatinib, the investigator does not need to follow the treatment 
guidance. Refer to Table 3 for guidelines regarding dose modification and supportive 
care.
Participants in the docetaxel arm should receive premedication with corticosteroids for 
3 days before docetaxel administration to reduce the risk of fluid retention and the severity of 
hypersensitivity reactions.
Refer to the approved product label for docetaxel dose interruptions and dose reductions.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of the evaluation of an event.
6.6.4.1
Systemic Corticosteroid Use
Systemic corticosteroids are permitted in the following situations:
•
For treatment of potential immune-related adverse events (irAEs), as indicated in Table 4.
•
As premedication for docetaxel administration.
•
As pre- or postmedication to prevent AEs associated with IV contrast material.
•
As considered necessary for a participant’s medical condition.
•
Brief, limited use (≤7 days) of systemic corticosteroids is permitted when considered 
SOC (eg, for exacerbation of chronic obstructive pulmonary disease).
Replacement doses of steroids (eg, prednisone 10 mg daily) are permitted during the study, 
as are local steroid injections and topical steroids.
6.7
Dose Modification (Escalation/Titration/Other)
6.7.1
Concomitant Combination Therapy
If either pembrolizumab is interrupted for >12 weeks (irAE) or >3 weeks (administrative 
reasons) or lenvatinib is interrupted for 28 consecutive days, the site must gain approval from 
the Sponsor prior to restarting treatment. Participants who must interrupt or discontinue 1 
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drug in the combination due to drug-related AEs may continue with the other drug in the 
combination until criteria for treatment discontinuation are met (eg, PD).
6.7.2
Lenvatinib Dose Modification and Toxicity Management
Lenvatinib dose reduction and interruption for participants who experience pembrolizumab + 
lenvatinib therapy-related toxicity will be in accordance with the dose modification 
guidelines described in Table 3. An interruption of study intervention for more than 28 days 
will require Sponsor approval before study intervention can be resumed.
AEs will be graded using NCI CTCAE, version 4.0. Investigators will decide the probability 
of events being related to 1 or both drugs to determine whether dose modification of 1 or 
both drugs is required.
The starting dose of lenvatinib is 20 mg/day for participants enrolled in the combination 
treatment arm (Arm 1). Lenvatinib dose reductions will take place in succession based on the 
previous dose level (14, 10, and 8 mg/day). Any dose reduction below 8 mg/day must be 
discussed with the Sponsor.
The starting dose of lenvatinib is 24 mg/day for participants enrolled in the monotherapy 
treatment arm (Arm 3). Lenvatinib dose reductions for Arm 3 will take place in succession 
based on the previous dose level (20, 14, and 10 mg/day). Any dose reduction below 
10 mg/day must be discussed with the Sponsor.
For both Arm 1 and Arm 3, once the dose has been reduced, it may not be increased at a later 
date unless the dose has been mistakenly decreased; in this situation, the Sponsor’s approval 
is required to increase the dose.
Refer to the sections below for management of hypertension (Section 6.6.2.1), proteinuria 
(Section 6.6.2.2), diarrhea (Section 6.6.2.3), hepatotoxicity (Section 6.6.2.4), 
thromboembolic events (Section 6.6.2.5), posterior reversible encephalopathy syndrome/ 
reversible posterior leukoencephalopathy syndrome (PRES/RPLS; Section 6.6.2.6), 
hypocalcemia (Section 6.6.2.7), hemorrhage (Section 6.6.2.8), gastrointestinal perforation or 
fistula formation (Section 6.6.2.9), QT prolongation (Section 6.6.2.10) and Osteonecrosis of 
the Jaw (Section 6.6.2.11) as appropriate, before consulting the dose modification table 
(Table 3). For overlapping toxicities of pembrolizumab and lenvatinib, refer to Section 6.6.4.
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Table 3
Dose Modification Guidelines for Lenvatinib-Related Adverse Events
Treatment-Related Toxicitya,b
Management
Dose Adjustment
Grade 1 or Tolerable Grade 2
Continue treatment
No change
Intolerable Grade 2c,d or Grade 3e
First occurrence
Interrupt lenvatinib until resolved 
to Grade 0-1 or tolerable Grade 2
Arm 1: Reduce lenvatinib dose 
from 20 mg QD to 14 mg QD 
(1-level reduction)
Arm 3: Reduce lenvatinib dose 
from 24 mg QD to 20 mg QD 
(1-level reduction) 
Second occurrence (same 
toxicity or new toxicity)
Interrupt lenvatinib until resolved 
to Grade 0-1 or tolerable Grade 2
Arm 1: Reduce lenvatinib dose 
from 14 mg QD to 10 mg QD 
(1-level reduction)
Arm 3: Reduce lenvatinib dose 
from 20 mg QD to 14 mg QD 
(1-level reduction)
Third occurrence (same toxicity 
or new toxicity)
Interrupt lenvatinib until resolved 
to Grade 0-1 or tolerable Grade 2
Arm 1: Reduce lenvatinib from 
10 mg QD to 8 mg QD (1-level 
reduction)
Arm 3: Reduce lenvatinib dose 
from 14 mg QD to 10 mg QD 
(1-level reduction)
Fourth occurrence (same toxicity 
or new toxicity)
Interrupt lenvatinib
Discuss with Sponsor
Grade 3 AE of thromboembolic events or Grade 4 AEsf: Permanently discontinue lenvatinib.
Abbreviations: AE = adverse event; BMI = body mass index; CTCAE = Common Terminology Criteria for Adverse 
Events; QD = once daily.
Note: For grading, see NCI CTCAE, version 4.0. Collect all AE grades (ie, decreasing and increasing NCI CTCAE 
grades).
a.
An interruption of lenvatinib for more than 28 days will require the Sponsor’s approval before lenvatinib can be 
resumed.
b.
Initiate optimal medical management for nausea, vomiting, hypertension, hypothyroidism, and/or diarrhea before 
any lenvatinib interruption or dose reduction.
c.
Applicable only to Grade 2 toxicities judged by the participant and/or physician to be intolerable.
d.
Obese participants (BMI≥30) with weight loss do not need to return to their baseline weight or 10% of baseline 
weight (ie, Grade 1 weight loss). These participants will restart lenvatinib at a lower dose once their weight remains 
stable for at least 1 week and they reach at least a BMI of 25. The new stable weight should be used as the new 
baseline for further dose reductions.
e.
For asymptomatic laboratory abnormalities, such as Grade≥3 elevations of amylase and lipase that are not 
considered clinically relevant by the investigator, continuation of lenvatinib should be discussed with the Sponsor.
f.
Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3.
6.7.2.1
Management of Hypertension
Hypertension is a recognized side effect of treatment with drugs inhibiting VEGF signaling. 
Investigators should therefore ensure that participants enrolled to receive pembrolizumab + 
lenvatinib must have BP ≤150/90 mm Hg at the time of study entry and, if known to be 
hypertensive, have been taking a stable dose of antihypertensive medication for at least 
1 week before C1D1. Early detection and effective management of hypertension are 
important to minimize the need for lenvatinib dose interruptions and reductions.
BP should be regularly assessed as detailed in the SoA (Section 1.3). Hypertension will be 
graded using NCI CTCAE, version 4.0, based on BP measurements only, and not on the 
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number of antihypertensive medications. If the participant’s initial BP is elevated (ie, systolic 
BP ≥140 mm Hg or diastolic BP ≥90 mm Hg), BP measurement should be repeated at least 
5 minutes later.
One BP assessment is defined as the mean value of 2 measurements at least 5 minutes apart. 
If the BP (ie, the mean of the 2 BP measurements obtained at least 5 minutes apart) is 
elevated (systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg), a confirmatory assessment 
should be obtained at least 30 minutes later by performing 2 measurements at least 5 minutes 
apart to yield a mean value.
Antihypertensive agents should be started as soon as elevated BP (systolic BP ≥140 mm Hg 
or diastolic BP ≥90 mm Hg) is confirmed at 2 assessments at least 30 minutes apart. The 
choice of antihypertensive treatment should be individualized to the participant’s clinical 
circumstances and follow standard medical practice. For previously normotensive 
participants, appropriate antihypertensive therapy should be started when systolic BP 
≥140 mm Hg or diastolic BP ≥90 mm Hg is first observed at 2 assessments at least 
30 minutes apart. For participants already taking antihypertensive medication, treatment 
modification may be necessary if hypertension persists.
Lenvatinib should be withheld in any instance where a participant is at imminent risk of 
developing a hypertensive crisis or has significant risk factors for severe complications of 
uncontrolled hypertension (eg, BP ≥160/100 mm Hg, significant risk factors for cardiac 
disease, intracerebral hemorrhage, or other significant comorbidities). Once the participant 
has been taking the same antihypertensive medications for at least 48 hours and BP is 
controlled, lenvatinib should be resumed as described below.
Participants who have had systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg must have 
their BP monitored on Day 15 of the current cycle (or more frequently as clinically indicated) 
until systolic BP has been ≤150 mm Hg and diastolic BP has been ≤95 mm Hg for 
2 consecutive treatment cycles. If a repeat event of systolic BP ≥160 mm Hg or diastolic BP 
≥100 mm Hg occurs, the participant must resume Day 15 evaluations until systolic BP has 
been ≤150 mm Hg and diastolic BP has been ≤95 mm Hg for 2 consecutive treatment cycles. 
Participants will have the option of having BP measurements between visits obtained locally 
by a health care professional. A diary will be provided as a tool to aid participants in 
collecting BP evaluations between study visits. The participant will bring the BP diary to the 
clinic at each visit; BP measurements will be recorded in the participant’s chart and eCRF.
The following guidelines should be followed for the management of systolic BP ≥160 mm 
Hg or diastolic BP ≥100 mm Hg confirmed at 2 BP assessments at least 30 minutes apart:
1. Continue lenvatinib and institute antihypertensive therapy for participants not already 
receiving this therapy.
2. For participants already taking antihypertensive medication, the dose of the current agent 
may be increased if appropriate, or 1 or more antihypertensive agents in a different class 
should be added. Study intervention can be continued without lenvatinib dose 
modification.
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3. If systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg persists despite maximal 
antihypertensive therapy, lenvatinib administration should be interrupted and restarted at 
1 dose level reduction only when systolic BP is ≤150 mm Hg and diastolic BP is ≤95 mm 
Hg and the participant has been receiving a stable dose of antihypertensive medication 
for at least 48 hours.
-
If systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg recurs at the first lenvatinib 
dose reduction despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or addition of a different class of 
antihypertensive), lenvatinib administration should be interrupted and restarted at an 
additional dose reduction only when systolic BP is ≤150 mm Hg and diastolic BP is 
≤95 mm Hg, and the participant has been receiving a stable dose of antihypertensive 
medication for at least 48 hours.
-
If systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg recurs at the second 
lenvatinib dose reduction despite optimal management of hypertension with 
antihypertensive medications (either by dose increase or the addition of a different 
class of antihypertensive), lenvatinib administration should be interrupted and 
restarted at a third dose reduction only when systolic BP is ≤150 mm Hg and diastolic 
BP is ≤95 mm Hg and the participant has been receiving a stable dose of 
antihypertensive medication for at least 48 hours.
-
Additional dose reduction should be discussed with the Sponsor.
The following guidelines should be followed for management of Grade 4 hypertension 
(life-threatening consequences):
a.
Institute appropriate medical management.
b. Discontinue lenvatinib.
6.7.2.2
Management of Proteinuria
Proteinuria should be regularly assessed as detailed in the SoA (Section 1.3). Guidelines for
assessment and management of proteinuria are as follows:
Detection and Confirmation
1. Perform urine dipstick or urinalysis testing per the SoA (Sections 1.3.1 and 1.3.3). Urine 
dipstick testing is the preferred method for testing for urinary protein, however, urinalysis 
may be used if the use of urine dipsticks is not feasible.
2. A 24-hour urine collection initiated as soon as possible and at least within 72 hours (or an 
immediate spot urine protein/creatinine ratio [UPCR] test) is required in the following 
situations:
•
The first (initial) occurrence of ≥2+ (≥100 mg/dL) proteinuria on urine dipstick 
testing or urinalysis while the participant is receiving lenvatinib.
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•
A subsequent increase in severity of proteinuria on urine dipstick testing or 
urinalysis at the same lenvatinib dose level.
•
When there has been a lenvatinib dose reduction and at the new dose level the urine 
protein dipstick or urinalysis result is ≥2+ (≥100 mg/dL).
3. A 24-hour urine collection (initiated as soon as possible and at least within 72 hours) to 
verify the grade of proteinuria is required when UPCR is ≥2.4.
Grading of Proteinuria
Grading according to NCI CTCAE, version 4.0, will be based on the 24-hour urinary protein 
result if available. If the participant has 4+ proteinuria by dipstick (≥1000 mg/dL by 
urinalysis), a 24-hour urinary protein result is required to confirm Grade 3 proteinuria.
Management of lenvatinib administration will be based on the proteinuria grade according to
Table 3.
In the event of nephrotic syndrome, lenvatinib must be discontinued.
Monitoring
Urine dipstick or urinalysis testing for participants with ≥2+ (≥100 mg/dL) proteinuria should 
be performed on Day 15 (or more frequently as clinically indicated) until results have been 
1+ (30 mg/dL) or negative for 2 consecutive treatment cycles (see Section 8.3.5.1.2 for 
additional details).
Monitoring of proteinuria may be performed by the local laboratory or at the investigator site 
but must be managed by the site physician.
6.7.2.3
Management of Diarrhea
An antidiarrheal agent should be recommended to participants at the start of study 
intervention, and participants should be instructed and educated to initiate antidiarrheal 
treatment at the first onset of soft bowel movements. The choice of antidiarrheal agent should 
be individualized to the participant’s clinical circumstances and should follow standard 
medical practice. If signs/symptoms of diarrhea persist despite optimal medical management, 
the instructions in Table 3 should be followed. For overlapping toxicities of pembrolizumab 
and lenvatinib, please refer to Section 6.6.4.
6.7.2.4
Management of Hepatotoxicity
LFTs (alanine aminotransferase [ALT], aspartate aminotransferase [AST], bilirubin) should 
be performed as detailed in the SoA (Section 1.3) and as clinically indicated. If 
signs/symptoms indicating liver injury occur, the instructions in Table 3 should be followed. 
Appropriate supportive care should be provided together with close monitoring. If hepatic 
failure occurs, lenvatinib must be discontinued. Hepatic failure is defined as the CTCAE 
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definition. For overlapping toxicities of pembrolizumab and lenvatinib, please refer to 
Section 6.6.4.
6.7.2.5
Management of Thromboembolic Events
Participants should be advised to pay attention to symptoms suggestive of venous 
thromboembolic events, including acute onset of shortness of breath, dyspnea, chest pain, 
cough, hemoptysis, tachypnea, tachycardia, cyanosis, and deep vein thrombosis signs (lower 
extremity swelling and warmth to touch or tenderness). If any of these symptoms appear, 
participants should be instructed to report these symptoms promptly to the treating physician. 
If a thromboembolic event is confirmed, the instructions in Table 3 should be followed. 
Appropriate supportive care should be provided together with close monitoring.
If a Grade 3 thromboembolic AE occurs, lenvatinib will be permanently discontinued. If a 
participant experiences a life-threatening (Grade 4) thromboembolic event, including 
pulmonary embolism, lenvatinib must be discontinued. Arterial thromboembolic events (eg, 
new onset of, worsening, or unstable angina, myocardial infarction, TIA, and cerebrovascular 
accident) of any grade require study intervention discontinuation.
6.7.2.6
Management of PRES/RPLS
PRES/RPLS is a neurologic disorder that can present with headache, seizure, lethargy, 
confusion, altered mental function, blindness, and other visual or neurologic disturbances. 
Mild to severe hypertension may be present. MRI is necessary to confirm the diagnosis of 
PRES/RPLS. Appropriate measures should be taken to control BP. In participants with signs 
or symptoms of PRES/RPLS, the instructions in Table 3 should be followed.
6.7.2.7
Management of Hypocalcemia
Serum calcium should be monitored per the SoA (Section 1.3). Corrected serum calcium 
should be used to assess the grade of hypocalcemia per NCI CTCAE, version 4.0, using the 
following formula: corrected calcium = ([4 −serum albumin (g/dL)] × 0.8 + serum calcium). 
This formula is not applicable when serum albumin concentration is normal (˃4 g/dL); if so, 
total (uncorrected) serum calcium should be used instead.
Hypocalcemia should be treated per institutional guidelines (eg, appropriate calcium, 
magnesium, and vitamin D supplementation) until resolution.
6.7.2.8
Management of Hemorrhage
The instructions in Table 3 should be followed for management of hemorrhage. Lenvatinib 
should either be resumed at a reduced dose or discontinued, depending on the severity and 
persistence of hemorrhage.
6.7.2.9
Management of Gastrointestinal Perforation or Fistula Formation
Permanently discontinue lenvatinib in any participant who develops gastrointestinal 
perforation of any grade or Grade 4 fistula.
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6.7.2.10
Management of QT Prolongation
Lenvatinib should be withheld in the event of development of QT interval prolongation 
greater than 500 msec. Lenvatinib should be resumed at a reduced dose when QTc 
prolongation is resolved to <480 msec or baseline. Monitor potassium, calcium and 
magnesium and replenish as appropriate.
6.7.2.11
Management of Osteonecrosis of the Jaw
Perform an oral examination prior to treatment with lenvatinib and periodically during 
lenvatinib treatment. Advise participants regarding good oral hygiene practices. Avoid 
invasive dental procedures, if possible, while on lenvatinib treatment, particularly in 
participants at higher risk. For participants requiring invasive dental procedures, 
discontinuation of bisphosphonate treatment may reduce the risk of ONJ. Withhold 
lenvatinib if ONJ develops and restart based on clinical judgment of adequate resolution (See 
Section 6.6.5).
6.7.3
Pembrolizumab
Pembrolizumab dose reductions are not permitted. Pembrolizumab may be interrupted or 
discontinued due to toxicity. Pembrolizumab may be interrupted for a maximum of 12 weeks 
(Section 6.4).
6.7.3.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated With 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids, and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation.
Based on the severity of irAEs, withhold or permanently discontinue pembrolizumab and 
administer corticosteroids.
Dose Modification and Toxicity Management Guidelines for irAEs Associated With 
Pembrolizumab Monotherapy, Coformulations, or IO Combinations are provided in Table 4.
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Table 4
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.  Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids.
2.  Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last treatment.
3.  The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.  If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 
after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
  Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
  Monitor participants for signs and symptoms of 
pneumonitis
  Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate corticosteroid 
treatment
  Add prophylactic antibiotics for opportunistic 
infections
Recurrent Grade 2 
or Grade 3 or 4 
Permanently 
discontinue
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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 anti-
hyperglycemic 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 non-selective 
beta-blockers (eg, 
propranolol) or thionamides 
as appropriate
  Monitor for signs and symptoms of thyroid disorders
Grade 3 or 4
Withhold or 
Permanently 
discontinue a
Hypothyroidism
Grade 2-4
Continue
  Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care
  Monitor for signs and symptoms of thyroid disorders
Nephritis and 
renal dysfunction
Grade 2
Withhold
  Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by 
taper
  Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1 
Withhold
  Based on severity of AE 
administer corticosteroids
  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(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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6.7.3.2
Dose Modification and Toxicity Management for 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 5.
Table 5
Dose Modification and Treatment Guidelines for Pembrolizumab Infusion 
Reactions
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:
-
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 the drug 
infusion, the infusion may be restarted at 50% of the 
original rate (eg, from 100 mL/h to 50 mL/h). Otherwise, 
withhold dosing 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.
The participant may be 
premedicated 1.5 hours 
(± 30 minutes) before infusion 
of pembrolizumab with:
-
Diphenhydramine 50 mg
PO (or equivalent dose of 
antihistamine).
-
Acetaminophen 500 to 
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 case of anaphylaxis, epinephrine should be used 
immediately.
The 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 = orally.
Appropriate resuscitation equipment should be available at the bedside, and a physician should be readily available 
during drug administration.
For further information, please refer to CTCAE, version 4.0, at http://ctep.cancer.gov
6.7.4
Dose Modification for Overlapping Toxicities
Based on the known toxicity profiles of pembrolizumab and lenvatinib, certain 
treatment-related AEs are uniquely associated with one drug versus the other. For example, 
hypertension, arterial thrombotic events, proteinuria, and hemorrhagic events are known risks 
of lenvatinib treatment, while irAEs are risks of pembrolizumab treatment. However, certain 
AEs, such as diarrhea, hypothyroidism, and liver enzyme elevation, may be initially 
considered attributable to either study intervention. Therefore, evaluation of attribution is 
important for determining the study intervention most likely related to the AE, or an 
alternative etiology, and subsequently proper clinical management. The following aspects 
should be considered:
1. Timing of AE Onset
Since lenvatinib is administered daily and continuously due to a relatively short half-life 
(28 hours) and pembrolizumab is administered Q3W due to a long half-life, lenvatinib 
can be interrupted to assess whether an AE improves/resolves with dechallenge (ie,
interruption of treatment) based on the following 2 scenarios:
•
If an AE is identified during a treatment cycle (ie, between 2 pembrolizumab doses), 
only lenvatinib dose interruption is needed.
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•
If an AE is identified at the beginning of a treatment cycle, lenvatinib can be 
interrupted, and dosing of pembrolizumab should be withheld.
If the participant recovers from an AE in response to lenvatinib interruption (ie, positive 
dechallenge), the event is more likely to be related to lenvatinib. Otherwise, after 
excluding other alternative explanations, an irAE should be considered.
2. Severity of AE
If an AE is suspected to be treatment-related and is severe/life-threatening at the time of 
onset or rapidly worsens, action, including interrupting both drugs and initiating 
treatment with a corticosteroid (with the exception of hypothyroidism and type 1 diabetes 
mellitus) and other supportive care should be taken promptly.
3. Participants receiving the combination therapy (pembrolizumab + lenvatinib) must 
discontinue study therapy if any of the following occur:
a) ALT or AST >5 × ULN for more than 2 weeks
Pembrolizumab will have already been permanently discontinued per Table 4, but 
lenvatinib may be administered at a reduced dose by the time this criterion is met and 
must be permanently discontinued immediately.
b) ALT or AST >3 × ULN and (TBL >2 × ULN or INR >1.5)
Although Table 4 advises pembrolizumab to be withheld (interrupted), and Table 3
advises lenvatinib to have no dose modification or a reduction, if this criterion is met, 
both drugs must be permanently discontinued immediately.
Participants who experience a toxicity that is attributable to lenvatinib should modify, 
interrupt, or discontinue lenvatinib as per the Dose Modification Guidelines for Lenvatinib-
Related Adverse Events, but may continue in the trial receiving pembrolizumab, unless or 
until unacceptability toxicity or progression occurs. Participants who experience a toxicity 
attributable to pembrolizumab should interrupt or discontinue pembrolizumab as per Dose
Modification Guidelines for Pembrolizumab Related Adverse Events, but may continue in 
the trial receiving lenvatinib, unless or until unacceptable toxicity or progression occurs.
6.7.5
Other Allowed Dose Interruptions
If a participant receiving lenvatinib requires surgery during the study, the stopping and 
restarting times for lenvatinib should be as follows:
•
For minor procedures, stop lenvatinib at least 2 days before the procedure and restart it at 
least 2 days afterward, once there is evidence of adequate healing and no risk of bleeding.
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•
For major procedures, stop lenvatinib at least 1 week (5 half-lives) before the surgery and 
restart it at least 2 weeks afterward, once there is evidence of adequate healing and no 
risk of bleeding.
Pembrolizumab may be interrupted for situations other than treatment-related AEs, such as 
medical/surgical events or logistic reasons not related to study therapy. Participants should be 
returned to 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. Imaging should not be delayed for delays in treatment cycles.
6.7.6
Docetaxel
Refer to the approved product label for docetaxel.
6.8
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.9
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study-site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
6.10
Standard Policies
Not applicable.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
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 Section 1.3.
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 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
ALT or AST elevation meeting the following criteria:
o
ALT or AST >5X ULN for more than 2 weeks
•
Pembrolizumab will have already been permanently discontinued per Table 4, but 
lenvatinib may be administered at a reduced dose by the time this criterion is met and 
must be permanently discontinued immediately.
o
ALT or AST >3X ULN and (TBL >2X ULN or INR >1.5)
•
Although Table 4 advises pembrolizumab to be withheld (interrupted), and Table 3
advises lenvatinib to have no dose modification or a reduction, if this criterion is met, 
both drugs must be permanently discontinued immediately.
•
The participant or participant’s legally acceptable representative (see Appendix 7, 
Section 10.7.1) requests to discontinue study intervention.
•
The participant interrupts study intervention administration for more than 28 days for 
lenvatinib or >12 weeks for pembrolizumab or docetaxel, 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 study intervention.
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•
The participant has a confirmed positive serum pregnancy test.
•
PD is radiographically documented and verified by BICR per RECIST 1.1 and, when 
clinically appropriate, confirmed by the site per iRECIST.
-
Note: If a participant has unconfirmed PD and is clinically stable, the assigned 
study intervention per protocol may be continued at the investigator’s discretion 
until PD is confirmed at least 28 days from the date of imaging suggesting PD. If 
subsequent imaging does not confirm PD, the participant should continue to receive 
study intervention and imaging to monitor disease status, as defined in Section 1.3.
•
If a participant has confirmed PD per RECIST 1.1, it is recommended that the participant 
be discontinued from the study unless, in the investigator’s opinion, the participant is 
deriving benefit from study intervention. Clinically stable** participants may continue to 
receive study intervention after consultation with the Sponsor.
•
**Clinical stability is defined as:
−
Absence of symptoms and signs (including worsening of laboratory values) 
indicating clinically significant PD.
−
No decline in ECOG performance status.
−
Absence of PD or progressive tumor at critical anatomic sites (eg, cord 
compression) requiring urgent alternative medical intervention.

The participant has intercurrent illness preventing further administration of study 
intervention.
•
The participant has any progression or recurrence of any malignancy, or any occurrence 
of another malignancy that requires active treatment. Exceptions to secondary 
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 follow-up.
•
The participant has unacceptable toxicities (Section 6.6).
•
Administrative reasons requiring cessation of study intervention.
•
The participant has recurrent Grade 2 pneumonitis.
•
Local treatment guidelines for docetaxel.
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7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
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 Note: A participant is not considered lost to follow-up until the last 
scheduled visit for the individual participant. The missing data for the participant will be 
managed via the prespecified statistical data handling and analysis guidelines.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical (or dental) decisions must be made by an investigator who is a 
qualified physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before providing documented informed consent may be 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.
The maximum amount of blood collected from each participant over the duration of the study 
will be provided in the Laboratory Manual. Repeat or unscheduled samples may be collected
for safety reasons or because of 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 (see Appendix 7, Section 10.7.1) prior to participating in this 
clinical study. 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 study protocol number, study 
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protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed 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, 
site personnel will add the allocation 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
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
is considered to be clinically significant by the investigator. Details regarding the 
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participant’s lung cancer will be recorded separately and not listed as medical history. The 
medical history will also include an assessment of smoking history.
The investigator or qualified designee will obtain prior and current details regarding the 
participant’s lung cancer.
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.
Prior anticancer treatment: The investigator or qualified designee will review and 
record all prior anticancer treatments including systemic treatments, radiation, and 
surgeries, regardless of the time before the first dose of study intervention. This will 
include platinum doublet chemotherapy and anti-PD-1/PD-LI therapy.
8.1.5.2
Concomitant Medications
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).
In addition, medications taken 30 days before the first dose of Second Course study 
intervention, during Second Course treatment, and for 30 days after the last dose of Second 
Course study intervention (or 90 days if used to treat an SAE) will be recorded.
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 study intervention
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 of screening/rescreening visit 
requirements are provided in Section 8.10.1.
8.1.7
Assignment of Allocation 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 randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
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A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Pembrolizumab or docetaxel: Administration of pembrolizumab or docetaxel will be 
witnessed by the investigator and/or study staff and or qualified designee per institutional 
guidelines and procedures.
Lenvatinib: Lenvatinib (20 mg [two 10-mg capsules] in Arm 1 and 24 mg [two 10-mg 
capsules and one 4-mg capsule] in Arm 3) will be administered in the clinic on Day 1 of each 
cycle. In Arm 1 only, lenvatinib will also be administered in the clinic on Day 15 of Cycle 1 
in the initial treatment phase. Lenvatinib will be taken at home (at approximately the same 
time each day) for all non-clinic doses in the initial treatment phase and in the Second Course 
phase.
8.1.8.1
Timing of Dose Administration
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 the infusion time 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 to +10 minutes is permitted (ie, infusion time is 30 minutes: –5min 
/+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.
Lenvatinib: Lenvatinib 20 mg (Arm 1) and 24 mg (Arm 3) will be taken orally once daily 
with water (with or without food) in 21-day cycles. On Day 1 of each cycle, participants in 
Arm 1 will receive lenvatinib 0 to 4 hours after the pembrolizumab infusion.
Participants will take lenvatinib at home on all other non-clinic days. If a lenvatinib dose is 
missed and cannot be taken within 12 hours, that day’s dose should be skipped, and the next 
dose should be taken at the usual time of administration.
Docetaxel: Docetaxel 75 mg/m2 will be administered as a 60-minute IV infusion every 
3 weeks on Day 1 of each 21-day cycle. Sites should make every effort to target the infusion 
time to be as close to 60 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 60 minutes: -5 min/+10 min).
After Cycle 1 Day 1, docetaxel may be administered up to 3 days before or after the 
scheduled Day 1 of each subsequent cycle for administrative reasons.
All participants receiving docetaxel should be premedicated with oral or injectable steroids 
according to the approved product label and/or standard practice. Additional premedications 
should be administered as per standard practice.
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8.1.8.2
Compliance
Pembrolizumab or docetaxel: Administration of pembrolizumab or docetaxel will be 
witnessed by the investigator and/or qualified designee. The total volume of study 
intervention infused will be compared with the total volume prepared to determine 
compliance with each dose administered.
Lenvatinib: Lenvatinib compliance will be calculated by the Sponsor 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.
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.
8.1.10
Participant Blinding/Unblinding
This is an open-label study.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.1.12
Demographics
Participant demographic information will be collected at the screening visit. Demographic 
information includes date of birth (or age), sex, and race/ethnicity.
8.1.13
Subsequent Antineoplastic Treatment
The investigator or qualified designee will review all new antineoplastic treatment initiated 
after the last dose of study intervention. Once new antineoplastic treatment has been initiated, 
the participant will move into survival follow-up. All antineoplastic treatment 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 email.
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8.2
Efficacy Assessments
8.2.1
Tumor Imaging and Assessment of Disease
As of Amendment 09, participants will no longer require tumor response assessments by 
BICR to be performed. Scans will no longer be submitted to the iCRO. Participants should 
continue tumor imaging assessment as assessed by investigator per protocol. Original 
protocol text that is contained in this section has been retained for reference.
The process for collection and transmission of images to the CIV is provided in the Site 
Imaging Manual. CT is strongly preferred for tumor imaging. For the abdomen and pelvis, 
contrast-enhanced MRI may be used when CT with iodinated contrast is contraindicated, or 
when mandated by local practice. MRI is the strongly preferred modality for imaging the 
brain. The same imaging modality, ideally the same scanner, and contrast administration 
should be used for a participant throughout the study to optimize reproducibility of the 
assessment of existing and new tumor burden and improve the accuracy of assessment of 
response or progression based on imaging.
Note: For the purposes of assessing tumor imaging, the term “investigator” refers to the local 
investigator at the site and/or the radiologic reviewer at the site or at an offsite facility.
Participant eligibility will be determined using local assessment (investigator assessment) 
based on RECIST 1.1. All scheduled images for all study participants from the sites will be 
submitted to the CIV. In addition, images (including those via other modalities) that are 
obtained at an unscheduled time point to determine PD, as well as images obtained for other 
reasons, but, which demonstrate radiologic progression, should be submitted to the CIV.
When the investigator identifies radiographic progression per RECIST 1.1, the CIV will 
perform expedited verification of radiologic PD and communicate the results to the trial site 
and Sponsor (see Section 8.2.1.6 and Figure 3). Study intervention should continue until PD 
has been verified. Regardless of whether PD is verified, if the investigator considers the 
participant to have progressed 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 CIV.
8.2.1.1
Pretrial Imaging to Confirm Disease Progression
The site’s study team must have reviewed images from at least 2 dates to confirm that 
radiographic progression has occurred per RECIST 1.1 on or after an anti-PD-1/PD-L1 
treatment. These images will be submitted to the CIV before randomization and should 
include the following:

Imaging prior to anti-PD-1/PD-L1 treatment or an image showing nadir during anti-
PD-1/PD-L1 treatment.

Imaging to determine that radiographic progression has occurred per RECIST 1.1 
within 12 weeks (84 days) from the last dose of an anti-PD-1/PD-L1mAb.
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•
Note: These scans may be from the baseline screening for the study.
The CIV must have received these images before randomization to confirm that the images 
are of diagnostic quality.
8.2.1.2
Initial Tumor Imaging
Initial tumor imaging at screening must be performed within 30 days before the date of 
randomization. The site study team must review screening images to confirm that the 
participant has measurable disease per RECIST 1.1.
Brain imaging will be performed in all participants at screening within 30 days before the 
date of randomization. When brain imaging is performed, MRI should be used if possible. If 
MRI is medically contraindicated, or is medically inappropriate, then CT with contrast is an 
acceptable alternative.
Imaging performed as part of routine clinical management is acceptable for use as screening 
tumor imaging if it is of diagnostic quality, is performed within 30 days before the date of 
randomization, and can be assessed by the CIV.
8.2.1.3
Tumor Imaging During the Study
The first on study imaging assessment should be performed at 6 weeks (42 days +7 days)
and again at 12 weeks (84 days +7 days) from the date of randomization. Subsequent tumor 
imaging should be performed every 6 weeks (42 days ±7 days), or more frequently if 
clinically indicated. After 36 weeks, participants who remain on study intervention will have 
imaging performed every 9 weeks (63 days ±7 days). Following Week 54, participants who 
remain on study intervention will have imaging performed every 12 weeks (84 days 
±7-days). Note: Imaging timing should follow calendar days and not be adjusted for 
delays in cycle starts and/or acquisition of unscheduled imaging. Imaging should 
continue to be performed until PD is identified by the investigator and verified by the CIV
(unless the investigator elects to continue study intervention and follow iRECIST), the start 
of new anticancer treatment, withdrawal of consent, or death, whichever occurs first. All 
supplemental imaging must be submitted to the CIV if imaging shows PD or to support 
response assessments.
Objective response should be confirmed by a repeat local imaging assessment. Tumor 
imaging to confirm PR or CR should be performed at least 4 weeks after the first indication 
of a response is observed. Participants will then return to regular scheduled imaging, starting 
with the next scheduled imaging time point. Participants who have additional imaging for 
confirmation do not need to undergo the next scheduled tumor imaging if it is less than 
4 weeks later; tumor imaging may resume at the subsequent scheduled imaging time point.
Per iRECIST (Section 8.2.1.7), PD should be confirmed by the site 4 to 8 weeks after central 
verification of site-assessed first radiologic evidence of PD in clinically stable participants. 
Participants with unconfirmed PD may continue on study intervention at the discretion of the 
investigator until progression is confirmed by the site, provided they have met the criteria for 
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clinical stability detailed in Section 8.2.1.7. Participants who have confirmatory imaging do 
not need to undergo the next scheduled tumor imaging if it is less than 4 weeks later; tumor 
imaging may resume at the subsequent scheduled imaging time point if participants are 
clinically stable. Participants with confirmed PD per iRECIST, as assessed by the site, will 
discontinue study intervention. Exceptions are detailed in Section 8.2.1.7.
8.2.1.4
End of Treatment and Follow-up Tumor Imaging
As of Amendment 09, further follow-up tumor imaging is only required for participants who 
are candidates for Second Course treatment.
For participants who discontinue study intervention, tumor imaging should be performed at 
the time of study intervention discontinuation (±4-week window). If previous imaging was 
obtained within 4 weeks before the date of discontinuation, imaging at study intervention 
discontinuation is not mandatory. For participants who discontinue study intervention 
because of documented PD, this is the final required tumor imaging if the investigator elects 
not to implement iRECIST. All images should be submitted to the CIV.
For participants who discontinue study intervention without documented PD, every effort 
should be made to continue monitoring disease status by tumor imaging using the same 
imaging schedule as during study intervention (every 6 weeks until Week 36, every 9 weeks 
until Week 54, and then every 12 weeks or more frequently if clinically indicated), until the 
start of new anticancer treatment, PD, pregnancy, death, withdrawal of consent, or the end of 
the study, or notification by the Sponsor, whichever occurs first.
8.2.1.5
Second Course Retreatment Tumor Imaging
Tumor imaging must be performed within 30 days before Second Course Cycle 1 of 
pembrolizumab. Local investigator assessment with site radiology department reading will be 
used to determine eligibility for Second Course treatment. All Second Course images should 
be submitted to the CIV for quality control, storage, and possible retrospective review.
The first on study imaging assessment should be performed 12 weeks (84 ±7 days) after 
Cycle 1. Subsequent tumor imaging should be performed every 12 weeks (±7 days) or more 
frequently, if clinically indicated.
Per iRECIST (Section 8.2.1.7), if tumor imaging shows initial PD, tumor assessment should 
be repeated 4 to 8 weeks later to confirm PD with the option of continuing study intervention
while awaiting radiologic confirmation of PD. Participants who have confirmatory imaging 
do not need to undergo scheduled tumor imaging if it is less than 4 weeks later and may wait 
until the next scheduled imaging time point if they are clinically stable.
Imaging should continue until PD, the start of new anticancer treatment, pregnancy, 
withdrawal of consent, death, or notification by the Sponsor, whichever occurs first. In 
clinically stable participants, PD may be confirmed by the investigator using iRECIST 4 to 8 
weeks after the first tumor imaging that indicates PD.
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For participants who discontinue Second Course treatment, tumor imaging should be 
performed at the time of study intervention discontinuation (±4 weeks). If previous imaging 
was obtained within 4 weeks before the date of discontinuation, imaging at study intervention 
discontinuation is not mandatory. For participants who discontinue study intervention due to 
documented PD, this is the final required tumor imaging.
For participants who discontinue Second Course treatment without documented PD, every 
effort should be made to continue monitoring disease status with imaging every 12 weeks 
(±7 days) until the start of a new anticancer treatment, PD, death, withdrawal of consent, or 
the end of the study, or notification by the Sponsor, whichever occurs first.
8.2.1.6
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 allows a maximum of 10 target lesions 
in total and 5 per organ if clinically relevant, to enable a broader sampling of tumor burden. 
Initial tumor imaging showing site-assessed PD should be submitted immediately for BICR 
verification of PD. The site will be notified if BICR verifies PD using RECIST 1.1.
Figure 3 illustrates the imaging flow involving verification of PD for clinically stable 
participants.
8.2.1.7
iRECIST Assessment of Disease for Immune-based Therapeutics
iRECIST is based on RECIST 1.1 but is adapted to account for the unique tumor response 
seen with immunotherapeutic drugs. iRECIST will be used by the investigator to assess 
tumor response and progression and make treatment decisions. When clinically stable**, 
participants should not be discontinued until PD is confirmed by the investigator working 
with the local radiologist, according to the rules outlined in Appendix 8. This allowing of 
continued treatment despite initial radiologic PD takes into account the observation that some 
participants can have a transient tumor flare in the first few months after the start of 
immunotherapy and can then experience subsequent disease response. These data will be 
captured in the clinical database.
Tumor flare includes any of the following scenarios:
•
Worsening of existing target lesion(s)
•
Worsening of existing nontarget lesion(s)
•
Development of new lesions(s)
**Clinical stability is defined as the following:
•
Absence of symptoms and signs indicating clinically significant PD
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•
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 imaging for 
confirmation of PD by iRECIST.
If the investigator decides to continue study intervention, the participant may continue 
receiving study intervention, and tumor assessment should be repeated 4 to 8 weeks later to 
confirm PD by iRECIST, per investigator assessment. Images should continue to be sent to 
the CIV for retrospective BICR.
If repeat imaging does not confirm PD per iRECIST as assessed by the investigator, and the 
participant continues to be clinically stable, study intervention may continue and follow the 
regular imaging schedule. If PD is confirmed, the participant will be discontinued from study 
intervention.
If a participant has confirmed radiographic PD as defined in Appendix 8, study intervention
should be discontinued. However, if the participant is achieving 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, imaging should 
continue at the intervals outlined in Section 1.3, and images should be submitted to the CIV.
A description of the adaptations and iRECIST process is provided in Appendix 8, with 
additional details in the iRECIST publication [Seymour, L., et al 2017]. A summary of 
imaging and treatment requirements after first radiologic evidence of progression is provided 
in Table 6 and illustrated as a flow chart in Figure 3.
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Table 6
Summary of Imaging and Treatment Requirements After First Radiologic Evidence of Disease 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 
investigator’s discretion and 
after obtaining participant’s 
consent.
Submit the imaging to BICR 
for verification.
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: BICR = blinded independent central review; CIV = central imaging vendor; iCPD = iRECIST-confirmed progressive disease; iCR = iRECIST-confirmed
complete response; iPR = iRECIST-confirmed partial response; iRECIST = modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; 
iSD = iRECIST-confirmed stable disease; iUPD = iRECIST-unconfirmed progressive disease; PD = progressive disease; RECIST 1.1 = Response Evaluation Criteria in 
Solid Tumors 1.1; VOP = verification of progression.
Note: If PD has been centrally verified, further management is by the site, based on iRECIST. Any further images should still be submitted to the CIV, but no rapid review 
will occur. If RECIST 1.1 PD has not been centrally verified, ideally the site should continue study intervention. Whether or not study intervention continues, images
should be collected and submitted to the CIV with VOP request until RECIST 1.1 PD is verified by BICR.
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Figure 3
Imaging and Treatment for Clinically Stable Participants Treated With 
Pembrolizumab After First Radiologic Evidence of Progressive Disease Assessed by the 
Investigator
8.2.1.8
Tumor Tissue Collection
The archival tumor tissue sample is a sample obtained any time from initial diagnosis of 
NSCLC and prior to receiving immunotherapy (anti-PD-1/PD-L1 mAb) and is to be 
submitted before randomization for PD-L1 status and stratification.
The newly obtained tissue biopsy is a sample obtained after completion of immunotherapy 
(anti-PD-1/PD-L1 mAb) from a core or excisional biopsy of a tumor lesion not previously 
irradiated (fine-needle aspiration is not adequate) submitted to a central laboratory before 
randomization. No systemic anticancer therapy may be administered between the newly 
obtained tissue sample and initiation of study treatment.
Note: Submission of FFPE tumor tissue blocks are preferred. If unstained slides are 
submitted, they should be freshly cut and submitted to the testing laboratory within 
14 days from the section date; otherwise, a new specimen will be requested.
The investigator and participant will be blinded to the central vendor PD-L1 TPS results. 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 study interventions are hypothesized to provide benefit regardless 
of TPS.
Rationale for archival and newly obtained tissue biopsy: Evaluating the differences 
between archival and newly obtained biopsies at the molecular level may help provide
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information on the underlying biology contributing to resistance mechanisms associated with 
immune-checkpoint inhibitors. It is hypothesized that patients who are refractory to immune-
checkpoint inhibitors may harbor certain biological characteristics such as increased
angiogenesis and epithelial-mesenchymal transition/stroma signaling. Analysis examining 
both an archival and a newly obtained tumor sample with prior information on the outcome 
of treatment with checkpoint inhibitors could help confirm if these possible resistance 
features exist and may help explain how some patients are more likely to benefit from 
pembrolizumab (anti-PD-1) + lenvatinib (VEGFR inhibitor) combination therapy.
8.2.2
Patient-reported Outcomes
As of Amendment 09, participants who are still on study treatment will no longer require 
ePRO assessments. Original protocol text that is contained in this section has been retained 
for reference.
Collection of ePRO data is required for all participants, as noted in the SoA (Section 1.3.1 
and Section 1.3.2). 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: 1) EORTC QLQ-C30; 2) EORTC QLQ-LC13; 3) EQ-5D-
5L. The questionnaires should be administered before dosing:
•
At every cycle through Cycle 17
•
At every other cycle through Cycle 35 (eg, Cycles 1-17, 19, 21, 23, 25, 27, 29, 31, 33, 
and 35)
•
At the End of Treatment (EOT) visit
•
At the 30-day Safety Follow-up visit
If the EOT visit takes place ≥30 days after the last dose of study intervention and is 
combined with the Safety Follow-up visit, PRO assessments only need to be performed at 
that visit.
It is best practice and strongly recommended that electronic patient-reported outcomes 
(ePROs) be determined for randomized participants before study intervention administration, 
AE evaluation, and disease status notification. If a participant does not complete the ePRO 
instruments at a scheduled time point, the MISS_MODE form must be completed to capture 
the reason that this assessment was not performed.
8.3
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
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8.3.1
Physical Examinations
During the screening period, a complete physical examination including oral examination 
will be performed by an investigator or medically qualified designee (consistent with local 
requirements) per the institutional standard as specified in the SoA (Section 1.3). Height and 
weight will also be measured and recorded. Documentation of the physical examination will 
be included in the source documentation at the investigational site. Significant findings 
before participant randomization will be recorded on the appropriate eCRF. Changes from 
screening physical examination findings that meet the definition of an AE will be recorded 
on the appropriate eCRF.
For cycles that do not require a complete physical examination, a brief directed physical 
examination including oral examination will be performed by the investigator or medically 
qualified designee (consistent with local requirements) per the institutional standard as 
specified in the SoA (Section 1.3). After the first dose of study intervention, new clinically 
significant abnormal findings should be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
•
Vital sign measurements (ie, systolic and diastolic BP [mm Hg], pulse [beats per minute], 
respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) will be 
obtained at the visits designated in the SoA (Section 1.3) by a validated method.
•
Blood pressure and pulse will be measured after the participant has been resting for 5 
minutes. All BP measurements should be performed on the same arm, preferably by the 
same person.
•
Only 1 BP measurement is needed for participants with systolic BP <140 mm Hg and 
diastolic BP <90 mm Hg. If the participant’s initial BP is elevated (ie, systolic BP ≥140 
mm Hg or diastolic BP ≥90 mm Hg), the BP measurement should be repeated at least 5 
minutes later. One BP assessment is defined as the mean value of 2 measurements at least 
5 minutes apart. If the BP assessment (ie, the mean of the 2 BP measurements obtained at 
least 5 minutes apart) shows an elevated BP (systolic BP ≥140 mm Hg or diastolic BP 
≥90 mm Hg), a confirmatory assessment should be obtained at least 30 minutes later by 
performing 2 measurements (at least 5 minutes apart) to yield a mean value.
•
Under exceptional circumstances, investigators and participants will have the option of 
having BP measured between visits, obtained locally by a health care professional. A 
diary will be provided as a tool to aid the participant in collecting BP evaluations 
between study visits.
8.3.3
Electrocardiograms
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 
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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 
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 CRF Completion Guidelines. In these instances, the AE corresponding 
to the ECG abnormality will be recorded on the appropriate CRF.
QTc prolongation has been seen in some lenvatinib studies. Monitor electrocardiograms 
every cycle (as specified in the Schedule of Assessments) in patients with congenital long QT 
syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known 
to prolong the QT interval, including Class Ia and III antiarrhythmics. Refer to the lenvatinib 
IB.
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 (Sections 1.3.1 and 1.3.2). MUGA or ECHO scans 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. LVEFs 
as assessed by the institution will be entered on the eCRF. Investigator assessment will be 
based on institutional reports.
8.3.5
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation In the study or within 30 days after the last dose of study 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.
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8.3.5.1
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
8.3.5.1.1
Hematology and Clinical Chemistry
Hematology and clinical chemistry assessments will be performed within 10 days before
administration of the first dose of study intervention, and within 3 days of dosing for all 
subsequent scheduled visits. The results must be reviewed before administration of study 
therapy. 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.
8.3.5.1.2
Urine Dipstick Testing/Urinalysis
Urine dipstick testing or urinalysis will be performed locally within 10 days before the start 
of study intervention. Urine dipstick testing will only be performed in participants taking 
lenvatinib. After screening, urine dipstick testing will be performed at every cycle while 
participants are taking lenvatinib and urinalysis will be performed at Cycle 6 and every 
6 cycles thereafter (Cycles 12, 18, 24, etc.). At visits when urinalysis is obtained the urine 
dipstick is not required. The sample can be collected within 3 days of Day 1 of each cycle 
(Section 1.3.1 and Section 1.3.2). During Second Course treatment, urine dipstick testing will 
be performed at every cycle only for participants taking lenvatinib, and urinalysis will be 
performed at Cycle 1 and then at Cycles 6 and 12 (Section 1.3.3).
Once participants are allocated, urine dipstick testing for participants with ≥2+ proteinuria 
should be performed on Day 15 (or more frequently as clinically indicated) until the results 
have been 1+ or negative for 2 consecutive treatment cycles. Urine dipstick testing should be 
performed at the investigational site. If a new event of ≥2+ proteinuria occurs, Day 15 urine 
dipstick testing for evaluation of proteinuria must be resumed until results are 1+ (30 mg/dL) 
or negative for 2 consecutive treatment cycles.
8.3.5.1.3
Thyroid Function Testing
Thyroid function testing will include determination of TSH, T3, and FT4. FT3 determination 
is acceptable at sites where T3 cannot be assessed. These tests can be performed by the 
central laboratory if they are unavailable at the local laboratory.
The screening blood sample for thyroid function testing should be obtained within 10 days 
before the first dose of study intervention.
Thyroid function testing will be performed within 3 days before Day 1 for all participants 
and at every other cycle beginning with Cycle 2 for participants receiving pembrolizumab 
and/or lenvatinib. Participants may be dosed in subsequent cycles after Cycle 1 Day 1 while 
thyroid function test results are pending. However, the results should be reviewed by the 
investigator when available.
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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 for 
urine or within 72 hours for serum before 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 
(see Appendix 7).
8.3.6
Eastern Cooperative Oncology Group Performance Status
The investigator or qualified designee will assess ECOG performance status (See Appendix 
9) at screening and at each treatment cycle, as specified in the SoA (Section 1.3).
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. The investigator, who is a qualified physician, 
will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity/toxicity, and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention allocation/randomization, must be 
reported by the investigator if the participant is receiving placebo run-in or other run-in 
treatment, if the event cause the participant to be excluded from the study, or is the result of a 
protocol-specified intervention, including, but not limited to washout or discontinuation of 
usual therapy, diet, or a procedure.
•
All AEs from the time of intervention allocation/randomization through 30 days after 
cessation of study intervention must be reported by the investigator.
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•
All AEs meeting serious criteria, from the time of intervention allocation/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, must 
be reported by the investigator.
•
All pregnancies and exposure during breastfeeding, from the time of intervention 
allocation/randomization through 120 days following cessation of study intervention, or 
30 days following cessation of study intervention if the participant initiates new 
anticancer therapy must be reported by the investigator.
•
Additionally, any SAE brought to the attention of an investigator at any time outside the 
time 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 the investigator 
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 7.
Participants who enter the separate Extension Study:
From the time of intervention randomization through up to the signing of consent to the 
extension study, all AEs, SAEs, and other reportable safety events must be reported by the 
investigator in this protocol (parent study). Laboratory values that meet criteria for reporting 
as AEs performed during parent study will be collected in the parent study.
Note: Once consented to the extension study, AEs and other reportable events meeting the 
criteria of the extension study, including those considered related to study intervention, will 
be collected in the extension study.
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Table 7
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
Report if:
- drug/vaccine 
related.
(Follow ongoing 
to outcome)
Within 24 hours 
of learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- due to intervention
- causes exclusion
Report all
Previously 
reported – Follow 
to 
completion/termin
ation; report 
outcome
Within 24 hours 
of learning of 
event
Event of Clinical 
Interest (require 
regulatory reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential drug-
induced liver 
injury (DILI)
- require 
regulatory 
reporting
Not required
Within 24 hours 
of learning of 
event
Event of Clinical 
Interest (do not 
require regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 
calendar days of 
learning of 
event
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended, nonleading verbal questioning of the participant is the 
preferred method of inquiring about AE occurrence.
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8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events, 
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in allocated 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 
Reaction (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) including the pregnancy of a male participant’s female 
partner, that occurs during the study are reportable to the Sponsor. All reported pregnancies 
must be followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage, and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of 
infant) must also be reported.
Pembrolizumab
It is not known whether pembrolizumab is excreted in human milk. No studies have been 
conducted to assess the impact of pembrolizumab on milk production or its presence in breast 
milk. Because many drugs are excreted in human milk, female participants must discontinue 
breastfeeding during treatment with pembrolizumab and for 4 months after the final dose
[U.S. Prescribing Information 2018].
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Lenvatinib
It is not known whether lenvatinib is excreted in human milk. However, lenvatinib and its 
metabolites are excreted in rat milk at concentrations higher than in maternal plasma. 
Because of the potential for SAEs from lenvatinib in nursing infants, female participants are 
advised to discontinue breastfeeding during treatment with lenvatinib [U.S. Prescribing 
Information 2018a].
Docetaxel
It is not known whether docetaxel is excreted in human milk. Because many drugs are 
excreted in human milk, and because of the potential for SAEs from docetaxel in nursing 
infants a decision should be made whether to discontinue nursing or to discontinue the drug, 
considering the importance of the drug to the mother [U.S. Prescribing Information 2018b].
See Table 7 for additional details regarding pregnancy.
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.
Specifically, the suspected/actual events covered in this exception include any event that is 
PD of the cancer under study.
The Sponsor will monitor aggregated efficacy endpoint events and safety data to ensure the 
safety of the participants in the study. Any suspected endpoint that, upon review, is not 
progression of the cancer under study will be forwarded to Global Pharmacovigilance as an 
SAE within 24 hours of determination that the event is not progression of the cancer under 
study.
8.4.7
Events of Clinical Interest (ECIs)
Selected serious and nonserious AEs 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. Lenvatinib overdose 
without an associated AE is not considered an ECI.
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.*
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*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
For purposes of this study, an overdose will be defined as any dose exceeding the prescribed 
dose for
•
Pembrolizumab: ≥5 times the protocol-specified dose
•
Lenvatinib: any dose above the protocol-prescribed dose if associated with an AE
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. There is no known 
antidote for docetaxel overdose. In the event of overdose, the specific intervention should be 
withheld, and the participant should be observed closely for signs of toxicity. Appropriate 
supportive treatment should be provided if clinically indicated.
Pembrolizumab:

If an AE(s) is associated with (“results from”) the overdose of study intervention, the 
AE(s) is reported as an SAE, even if no other seriousness criteria are met.

If a dose of the study intervention meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a nonserious ECI, using the terminology “accidental or intentional overdose 
without adverse effect.”
Lenvatinib:

An overdose associated with lenvatinib should be reported as a nonserious event of 
clinical interest, unless the AE itself meets criteria for an SAE.
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.
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8.6
Pharmacokinetics
As of Amendment 09, participants who are still on study treatment will no longer require PK 
assessments. Original protocol text that is contained in this section has been retained for 
reference.
Blood samples will be collected from the first 90 participants receiving study intervention in 
Arm 1 (pembrolizumab + lenvatinib) as specified in the SoA (Section 1.3.1). Study sites 
must have appropriately trained staff and adequate equipment for procuring and processing 
specimens. Instructions for collection, handling, and shipping of PK samples will be 
provided in the Laboratory Manual.
If, at some point during enrollment, prospective PK blood sample collection is no longer 
required, the sites will be notified accordingly.
8.6.1
Blood Collection for Serum Pembrolizumab
To evaluate pembrolizumab immunogenicity and exposure during treatment with 
pembrolizumab + lenvatinib, sample collections for analysis of antidrug antibodies (ADA) 
and PK are currently planned for the first 90 participants in Arm 1 (pembrolizumab + 
lenvatinib), as shown in the SoA (Section 1.3.1). Blood samples will be obtained to measure 
PK and ADA for serum pembrolizumab. These samples may be stored, and analysis may be 
performed if required. If ongoing ADA and/or PK results are deemed unnecessary by the 
Sponsor, it may be decided to discontinue or reduce further sample collection in this study. 
Should this occur, it will be communicated by an administrative memo. If PK and/or ADA 
analyses are performed, the results of these analyses will be reported separately.
8.6.2
Blood Collection for Plasma Lenvatinib
Plasma concentrations of lenvatinib coadministered with pembrolizumab (Arm 1) will be 
measured for the first 90 participants randomized to this treatment arm. Lenvatinib data will 
be analyzed using a PopPK approach. Lenvatinib will be quantified by validated tandem 
high-performance liquid chromatography/mass spectroscopy.
8.7
Pharmacodynamics
Not applicable.
8.8
Biomarkers
As of Amendment 09, participants who are still on study treatment will no longer require 
biomarker assessments. Original protocol text that is contained in this section has been 
retained for reference.
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To identify novel biomarkers, the following biospecimens to support exploratory analysis of 
cellular components (eg, protein, RNA, DNA, metabolites) and other circulating molecules 
will be collected from all participants as specified in the SoA:
•
Blood for genetic analysis
•
Blood for RNA analysis
•
Blood for circulating tumor nucleic acid
•
Blood for plasma biomarker analyses
•
Blood for serum biomarker analyses
•
Archival tumor tissue
•
Newly obtained biopsy
Sample collection, storage, and shipment instructions for exploratory biomarker specimens 
will be provided in the Laboratory Manual.
8.8.1
Planned Genetic Analysis Sample Collection
Samples should 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/Independent Ethics Committee [IEC] does not approve) sample collection for these 
purposes, then such samples should not be collected at the corresponding sites.
8.9
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics data associated with medical encounters 
will be collected in the eCRF by the investigator and study-site personnel for all participants 
throughout the study.
Protocol-mandated procedures, tests, and encounters are excluded.
The data collected may be used to conduct exploratory economic analyses. All-cause 
hospitalizations and emergency room visits must be reported on the eCRF from the time of 
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.
8.10
Visit Requirements
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 study.
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8.10.1
Screening
Forty-two days before randomization, potential participants will be evaluated to determine that 
they fulfill the entry requirements as provided in Section 5. Note: Screening procedures may 
be repeated after consultation with the Sponsor.
Documented informed consent must be obtained before performing any protocol-specific 
procedures. Results of a test performed before the participant’s documented informed 
consent as part of routine clinical management are acceptable in lieu of a screening test if 
performed within the specified time frame. Screening procedures are to be completed within 
42 days before the first dose of study intervention except for the following:

Laboratory tests are to be performed within 10 days before the first dose of study 
intervention. An exception is hepatitis and HIV testing, which may be done up to 28 days 
before the first dose of study intervention, if applicable. Repeated laboratory evaluation 
to establish eligibility is not allowed unless discussed and agreed upon with the Sponsor.

Baseline imaging is to be performed within 30 days before the first dose of study 
intervention.

ECOG performance status is to be evaluated within 7 days before the date of the first 
dose of study intervention. If screening ECOG performance status is obtained within 3 
days before C1D1, it is not necessary to repeat at C1.

Full physical examination including an oral examination is to be performed before start 
of study intervention.

For WOCBP, a urine pregnancy test will be performed within 24 hours or serum 
pregnancy test will be performed within 72 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 trial site laboratory).

If a newly obtained biopsy, meeting all the eligibility requirements, was obtained prior to 
screening, this sample may be used for the study.
8.10.1.1
Rescreening
Participants may be rescreened after initially failing to meet inclusion/exclusion criteria. 
Results of assessments during the original screening period are acceptable in lieu of repeat 
screening tests if obtained within the specified time frame and the corresponding criteria are 
met. Rescreened participants will retain their original screening numbers.
8.10.2
Initial Treatment
Visit requirements are outlined in the SoA (Section 1.3). Assessments/procedures are to be 
performed before administration of study intervention.
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8.10.2.1
Telephone Contact or Visit
A telephone contact or visit will be conducted on Cycle 1 Day 8 to assess participants for 
development of early toxicity, as outlined in the SoA (Section 1.3.1).
8.10.3
Second Course Treatment
Note: In alignment with the study-specific investigator letter dated 22-SEP-2023, all study 
participants still receiving study treatment should continue to receive therapy on study and 
undergo modified protocol study procedures as specified in this amendment. Participants 
currently on study treatment with lenvatinib or docetaxel can continue treatment per 
investigator’s discretion. Participants who are potential candidates for Second Course 
treatment will continue in Efficacy Follow-up.
All participants enrolled in the lenvatinib + pembrolizumab arm (Arm 1) who have SD, PR, 
or CR may be eligible for up to an additional 17 cycles of pembrolizumab treatment if there 
is radiographic disease progression by investigator assessment after initial treatment or First 
Course has been completed or stopped for confirmed CR. This retreatment is the Second 
Course of this study.
Participants in the lenvatinib + pembrolizumab arm (Arm 1) may enter the Second Course if 
all of the following criteria are also met:
1. The participant received pembrolizumab
2. No new anticancer treatment was administered after the last dose of study intervention
3. The participant meets all of the inclusion criteria and none of the exclusion criteria
4. The study is ongoing
An objective response or disease progression that occurs during the Second Course will not 
be counted as an event for the primary analysis of either endpoint in this study.
Pembrolizumab will be administered every 21 days for up to 17 treatment cycles 
(approximately 1 year). Treatment may continue until a discontinuation criterion is met 
(Section 7.1).
The decision of whether to continue lenvatinib during Second Course treatment will be at the 
discretion of the investigator, provided that lenvatinib was not discontinued due to toxicity. If 
lenvatinib is continued or restarted, participants will be retreated at the same dose level as 
when they last received pembrolizumab + lenvatinib. Treatment with lenvatinib will continue 
until a discontinuation criterion (Section 7.1) is met.
Second Course visit requirements are outlined in the SoA (Section 1.3.3). Specific 
procedure-related details are provided in Section 8.1.
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An objective response or PD occurring during the Second Course phase will not be counted 
as an event for the primary analysis of either endpoint in this study.
8.10.4
Discontinued Participants Continuing to be Monitored in the Study
The discontinuation visit should take place at the time study intervention is discontinued for 
any reason. If the discontinuation visit takes place 30 days from the last dose of study 
intervention, at the time of the mandatory Safety Follow-up visit, the visit is not required. All 
procedures required at the discontinuation visit and at the 30-day Safety Follow-up visit 
should be performed.
8.10.5
Posttreatment Visit
8.10.5.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before initiation of a new anticancer treatment, whichever 
comes first.
Participants who are eligible for Second Course retreatment may have up to 2 Safety 
Follow-up visits, 1 after initial treatment and 1 after Second Course treatment.
8.10.5.2
Follow-up Visits
Participants who discontinue study intervention for a reason other than PD will move into the 
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, end of study, or the participant begins 
retreatment as detailed in Section 8.10.3. Information regarding poststudy anticancer 
treatment will be collected if new treatment is initiated.
Participants who are eligible for retreatment according to the criteria in Section 8.10.3 may 
move from follow-up to the Second Course Phase if they experience PD. Details are 
provided in the SoA (Section 1.3.3).
8.10.5.3
Survival Follow-up Contacts
Participants who experience confirmed PD or start new anticancer therapy will move into the 
Survival Follow-up Phase and should be contacted by telephone approximately every 12 
weeks to assess for survival status until death, withdrawal of consent, end of the study, or 
notification by the Sponsor, whichever occurs first.
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8.10.6
Survival Status
To ensure that current and complete survival data are available at the time of database locks, 
updated survival data may be requested during the study by the Sponsor. For example, 
updated survival data may be requested before, but not limited to, an external data 
monitoring committee (eDMC) review or an interim or final analysis. Upon Sponsor 
notification, all participants who do not or will not have a scheduled study visit or study 
contact during the Sponsor-defined period will be contacted for their survival status.
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9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If changes 
are made to primary and/or key secondary hypotheses or the statistical methods related to 
these hypotheses after the study has begun, but before any unblinding/final database lock, the 
protocol will be amended (consistent with International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use [ICH] Guideline E9). Changes 
to the 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.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan (SAP) are summarized below. The 
comprehensive plan is provided in Sections 9.2 through 9.12.
Study Design 
Overview
A Phase 3, randomized, active-controlled, parallel-group, multi-site, open-label 
study of pembrolizumab + lenvatinib versus docetaxel or lenvatinib in 
participants with metastatic NSCLC who have PD during/after platinum doublet 
chemotherapy, and previous exposure to one anti-PD-1/PD-L1 mAb.
Treatment Assignment
Approximately 405 participants will be randomized in a 4:4:1 ratio among 3 
treatment arms: pembrolizumab + lenvatinib (Arm 1), docetaxel (Arm 2), and 
lenvatinib monotherapy (Arm 3).
Stratification factors are as follows:

Anti-PD-1/PD-L1 mAb (immediate prior therapy versus not the immediate 
prior therapy)

PD-L1 TPS (<50% versus ≥50%)

ECOG performance status (0 versus 1)
Analysis Populations
Efficacy: Intention-to-Treat (ITT)
Safety: All Participants as Treated (APaT)
PRO: Full Analysis Set (FAS) population
Primary Endpoints

Overall survival (OS)

Progression-free survival (PFS) based on RECIST 1.1 as assessed by BICR 
Secondary Endpoints

Objective response based on RECIST 1.1 as assessed by BICR

DOR based on RECIST 1.1 as assessed by BICR

AEs and discontinuations due to AEs

Scores for global health status/QoL, cough, chest pain, dyspnea, and physical 
functioning

TTD in global health status/QoL, cough, chest pain, dyspnea, and physical 
functioning
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Statistical Methods for
Key Efficacy Analyses
The primary hypotheses will be evaluated by comparing the pembrolizumab + 
lenvatinib arm to the docetaxel arm using a stratified log-rank test for PFS and 
OS. The hazard ratio (HR) will be estimated using a stratified Cox regression 
model. Event rates over time will be estimated within each treatment arm using 
the Kaplan-Meier method. The difference in objective response rate (ORR) in 
pembrolizumab + lenvatinib versus docetaxel will be estimated using the 
stratified Miettinen and Nurminen method with strata weighting by sample size.
The difference in ORR in pembrolizumab + lenvatinib versus lenvatinib will be 
estimated using the Miettinen and Nurminen method without stratification.
Statistical Methods for
Key Safety Analyses
The analysis of safety results will follow a tiered approach. There is no Tier 1 
safety endpoint for this study. Tier 2 parameters will be assessed via point 
estimates by treatment arm with 95% confidence intervals (CIs) provided for 
between-arm comparisons of pembrolizumab + lenvatinib to docetaxel; only 
point estimates by treatment arm 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
The study includes 1 single-arm futility analysis, 2 interim analyses, and a final 
analysis:
-
Single-arm futility analysis: 18 participants in the pembrolizumab + 
lenvatinib arm have been followed up for at least 20 weeks (~10 months 
after the first participant randomized):
-
The non-binding criteria for passing futility is to have 1) ≥3 objective 
responses (ie, confirmed CR or PR) or 2) DCR12 >50% and ≥1 objective 
response.
-
Interim analysis 1 (IA1): 200 participants in Arms 1 and 2 have been 
followed up for 6 months (~18 months after the first participant 
randomized).
-
Primary purpose: ORR analysis to compare pembrolizumab + lenvatinib 
to docetaxel
-
Interim analysis 2 (IA2): ~279 PFS events in Arms 1 and 2 have been 
observed AND at least 6 months follow-up after the last participant is 
randomized (~36 months after the first participant randomized. ~240 deaths 
are expected in Arms 1 and 2)
-
Primary purpose: PFS analysis
-
Interim OS analysis
-
ORR analysis to compare pembrolizumab + lenvatinib to lenvatinib 
monotherapy
-
Final analysis (FA): ~299 deaths have occurred in Arms 1 and 2 AND a 
minimum of 12 months follow-up after the last participant randomized (~48 
months after the first participant randomized)
-
Primary purpose: Final OS analysis
Multiplicity
The study will use the graphic method of Maurer and Bretz to control 
multiplicity for multiple hypotheses as well as IAs. The overall Type I error rate 
over the multiple endpoints will be controlled at 2.5% (1-sided). A small alpha 
penalty of 0.01% will be paid for single-arm futility analysis. A 0.3% (1-sided) 
Type I error rate will be initially allocated to test ORR in pembrolizumab + 
lenvatinib versus docetaxel; 0.29% (1-sided) allocated to test PFS; 1.9% (1-
sided) allocated to test OS; and 0% (1-sided) allocated to test ORR in 
pembrolizumab + lenvatinib versus lenvatinib. Type I errors will be reallocated 
among the hypotheses of PFS, OS, ORR in pembrolizumab + lenvatinib versus 
docetaxel, and ORR in pembrolizumab + lenvatinib versus lenvatinib. Lan-
DeMets O’Brien-Fleming group sequential methods will be used to allocate α 
among the interim and final analyses for the OS endpoints.
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Sample Size and 
Power
The planned sample size is approximately 405 participants with 360 participants 
in either pembrolizumab + lenvatinib or docetaxel arms, and 45 participants in 
lenvatinib arm. For PFS, based on ~279 events in 360 participants in 
pembrolizumab + lenvatinib and docetaxel arms and at least 6 months follow-up 
after the last participant randomized, the study has 93.6% power to detect a HR 
of 0.60 (pembrolizumab + lenvatinib versus docetaxel) at α = 0.29% (1-sided), 
with assumed PFS median of 4.1 months in docetaxel arm. For OS, based on a 
target number of ~299 events in 360 participants in pembrolizumab + lenvatinib 
and docetaxel arms, the study has 93.3% power to detect an HR of 0.66 
(pembrolizumab + lenvatinib versus docetaxel) at α = 1.9% (1-sided), with 
assumed OS median of 8.6 months for the docetaxel arm. For ORR based on the 
200 randomized participants in pembrolizumab + lenvatinib and docetaxel arms 
that were treated for at least 6 months, the study has 80.6% power to detect a 20 
percent point increase for pembrolizumab + lenvatinib versus docetaxel at α = 
0.3% (1-sided) (assuming 10% response rate in the docetaxel arm).
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Sponsor’s Clinical Biostatistics department.
The Sponsor will generate the randomized allocation schedule for study intervention 
assignment as appropriate in this protocol, and the allocation will be implemented in IRT.
Although the trial is an open-label study, with analyses or summaries generated by study 
intervention assignment, access to the information of actual treatment received will be 
limited and documented. Further documentation will be provided in the sSAP. In addition, 
independent radiologists will perform the central imaging review without knowledge of 
treatment assignments.
An internal unblinded statistician will monitor the total number of PFS and OS events in the 
combined pembrolizumab + lenvatinib and docetaxel arms to estimate the timing of the 
interim analysis. In-house blinding procedures related to the planned interim analyses are 
described in Section 9.7.
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 are listed below.
9.4.1
Efficacy Endpoints
Primary Endpoints
•
OS: time from randomization to the date of death due to any cause.
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•
PFS: time from randomization to the first documented PD per RECIST 1.1 based on 
BICR or death due to any cause, whichever occurs first. See Section 9.6.1 for the 
definition of censoring.
Secondary Endpoints
•
Objective Response: a confirmed CR or PR per RECIST 1.1 based on BICR. ORR is the 
proportion of participants with objective response.
•
DOR: time from the first documented evidence of CR or PR until PD per RECIST 1.1 as 
assessed by BICR or death due to any cause, whichever occurs first, in participants 
demonstrating CR or PR.
Tertiary/Exploratory Endpoint
•
Disease control at 12 weeks: a CR, PR or SD at 12 weeks per RECIST 1.1 based on 
BICR. DCR12 is the proportion of participants with disease control at 12 weeks.
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
PRO Endpoints
The following secondary PRO endpoints will be evaluated as described in Section 4.2.1.3:
•
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).
•
Composite symptom endpoint: cough (QLQ-LC13 Item 31), chest pain (QLQ-LC13 Item 
40), or dyspnea (QLQ-C30 Item 8).
•
Physical functioning scale (QLQ-C30 Items 1-5).
•
TTD for the PRO score 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) 
which is defined as the time from baseline to the first onset of a ≥10-point decrease from 
baseline in PRO score with confirmation by the subsequent visit of a ≥10-point 
deterioration from baseline in any of the items.
The EQ-5D-5L will be evaluated as an exploratory endpoint.
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The analyses and the approach to handling missing data for PRO endpoints will be described 
in the sSAP.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Population
The analyses of primary efficacy endpoints are based on the intention-to-treat (ITT) 
population. All randomized participants will be included in this population. Participants will 
be analyzed in the treatment arm to which they are randomized. Details of the approach to 
handling missing data are provided in Section 9.6.1.5.
9.5.2
Safety Analysis Population
The APaT population will be used for the analysis of safety data. The ApaT population 
consists of all allocated participants who receive at least 1 dose of study intervention. 
Participants will be analyzed in the treatment arm corresponding to the study intervention 
they actually receive. For most participants, this will be the treatment arm to which they are 
assigned. Participants who receive incorrect study intervention for the entire treatment period 
will be included in the treatment arm corresponding to the study intervention actually 
received. Any participant who receives incorrect study intervention for 1 cycle, but receives 
the correct intervention for all other cycles, will be analyzed according to the correct 
treatment arm, 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 or vital sign measurement obtained subsequent to at least 1 dose of 
study intervention is required for inclusion in the analysis of each specific parameter. To 
assess change from baseline, a baseline measurement is also required.
9.5.3
Pharmacokinetic Analysis Population
The population for PK analysis includes the first 90 participants in the pembrolizumab + 
lenvatinib arm (Arm 1) who have received at least 1 dose of study intervention with 
documented dosing history and have measurable plasma levels of lenvatinib or serum levels 
of pembrolizumab.
9.5.4
PRO Analysis Population
The PRO analyses are based on the PRO full analysis set (FAS) population, defined as 
randomized participants who have at least 1 PRO assessment available and have received at 
least 1 dose of study intervention. PRO data will be collected in all participants.
9.6
Statistical Methods
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 
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results that will be deemed to be statistically significant after consideration of the Type I 
error control strategy are described in Section 9.8. Nominal p values will be computed for 
other efficacy analyses but should be interpreted with caution due to potential issues of 
multiplicity.
An objective response or PD that occurs during Second Course treatment will not be counted 
as an event for the primary analyses of either endpoint in this study.
9.6.1.1
Overall Survival
The nonparametric Kaplan-Meier method will be used to estimate the survival curves in each 
treatment arm. Formal hypothesis testing will be conducted to compare pembrolizumab + 
lenvatinib versus docetaxel. The treatment difference in survival will be assessed by the 
stratified log-rank test. A stratified Cox proportional hazard model with Efron’s method of tie 
handling will be used to assess the magnitude of the treatment difference (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 allocation (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. Analysis 
using the Restricted Mean Survival Time method may be conducted for OS to account for the 
possible nonproportional hazards effect and to estimate the absolute benefit of experimental 
treatment.
9.6.1.2
Progression-free Survival
The nonparametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment arm. Formal hypothesis testing will be conducted to compare pembrolizumab + 
lenvatinib versus docetaxel. The treatment difference in PFS will be assessed by the stratified 
log-rank test. A stratified Cox proportional hazard model with Efron’s method of tie handling 
will be used to assess the magnitude of the treatment difference (ie, the HR) between the 
treatment arms. The HR and its 95% CI from the stratified Cox model with Efron’s method 
of tie handling and with a single treatment covariate will be reported. The stratification 
factors used for allocation (Section 6.3.2) will be applied to both the stratified log-rank test 
and the stratified Cox model. Analysis using the Restricted Mean Survival Time method may 
be conducted for PFS to account for the possible nonproportional hazards effect and to 
estimate the absolute benefit of experimental treatment.
Since PD is assessed periodically, PD can occur any time in the interval between the last 
assessment when PD is not documented and the assessment when PD is documented. For the 
primary analysis, for participants with 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, based on 
BICR by the CIV. Death is always considered as a confirmed PD event. Participants who do 
not experience a PFS event will be censored at the last disease assessment. Sensitivity 
analyses will be performed for comparison of PFS based on the investigator’s assessment.
To evaluate the robustness of the PFS endpoint per RECIST 1.1 based on BICR by the CIV, 
1 primary and 2 sensitivity analyses with a different set of censoring rules will be performed. 
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For the primary analysis, if the events (PD or death) are immediately after more than 
1 missed disease assessment, the data are censored at the last disease assessment before the 
missed visits. Data after new anticancer therapy are censored at the last disease assessment 
before the initiation of new anticancer therapy. The first sensitivity analysis follows the ITT 
principle (ie, PD/deaths are counted as events regardless of missed study visits or initiation of 
new anticancer therapy). The second sensitivity analysis considers discontinuation of 
treatment due to reasons other than CR or initiation of new anticancer treatment, 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
PD or death 
documented after ≤1 
missed disease 
assessment, and before 
new anticancer therapy, 
if any
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or death
PD or death 
documented 
immediately after ≥2 
consecutive missed 
disease assessments or 
after new anticancer 
therapy, if any
Censored at last disease 
assessment before 
the earlier date of ≥2 
consecutive missed 
disease assessments and 
new anticancer therapy, 
if any
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or death
No PD and no death; 
new anticancer 
treatment is not initiated
Censored at last disease 
assessment
Censored at last disease 
assessment
Progressed at treatment 
discontinuation due to 
reasons other than 
complete response; 
otherwise censored at last 
disease assessment if 
participant is still 
receiving study treatment 
or has completed study 
treatment
No PD and no death; 
new anticancer 
treatment is initiated
Censored at last disease 
assessment before new 
anticancer treatment
Censored at last disease 
assessment
Progressed at date of new 
anticancer treatment
Abbreviation: PD = progressive disease
9.6.1.3
Objective Response
Formal hypothesis testing of ORR in pembrolizumab + lenvatinib versus docetaxel at IA1 
will be conducted, as secondary efficacy analysis, to support the efficacy of pembrolizumab 
+ lenvatinib over docetaxel, in addition to OS and PFS analysis. Formal hypothesis testing of 
ORR in pembrolizumab + lenvatinib versus lenvatinib at IA2, as a secondary efficacy 
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analysis, will be conducted to evaluate the efficacy of pembrolizumab + lenvatinib over 
lenvatinib.
The Miettinen and Nurminen method will be used for the pairwise comparison of the ORR. 
The difference in ORR in pembrolizumab + lenvatinib versus docetaxel and its 95% CI from 
the stratified Miettinen and Nurminen method with strata weighting by sample size will be
reported. The stratification factors used for allocation (Section 6.3.2) will be used as 
stratification factors in the analysis. The Miettinen and Nurminen method without 
stratification will be used for comparison of ORR in pembrolizumab + lenvatinib versus 
lenvatinib and ORR in lenvatinib versus docetaxel.
9.6.1.4
Duration of Response
For participants with a 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. Censoring 
rules for DOR are summarized in Table 9. DOR will be assessed using RECIST 1.1 by 
BICR.
For each DOR analysis, a corresponding summary of the reasons for which responding 
participants are censored will also be provided. Responses in participants who are alive, have 
not progressed, have not initiated new anticancer treatment, and have not been determined to 
be lost to follow-up, and who have had a disease assessment within approximately 5 months 
of the data cutoff date, are considered ongoing at the time of analysis. If a participant meets 
multiple criteria for censoring, the censoring criterion that occurs earliest will be applied.
If the sample size permits, DOR will be summarized descriptively using Kaplan-Meier 
medians and quartiles. Only the subset of participants with a confirmed CR or PR will be 
included in this analysis.
Table 9
Censoring Rules for Duration of Response
Situation
Date of Progression 
or Censoring
Outcome
No progression nor death, no new 
anticancer therapy initiated
Last adequate disease assessment
Censor
(non-event)
No progression nor death, new 
anticancer therapy initiated
Last adequate disease assessment 
before new anticancer therapy was 
initiated
Censor
(non-event)
Death or progression 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
(non-event)
Death or progression after ≤1 
missed disease assessments and 
before new anticancer therapy, if 
any
PD or death
End of response
(Event)
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for 
evaluation of response.
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9.6.1.5
Analysis Strategy for Key Efficacy Endpoints
A summary of the primary analysis strategy for the key efficacy endpoints is provided in 
Table 10.
Table 10
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Analyses (Pembrolizumab + Lenvatinib versus Docetaxel)
OS
Testing: stratified log-rank test
Estimation: stratified Cox 
model with Efron’s tie-
handling method
ITT
Censored at last known alive date
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
Secondary Analyses (Pembrolizumab + Lenvatinib versus Docetaxel)
Objective Response 
(RECIST 1.1) by 
BICR
Testing and estimation:
Stratified Miettinen and 
Nurminen method with 
stratification
ITT
Participants with missing data are 
considered nonresponders
DOR (RECIST 1.1) 
by BICR
Summary statistics using 
Kaplan-Meier method
All 
responders 
in ITT 
Censored according to rules in 
Table 9
Secondary Analyses (Pembrolizumab + Lenvatinib versus Lenvatinib)
Objective Response 
(RECIST 1.1) by 
BICR
Testing and estimation:
Miettinen and Nurminen 
method without stratification
ITT
Participants with missing data are 
considered nonresponders
Abbreviations: BICR = blinded independent central review; DOR = duration of response; ITT = intention-to-
treat; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; RECIST 
1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1.
Sensitivity analyses will be performed for PFS, ORR, and DOR based on investigator’s assessment.
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 11). 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 sign, and 
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ECG parameters are either prespecified as Tier 1 events or will be classified as belonging to 
Tier 2 or Tier 3 based on the number of events observed.
Tier 1 Events
Safety parameters or adverse events of special interest (AEOSIs) that are identified a priori
constitute Tier 1 safety events that will be subject to inferential testing for statistical 
significance. There are no Tier 1 events for this protocol. AEOSIs that are immune-mediated 
or potentially immune-mediated are well documented and will be evaluated separately; 
however, these events have been characterized consistently throughout the pembrolizumab 
clinical development program and determination of statistical significance is not expected to 
add value to the safety evaluation. 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.
Tier 2 Events
Tier 2 events will be assessed via point estimates by treatment arm. In addition, 95% CIs for 
differences in the proportion of participants with events between pembrolizumab + lenvatinib 
and docetaxel will be provided using the Miettinen and Nurminen method [Miettinen, O. and 
Nurminen, M. 1985], an unconditional, asymptotic method.
Membership in Tier 2 requires that at least 10% of participants in either the pembrolizumab + 
lenvatinib or docetaxel treatment arm exhibit the event. The threshold of at least 10% was 
chosen because participants enrolled in this study are in critical condition and usually 
experience various AEs of similar types regardless of treatment; events reported less 
frequently than in 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, Grades 3 to 5 AEs (≥5% of participants in either the pembrolizumab + lenvatinib or 
docetaxel treatment arm) and SAEs (≥5% of participants in either the pembrolizumab + 
lenvatinib or docetaxel arm) will be considered Tier 2 events. 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-treatment differences.
Tier 3 Events
Safety events that are not Tier 1 or Tier 2 events will be considered Tier 3 events. Only point 
estimates by treatment arm will be 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 
may be provided by treatment arm in table format.
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Table 11
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE (≥10% of participants in either the 
pembrolizumab + lenvatinib or docetaxel arm)
X
X
Any Grades 3 to 5 AE (≥5% of participants in either 
the pembrolizumab + lenvatinib or docetaxel arm)
X
X
Any serious AE (≥5% of participants in either the 
pembrolizumab + lenvatinib or docetaxel arm)
X
X
Tier 3
Any AE
X
Any change from baseline results (laboratory tests, 
vital signs, ECGs)
X
Abbreviations: AE = adverse event; CI = confidence interval; ECG = electrocardiogram.
95% CI for treatment comparison between pembrolizumab + lenvatinib and docetaxel will be performed.
The safety data in the lenvatinib monotherapy arm (Arm 3) will be summarized by 
descriptive statistics separately.
9.6.3
Statistical Methods for Patient-Reported Outcomes
Change from baseline in the following secondary PRO endpoints from the EORTC QLQ C30 
and EORTC QLQ-LC13 will be assessed:
•
Global health status/QoL score (EORTC QLQ-C30 Items 29 and 30)
•
Cough score (EORTC QLQ-LC13 Item 31)
•
Chest pain score (EORTC QLQ-LC13 Item 40)
•
Dyspnea score (EORTC QLQ-C30 Item 8)
•
Physical functioning score (QLQ-C30 Items 1 to 5)
A constrained longitudinal data analysis model will be applied, with the PRO score as the 
response variable, and treatment, time, treatment by time interaction, and clinical trial 
stratification factors as covariates. Least squares mean change from baseline will be 
summarized for each outcome. Treatment effect on PRO score change from baseline will 
primarily be evaluated at Week 12. If the overall PRO completion or compliance rates at 
Week 12 are less than 60% or 80%, respectively, then the analysis time point will be moved 
to the next earliest time point in which the rates are at least 60% for completion and at least 
80% for compliance. The difference in the least squares mean change from baseline will be 
reported at the primary analysis time point.
Descriptive analyses will assess the empirical mean change (with 95% CI)from baseline 
across all time points. Details of PRO analyses will be described in the sSAP.
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The Kaplan-Meier method will be used to estimate the TTD survival curves for 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 to 5) in each treatment arm. In addition, TTD 
survival curves will be estimated for the composite endpoint of cough, chest pain, or dyspnea 
by treatment arm. Stratified Cox proportional hazards models with Efron’s method of tie 
handling will be used to assess the magnitude of the treatment difference for pembrolizumab 
+ lenvatinib compared with docetaxel. Stratification factors used for allocation will be used 
in the stratified Cox proportional hazards models. The HR, 95% CI, and nominal p value will 
be reported.
Details of additional PRO analyses will be included in the sSAP.
9.6.4
Summaries of Baseline Characteristics
The comparability of the treatment arms for each relevant demographic and baseline 
characteristic will be assessed using tables and/or graphs. No statistical hypothesis tests will 
be performed on these characteristics. The number and percentage of participants randomized 
and the primary reason for discontinuation will be displayed. Demographic variables (such as 
age) and baseline characteristics will be summarized by treatment either by descriptive 
statistics or categorical tables. The reasons for exclusion from the ITT population (if any) 
will be summarized.
9.7
Interim Analyses
The treatment-level results of the interim analyses will not be shared with the investigator 
before completion of the study.
An eDMC will review the unblinded efficacy results and accumulating safety data at planned 
interim analyses. Treatment-level results of the interim analyses will be provided by the 
internal unblinded statistician to the eDMC. The eDMC responsibilities and review schedules 
will be outlined in the Data Monitoring Committee (DMC) Charter. The recommendations of 
the eDMC will be communicated to the Executive Oversight Committee (EOC). If the eDMC 
recommends modifications to the design of the protocol or discontinuation of the study, the 
EOC, and possibly other limited numbers of additional Sponsor personnel, may be unblinded 
to results at the treatment level to act on these recommendations. Participant-level unblinding 
to support regulatory filing, should this occur before the end of the study, will be restricted to 
a designated Sponsor team, who will have no other responsibilities associated with the study. 
The extent to which individuals are unblinded with respect to the results will be documented. 
Additional logistical details, revisions to the above plan, and data monitoring guidance will 
be provided in the eDMC charter.
9.7.1
Safety Interim Analyses
The eDMC will review accumulating safety data periodically to provide an opportunity to 
terminate the study early if there are safety concerns. The timing of the safety monitoring 
will be specified in the eDMC charter.
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9.7.2
Efficacy Interim Analyses
Futility Analysis
A single-arm futility check will occur when 18 participants treated in the pembrolizumab + 
lenvatinib arm have at least 20 weeks of follow-up. The futility analysis is intended to 
evaluate objective response and disease control at 12 weeks in the first 18 participants treated 
with pembrolizumab + lenvatinib with at least 20 weeks of follow-up. The analysis will 
likely occur approximately 10 months after study initiation.
In addition, the objective response and disease control at 12 weeks for participants treated 
with pembrolizumab + lenvatinib who have at least 12 weeks of follow-up at the time of the 
futility analysis will be evaluated as supportive analyses for the futility assessment. It is 
estimated that, by the time of the single-arm futility analysis, approximately 100 participants
will have been randomized into the study. It is estimated that 35 participants (of 
approximately 45 randomized into the pembrolizumab + lenvatinib arm) will be eligible for 
these supportive analyses.
For the evaluation of objective response, participants will be coded as responders if they have 
an objective response (ie, confirmed CR or PR). Participants not known to have an objective 
response will be considered as nonresponders.
For evaluation of DCR12, participants will be considered to have disease control at 12 weeks 
if they have CR, PR, or SD at 12 weeks (±2-week window). Participants will also be 
considered to have disease control at 12 weeks if they have CR, PR or SD in the first imaging 
assessment, and have nonevaluable or no imaging assessment at 12 weeks (±2-week 
window), and subsequent assessment shows CR, PR, or SD before the timing of futility 
check. Participants not known to have disease control at 12 weeks before the timing of 
futility check will be considered as not having disease control at 12 weeks.
The non-binding criteria for passing futility are: 1) there are 3 or more objective responses 
among the first 18 participants treated with pembrolizumab + lenvatinib or 2) DCR12 is 
>50% and there is at least 1 objective response among the first 18 participants treated with 
pembrolizumab + lenvatinib. If neither of these criteria is met, the continuation of the study 
will be reassessed by the EOC considering the totality of the data for pembrolizumab + 
lenvatinib. The probability of passing the futility analysis based on ORR and DCR12 is 
shown in Table 12.
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Table 12
Probability of Passing Single-arm Futility Analysis
ORR
Difference Between DCR12 and ORR 
+0.25
+0.3
+0.35
+0.4
+0.45
+0.5
0.05
8.6
12.2
18.1
25.9
34.7
43.3
0.1
34.1
40.6
49.1
58.6
67.6
75.0
0.15
62.7
69.0
75.8
82.3
87.6
91.2
0.2
83.1
87.2
91.1
94.1
96.2
97.4
0.25
93.9
95.8
97.4
98.5
99.1
99.3
Abbreviations: DCR12 = disease control rate at 12 weeks; ORR = objective response rate.
For example, if the true ORR is 25% and the difference between DCR12 and true ORR is 
30% (ie, the DCR12 is 55% [25% + 30%]), the probability of passing the futility analysis 
based on these criteria is 95.8%.
Efficacy Analyses
In addition, 2 interim analyses (IAs) are planned in addition to the final analyses. The 
analyses, endpoints evaluated, and drivers of timing are summarized in Table 13.
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Table 13
Summary of Efficacy Analysis in Interim and Final Analyses
Analyses
Key
Endpoints
Timing*
Estimated Time 
After First 
Participant 
Randomized
Primary Purpose
of Analysis
IA1
Objective 
response
200 participants* have 
been followed up for 
6 months.
~18 months
ORR analysis 
(pembrolizumab + 
lenvatinib versus 
docetaxel)
IA2
PFS
OS
Objective 
response
~279 PFS events* have 
been observed and a 
minimum of 6 months 
follow-up after last 
participant randomized.
~240 death events are 
expected.
~36 months
Final PFS analysis
Interim OS analysis
ORR analysis 
(pembrolizumab + 
lenvatinib versus 
lenvatinib)
Final Analysis
OS
~299 death events* 
have been observed and 
a minimum of 12 
months follow-up after 
last participant
randomized.
~48 months
Final OS analysis
*Timings of IA1 and final analysis are based on the number of participants or events in Arm 1 and Arm 2. 
Timing of IA2 is based on number of events in Arm 1 and Arm 2 AND at least 6 months after the last 
participant is randomized.
Timing of final analysis is based on number of events in Arm 1 and Arm 2 AND at least 12 months after the 
last participant is randomized.
Abbreviations: IA1 = interim analysis 1; IA2 = interim analysis 2; ORR = objective response rate; 
OS = overall survival; PFS = progression-free survival.
9.8
Multiplicity
The study includes 1 single-arm futility analysis. A small α penalty of 0.0001 will be paid for 
looking at the data. The study will use the graphic method of Maurer and Bretz to control 
multiplicity for multiple hypotheses as well as IAs [Maurer, W. and Bretz, F. 2013]. The 
overall Type I error rate over the multiple endpoints will be controlled at 0.025 (1-sided). 
According to this approach, study hypotheses may be tested more than once, and, when a 
particular null hypothesis is rejected, the α allocated to that hypothesis can be reallocated to 
other hypothesis tests.
Figure 4 shows the initial 1-sided α allocation for each hypothesis in the ellipse representing 
the hypothesis. The weights for reallocation from each hypothesis to the others are 
represented in the boxes on the lines connecting hypotheses.
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Figure 4
Multiplicity Diagram for Type I Error Control
Abbreviations: P+L = pembrolizumab + lenvatinib arm. D = docetaxel arm. L = lenvatinib arm. 
ORR = objective response rate; OS = overall survival; PFS = progression-free survival.
A small α penalty of 0.0001 is paid for futility analysis.
9.8.1
Objective Response Rate
9.8.1.1
Objective Response Rate – Pembrolizumab + Lenvatinib Versus Docetaxel
This study allocates α = 0.003 (1-sided) to compare ORR in pembrolizumab + lenvatinib to 
docetaxel, and ORR is tested only at the first interim analysis (IA1). However, if the test does 
not achieve statistical significance at IA1, the p value from IA1 can be compared to an 
updated α level if the null hypotheses for both PFS and OS are rejected and ORR in 
pembrolizumab + lenvatinib arm versus lenvatinib arm is rejected at a later time. Based on 
200 randomized participants (in the pembrolizumab + lenvatinib and docetaxel arms) treated 
for at least 6 months, power and the approximate treatment difference required to reach the 
bound (ΔORR) are shown in Table 14, assuming 10% and 30% response rates in the 
docetaxel and pembrolizumab + lenvatinib arms, respectively.
Table 14
Possible Alpha Level and Approximate ORR Difference Between 
Pembrolizumab + Lenvatinib Arm and Docetaxel Arm Required to Demonstrate Efficacy for 
ORR at Interim Analysis 1
Alpha Level
~Δ Objective Response Rate
Power
0.003
~0.146
0.806
0.0249
~0.098
0.956
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9.8.1.2
Objective Response Rate – Pembrolizumab + Lenvatinib Versus Lenvatinib
No initial alpha is allocated to compare ORR in pembrolizumab + lenvatinib versus 
lenvatinib and the ORR is tested only if the null hypothesis for OS is rejected at IA2 or the 
final analysis. If OS null hypothesis is rejected at IA2, alpha is fully reallocated to hypothesis 
testing for ORR in pembrolizumab + lenvatinib versus lenvatinib. If OS null hypothesis does 
not achieve statistical significance at IA2, the p value of ORR from IA2 can be compared to 
an updated α level if the null hypothesis for OS is rejected in the final analysis. Null 
hypothesis for ORR in pembrolizumab + lenvatinib versus lenvatinib may be tested at α = 
0.019 (if OS null hypothesis is rejected, but not PFS null hypothesis), α = 0.0219 (if both OS 
and PFS null hypotheses are rejected, but not the null hypothesis for ORR in pembrolizumab 
+ lenvatinib versus docetaxel), or α = 0.0249 (if all null hypotheses for PFS, OS and ORR in 
pembrolizumab + lenvatinib versus docetaxel are rejected). Based on 180 participants in 
pembrolizumab + lenvatinib arm and 45 participants in lenvatinib arm at IA2, the power and 
the approximate treatment difference required to reach the bound (ΔORR) are shown in
Table 15, assuming 10% and 30% response rates in the lenvatinib and pembrolizumab + 
lenvatinib arms, respectively.
Table 15
Possible Alpha Level and Approximate ORR Difference Between 
Pembrolizumab + Lenvatinib and Lenvatinib Required to Demonstrate Efficacy for ORR
Alpha Level
~Δ Objective Response Rate
Power
0.019
~0.138
0.813
0.0219
~0.132
0.829
0.0249
~0.130
0.847
9.8.2
Progression-free Survival
This study allocates an α level of 0.0029 (1-sided) to test PFS, and PFS is tested only at IA2. 
Figure 4 shows that if the null hypothesis for ORR in pembrolizumab + lenvatinib versus 
docetaxel is rejected, α=0.003 is fully reallocated to PFS hypothesis testing. If the null 
hypothesis for OS is rejected and null hypothesis for ORR in pembrolizumab + lenvatinib 
versus lenvatinib is rejected with reallocated α level (α=0.019), then α=0.019 is essentially 
fully reallocated to PFS hypothesis testing. Thus, the PFS null hypothesis may be tested at 
α=0.0029, α=0.0059 (if the ORR in pembrolizumab + lenvatinib versus docetaxel null 
hypothesis is rejected), α=0.0219 (if the OS null hypothesis is rejected and ORR in 
pembrolizumab + lenvatinib versus lenvatinib null hypothesis is rejected, but not the ORR in 
pembrolizumab + lenvatinib versus docetaxel null hypothesis), or α=0.0249 (if OS null 
hypothesis and both the ORR null hypotheses are rejected). However, if the test of PFS does 
not achieve statistical significance at IA2, the p value of PFS from IA2 can be compared to 
an updated α level if the null hypotheses for OS is rejected and null hypothesis for ORR in 
pembrolizumab + lenvatinib versus lenvatinib from IA2 is rejected. Table 16 shows the 
bounds and boundary properties for PFS hypothesis testing for each of these α-levels. Note 
that the final row indicates the total power to reject the null hypothesis for PFS at each α-
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level. If either ORR null hypothesis is rejected, PFS test may be compared to its updated 
bounds, considering the α reallocation from the 2 ORR hypotheses.
Table 16
Efficacy Boundaries and Properties for Progression-free Survival Analyses
Analysis
Value
= 0.0029
= 0.0059
= 0.0219
= 0.0249
IA2: 100%
N = 360
Events: 279*
Month: ~36
Z 
2.7589 
2.5181 
2.0161 
1.9618 
p (1-sided)a
0.0029
0.0059 
0.0219 
0.0249 
HR at boundb
0.7185 
0.7396 
0.7854 
0.7906 
P(Cross) if HR=1c
0.0029
0.0059
0.0219
0.0249
P(Cross) if HR=0.6d
0.9360 
0.9610 
0.9880 
0.9896 
Abbreviations: HR = hazard ratio; IA2 = interim analysis 2.
* Timing of IA2 is based on number of PFS events in Arm 1 and Arm 2 AND at least 6 months after the last participant 
is randomized.
a
p (1-sided) is the nominal α for testing.
b
HR at bound is the approximate HR required to reach an efficacy bound.
c
P(Cross if HR=1) is the probability of crossing a bound under the null hypothesis.
d
P(Cross if HR=0.6) is the probability of crossing a bound under the alternative hypothesis.
9.8.3
Overall Survival
OS is tested at IA2 and the final analysis. The OS hypothesis may be tested at α = 0.019 
(initially allocated α), α = 0.0219 (if the PFS but not the ORR in pembrolizumab + lenvatinib 
versus docetaxel null hypothesis is rejected), or α = 0.0249 (if both the PFS and ORR in 
pembrolizumab + lenvatinib versus docetaxel null hypotheses are rejected). 
Table 17 shows the bounds and boundary properties for OS hypothesis testing, derived using 
a Lan-DeMets O’Brien-Fleming spending function with α = 0.019, 0.0219, or 0.0249. If the 
actual number of OS events at the interim and final analyses differs from those specified in 
the table, the bounds will be adjusted using the Lan-DeMets O’Brien-Fleming spending 
function accordingly, with spending time determined by the minimum of the actual 
information fraction and the expected information fraction. For instance, if events accrue 
more slowly than expected or the same as expected, spending will be based on the actual 
information fraction. If events accrue more quickly than expected, cumulative spending 
based on the expected information fraction will be used, to save some α for analyses that will 
be performed with more than the originally planned maximum number of events. Also, note 
that if the PFS or ORR in pembrolizumab + lenvatinib versus docetaxel null hypothesis is 
rejected, each OS interim and final analysis test may be compared to its updated bounds, 
considering the α reallocation from the PFS or ORR hypothesis.
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Table 17
Efficacy Boundaries and Properties for Overall Survival Analyses
Analysis
Value
= 0.019
= 0.0219
= 0.0249
IA2: 80%a
N = 360
Events: 240
Month: ~36
Z 
2.3768 
2.3120 
2.2523 
p (1-sided)b
0.0087 
0.0104 
0.0122 
HR at boundc
0.7354 
0.7415 
0.7473 
P(Cross) if HR=1d
0.0087
0.0104
0.0122
P(Cross) if HR=0.66e
0.8009 
0.8183 
0.8335 
Final
N: 360
Events: 299*
Month: ~48
Z 
2.1338 
2.0780 
2.0265 
p (1-sided)b
0.0164 
0.0189 
0.0214 
HR at boundc
0.7813 
0.7863 
0.7910 
P(Cross) if HR=1d
0.0190
0.0219
0.0249
P(Cross) if HR=0.66e
0.9327 
0.9398 
0.9458 
Abbreviations: HR = hazard ratio; IA2 = interim analysis 2.
* Timing of final analysis is based on number of OS events in Arm 1 and Arm 2 AND at least 12 months follow-up after 
the last participant is randomized.
a
Percentage of expected number of events at final analysis anticipated at interim analysis.
b
p (1-sided) is the nominal α for testing.
c
HR at bound is the approximate HR required to reach an efficacy bound.
d
P(Cross if HR=1) is the probability of crossing a bound under the null hypothesis.
e
P(Cross if HR=0.66) is the probability of crossing a bound under the alternative hypothesis.
9.8.4
Safety Analyses
The eDMC has responsibility for assessment of the overall risk/benefit relationship. When 
prompted by safety concerns, the eDMC can request corresponding efficacy data. eDMC 
review of efficacy data to assess the overall ratio of risk/benefit to study participants will not 
require a multiplicity adjustment typically associated with a planned efficacy IA. However, 
to account for any multiplicity concerns raised by the eDMC review of unplanned efficacy 
data prompted by safety concerns, a sensitivity analysis for ORR, PFS, and OS, adopting a 
conservative multiplicity adjustment, will be prespecified in the sSAP.
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9.9
Sample Size and Power Calculations
The study will randomize 405 participants in a 4:4:1 ratio into the pembrolizumab + 
lenvatinib, docetaxel, and lenvatinib arms. PFS and OS are primary endpoints for the study, 
with ORR and DOR as secondary endpoints. For the PFS endpoint, based on a target number 
of ~279 events at IA2 in 360 participants in pembrolizumab + lenvatinib and docetaxel arms 
the study has approximately 93.6% power to detect an HR of 0.6 at an overall α level of 
0.29% (1-sided). For the OS endpoint, based on a target number of ~299 events in 360 
participants in pembrolizumab + lenvatinib and docetaxel arms, with approximately 80% of 
the target number events at IA2, the study has approximately 93.3% power to detect an HR 
of 0.66 at an overall α level of 1.9% (1-sided). The above sample size and power calculations 
for PFS and OS assume the following:
•
PFS follows an exponential distribution, with a median of 4.1 months for the docetaxel 
arm.
•
OS follows an exponential distribution, with a median of 8.6 months for the docetaxel 
arm.
•
The enrollment period is 30 months.
•
The monthly drop-out rate is 2% and 0.17% for PFS and OS, respectively.
•
The follow-up period is 18 months after the last participant is randomized.
The power calculations for ORR assume 10%, 10%, and 30% response rate in docetaxel, 
lenvatinib, and pembrolizumab + lenvatinib arms, respectively.
Based on 200 participants followed up for 6 months in pembrolizumab + lenvatinib and 
docetaxel arms at IA1, the power of ORR testing at the allocated α = 0.003 is approximately 
80.6% to detect a 20 percent point difference between an underlying 10% response rate in the 
docetaxel arm and a 30% response rate in the pembrolizumab + lenvatinib arm.
No initial alpha is allocated to compare ORR in pembrolizumab + lenvatinib versus 
lenvatinib and the ORR is tested only if the null hypotheses for OS is rejected at IA2 or final 
analysis.
Based on 180 participants in pembrolizumab + lenvatinib arm and 45 participants in 
lenvatinib arm at final analysis, the power of ORR testing at the allocated α = 0.019 
(reallocated from OS alpha) is approximately 81.3% to detect a 20 percent point difference 
between an underlying 10% response rate in the lenvatinib arm and a 30% response rate in 
the pembrolizumab + lenvatinib arm.
The sample size and power calculations were performed in R (“gsDesign” package) and with 
EAST 6.2.
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9.10
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
between-group treatment effect (pembrolizumab + lenvatinib versus docetaxel) for OS, PFS, 
and ORR will be estimated and plotted by treatment arm within each category of the 
following classification variables:
•
Stratification factors
-
Anti-PD-1/PD-L1 mAb (immediate prior therapy; not the immediate prior therapy)
-
TPS (<50%; ≥50%)
-
ECOG performance status (0;1)
•
Histology (nonsquamous; squamous)
•
Prior anti-PD-1/PD-L1 mAb (pembrolizumab as the only anti-PD-1/PD-L1 mAb [as 
monotherapy or combination therapy]); (other drug as the only anti-PD-1/PD-L1 mAb [as 
monotherapy or combination therapy])
•
Age category (<65 years; ≥65 years)
•
Sex (female; male)
•
Smoking status (never; former/current smoker)
•
Brain metastasis (present; absent)
•
Liver metastasis (present; absent)
•
Geographic region (east Asia; non-east Asia)
For subgroup analysis to take place, a given subgroup must include ≥10% of the total sample 
size in the two treatment arms to be compared.
9.11
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
9.12
Extent of Exposure
Extent of exposure for a participant is defined as the number of cycles in which the 
participant receives the study intervention. Summary statistics will be provided on the 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)
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 of clinical trials. In all cases, MSD clinical trials 
will be conducted in compliance with local and/or national regulations (eg, 
International Council for Harmonisation Good Clinical Practice [ICH-GCP]) and in 
accordance with the ethical principles that have their origin in the Declaration of 
Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical 
interventional investigations sponsored by MSD irrespective of the party (parties) 
employed for their execution (eg, contract research organizations, collaborative 
research efforts). This Code is not intended to apply to trials that are observational in 
nature, or which are retrospective. Further, this Code does not apply to investigator-
initiated trials, which are not under the full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-
driven to assess safety, efficacy, and/or pharmacokinetic or pharmacodynamic 
indices of MSD or comparator products. Alternatively, MSD may conduct 
outcomes research trials, trials to assess or validate various endpoint measures, or 
trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be 
adequate to address the specific purpose of the trial. 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 
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trials, as well as budgetary considerations. Prior to trial initiation, sites are 
evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol 
and general principles of Good Clinical Practice (GCP). MSD reviews clinical 
data for accuracy, completeness, and consistency. Data are verified versus source 
documentation according to standard operating procedures. Per MSD policies and 
procedures, if fraud, scientific/research misconduct, or serious GCP-
noncompliance is suspected, the issues are investigated. When necessary, the 
clinical site will be closed, the responsible regulatory authorities and ethics review 
committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results 
of its registered trials of marketed products in which treatment is assigned, according 
to the prespecified plans for data analysis. To the extent scientifically appropriate, 
MSD seeks to publish the results of other analyses it conducts that are important to 
patients, physicians, and payers. Some early phase or pilot trials are intended to be 
hypothesis generating rather than hypothesis testing; in such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses 
complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the 
International Committee of Medical Journal Editors (ICMJE). In summary,
authorship should reflect significant contribution to the design and conduct of the 
trial, performance or interpretation of the analysis, and/or writing of the manuscript. 
All named authors must be able to defend the trial results and conclusions. MSD 
funding of a trial will be acknowledged in publications.
III.Participant Protection
A. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated 
at each site. Significant changes or revisions to the protocol will be approved by the 
ethics committee prior to implementation, except changes required urgently to protect 
participant safety that may be enacted in anticipation of ethics committee approval. 
For each site, the ethics committee and MSD will approve the participant informed 
consent form.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is 
of primary importance. Potential participants will be informed of the risks and 
benefits of, as well as alternatives to, trial participation. At a minimum, trial designs 
will take into account the local standard of care.
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All participation in MSD clinical trials is voluntary. Participants enter the trial only 
after informed consent is obtained. Participants may withdraw from an MSD trial at 
any time, without any influence on their access to, or receipt of, medical care that 
may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent 
possible. Unless required by law, only the investigator, Sponsor (or representative), 
ethics committee, and/or regulatory authorities will have access to confidential 
medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
IV.Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate 
investigators (or the sponsoring institution) in a fair manner for the work performed 
in support of MSD trials. MSD does not pay incentives to enroll participants in its 
trials. However, when enrollment is particularly challenging, additional payments 
may be made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate 
referring physicians for time spent on chart review to identify potentially eligible 
participants.
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.
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10.1.2
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
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.
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 
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worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules, 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Steering Committee
This study will be conducted in consultation with a Steering Committee. The Steering 
Committee may be comprised of some or all of the following members:
•
Sponsor personnel,
•
Eisai personnel,
•
Investigators participating in the study, and
•
Consulting therapeutic-area and clinical study experts.
The Steering Committee will provide guidance on the operational aspects of the study, 
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 on any recommendations made by the eDMC 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 eDMC 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 
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(eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The eDMC will make recommendations to the EOC regarding steps to ensure both 
participant safety and the continued ethical integrity of the study. Also, the eDMC will 
review interim study results, consider the overall risk and benefit to study participants 
(Section 9.7; Interim Analyses), and recommend to the EOC whether the study should 
continue in accordance with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of eDMC reports, minutes, and recommendations will be described in the eDMC charter that 
is reviewed and approved by all the eDMC 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.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical 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 trials 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.
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10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, 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.
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.
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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.
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 terminate the study or study site participation in the study 
for medical, safety, regulatory, administrative, or other reasons consistent with applicable 
laws, regulations, and GCP, or upon advice of the eDMC. If the eDMC makes a 
recommendation to alter the study conduct, it may be implemented by the Sponsor 
immediately upon EOC advice. In the event the Sponsor prematurely terminates a particular 
study or study site, the Sponsor will promptly notify the study site’s investigators, health 
authorities, and IRB/IEC.
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The DMC will recommend termination of the study if warranted, as described in Section 
10.1.4.3. In addition, early study termination may occur based on clinical criteria specified 
below:
1.
Quality or quantity of data recording is inaccurate or incomplete;
2.
Poor adherence to protocol and regulatory requirements;
3.
Incidence or severity of adverse drug reaction in this or other studies indicates a 
potential health hazard to participants;
4.
Plans to modify or discontinue the development of the study drug.
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests listed in Table 18 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 (see Appendix 7).
•
Pregnancy testing:
o
Pregnancy testing requirements for study inclusion are described in Section 5.1.
o
Pregnancy testing (urine or serum) should be performed as required by local 
regulations during study treatment.
o
Pregnancy testing (urine or serum) should be performed as required by local 
regulations at the end of relevant systemic exposure and correspond with the time 
frame for female participant contraception in Section 5.1.
o
Additional urine or serum pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulations, to establish the 
absence of pregnancy at any time during the participant’s participation in the 
study.
Table 18
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC indices:
MCVc
MCHc
% reticulocytesc
WBC count with 
differentiala:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUNb
Potassium
AST/SGOT
Total bilirubin (and 
direct bilirubin, if 
total bilirubin is 
elevated above the 
upper limit of 
normal)
Albumin
Bicarbonatec
Chloridec
Phosphorusc
Creatinined
Sodium
ALT/SGPT
Total proteinc
Glucose 
Calcium
Alkaline 
phosphatase
Magnesium
TSH
Free thyroxinee
Lactate 
dehydrogenasec
Amylase
Lipase
Triiodothyronine 
(Total T3)e
Pregnancy test
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Laboratory 
Assessments
Parameters
Routine 
Urinalysisf
Specific gravity
pH, glucose, proteing, hemoglobin or blood, ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Other 
Screening Tests
PT/INR and aPTT/PTTh
Serology (HIV RNA, HbsAg, and HCV antibody)
Serum or urine β HCG pregnancy test (as needed for WOCBP)
Abbreviations: ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); aPTT = activated 
partial thromboplastin time; AST (SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic transaminase); 
β HCG = β human chorionic gonadotropin; BUN = blood urea nitrogen; C = Cycle; CO2 = carbon dioxide; 
CPK = creatine phosphokinase; FSH = follicle stimulating hormone; FT3 = free triiodothyronine; FT4 = free 
thyroxine; HbsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
INR = international normalized ratio; MCH = mean corpuscular hemoglobin; MCV, mean corpuscular volume; PK 
= pharmacokinetic(s); PT = prothrombin time; PTT = partial thromboplastin time; RBC = red blood cells; RNA = 
ribonucleic acid; SOC = standard of care; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating 
hormone; ULN = upper limit of normal; WBC = white blood cell; WOCBP = women of childbearing potential.
a Absolute or % acceptable per institutional standard.
b Urea is acceptable if BUN is not available as per institutional standard.
c Performed only if considered local standard of care.
d Glomerular filtration rate (GFR) (measured or calculated) or creatinine clearance can be used in place of creatinine.
e Free T4, total T3, and TSH levels will be determined during screening and then repeated on Day 1 of every other 
cycle (starting C2), at the time of discontinuation end of treatment), and at the safety follow-up visits. Free T3 is 
acceptable where total T3 cannot be determined. There may be instances when sites are unable to obtain thyroid 
function test results before scheduled dosing. After C1, review of thyroid function test results after dosing is 
acceptable. 
f If urine dipstick testing suggests a urinary tract infection, or if clinically indicated, a urine microscopy, culture, and 
sensitivity should be performed at the institution’s laboratory.
g If urine protein is ≥2+ (first occurrence or a subsequent increase in severity of urine dipstick proteinuria occurring on 
the same lenvatinib dose level), then a 24-hour urine collection or an immediate spot urine protein-to-creatinine 
(UPCR) test should be done to quantify the 24-hour urine protein excretion. A 24-hour urine collection (initiated as 
soon as possible and at least within 72 hours) to verify the grade of proteinuria is required when UPCR is ≥2.4.
h Performed as part of the screening assessment and as clinically indicated for participants taking anticoagulants.
The investigator (or medically qualified designee) must document his or her review of each 
laboratory safety report.
No laboratory results will be blinded, with the exception of PD-L1 TPS, to which 
investigators and participants will be blinded.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, 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.
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•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.” Lenvatinib 
overdose without an associated AE is not reportable as an AE. Refer to Section 8.5 for 
the definition of overdose.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
-
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
-
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
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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.
-
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
-
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
-
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
-
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
Additional Events Reported on the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes..
•
Is a new cancer (that is not a condition of the study).
•
Is associated with an overdose.
10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
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•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI 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
•
Did the study intervention cause the AE?
•
The determination of the likelihood that the study intervention caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
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•
The following components are to be used to assess the relationship between the 
study intervention and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the study 
intervention caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc), expected pharmacologic effect, or measurement of drug/metabolite in 
bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the study intervention? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with IMP)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the study intervention discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the study 
intervention; (3) the study is a single-dose drug study; or (4) study intervention (s) 
is/are only used 1 time.)
-
Rechallenge: Was the participant reexposed to the study intervention in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability; (2) the study is a single-dose drug study; or (3) study 
intervention (s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE STUDY INTERVENTION, OR IF REEXPOSURE 
TO THE STUDY INTERVENTION POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the study intervention or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
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•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a study intervention relationship).
-
Yes, there is a reasonable possibility of study intervention relationship:
◦
There is evidence of exposure to the study intervention. The temporal sequence of 
the AE onset relative to the administration of the study intervention is reasonable. 
The AE is more likely explained by the study intervention than by another cause.
-
No, there is not a reasonable possibility of study intervention relationship:
◦
Participant did not receive the study intervention OR temporal sequence of the AE 
onset relative to administration of the study intervention is not reasonable OR the 
AE is more likely explained by another cause than the study intervention. (Also 
entered for a participant with overdose without an associated AE.)
•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
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10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool (EDC)
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
-
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure email of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
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 the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:

Premenarchal

Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.

Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.
◦
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with 2 FSH measurements in the 
postmenopausal range is required.
Females on HRT and whose menopausal status is in doubt will be required to use one of the 
nonhormonal highly effective contraception methods if they wish to continue their HRT 
during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea
Highly Effective 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
●
Nonhormonal 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 in clinical studies.
b
If locally required, in accordance with Clinical Trial Facilitation Group guidelines, acceptable hormonal 
contraceptives are limited to those, which inhibit ovulation.
c
An IUS is a progestin-releasing IUD.
Note: The following are not acceptable methods of contraception:
-
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and 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.
Following initiation of study intervention, additional pregnancy testing will be performed as 
indicated in Section 1.3, during the treatment period and at least every 30 days up to at least 
120 days after the last dose of pembrolizumab or lenvatinib or up to 30 days after the last 
dose of docetaxel, and as required locally.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
Not applicable.
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Germany-specific Requirements
1. Exclusion Criterion 21: HIV testing is mandatory.
2. Exclusion Criterion 22: Hepatitis B and C testing is mandatory.
3. Exclusion Criterion 23: Tuberculosis testing is mandatory.
4. Section 6.6.3.1 (Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue): Participants should be discontinued from study treatment if any of the 
following AEs occur:

Stevens-Johnson syndrome

Toxic epidermal necrolysis
5. Please refer to the current pembrolizumab SmPC for additional guidance on management 
of immune-related AEs associated with pembrolizumab.
6. Please refer to the current lenvatinib SmPC for additional guidance on management of 
AEs associated with lenvatinib administration and other contraindications.
7. Section 8.4.1 (Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information): All AEs meeting serious criteria are to be collected for 120 
days after the last dose of study intervention.
8. For participants to be eligible to participate in Germany, they must be capable of 
providing documented Informed Consent and Legally Acceptable Representative are not 
acceptable.
10.7.2
UK-specific Requirements
1. HIV, Hepatitis B and C testing is to be performed per local standards.
2. Section 6.5.2 (Prohibited Concomitant Medications): Live vaccines must not be 
administered for 90 days after the last dose of study intervention.
Note: Any licensed COVID-19 vaccine (including for Emergency Use) is allowed in the 
study as long as they are mRNA vaccines, replication-incompetent adenoviral vaccines, 
or inactivated vaccines. These vaccines will be treated just as any other concomitant 
therapy.
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10.7.3
Japan-specific Requirements
1. To assist early diagnosis of pneumonitis/interstitial lung disease (ILD) in study 
participants, the following parameters, including pulse oximetry monitoring (peripheral 
capillary oxygen saturation [SpO2]), C-reactive protein (CRP), KL-6, and surfactant 
protein D (SP-D) will be measured in this study. These parameters should be measured at 
the following times:
-
SpO2: at the time of vital sign assessment.
-
CRP, KL-6 and SP-D: at screening*, predose on Day 1 of every cycle, at the end of 
treatment, and at the safety follow-up visit (30 days after the last dose).
*At the time of clinical laboratory tests, such as CBC and chemistry.
2. If pneumonitis/ILD occurs, regardless of causality, an independent ILD evaluation 
committee will conduct adjudication pneumonitis/ILD. For this purpose, relevant data 
such as chest imaging (from baseline to the recovery from pneumonitis/ILD) will be 
submitted to MSD K.K.
3. Section 6.1 (Study Intervention(s) Administered) Table 2 (Study Interventions): 
Pembrolizumab used in this study is categorized as “product(s) used in the clinical trial 
other than test product(s)” in Japan local regulation.
10.7.4
France-specific Requirements
Section 6.6.3.1 (Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue): Participants should be discontinued from study treatment if any of the 
following AEs occur:

Stevens-Johnson syndrome

Toxic epidermal necrolysis
Please refer to the current pembrolizumab SmPC for additional guidance on management of 
immune-related AEs associated with pembrolizumab.
Please refer to the current lenvatinib SmPC for additional guidance on management of AEs 
associated with lenvatinib administration and other contraindications.
10.7.5
Canada-specific Requirements
Section 6.6.2.9
Lenvatinib should be discontinued in any participant who develops gastrointestinal 
perforation of any grade or ≥Grade 3 fistula.
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10.7.6
Italy-specific Requirements
1. Section 6.6.3.1 (Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue): Participants should be discontinued from study treatment if any of the 
following AEs occur:

Stevens-Johnson syndrome

Toxic epidermal necrolysis
Please refer to the current pembrolizumab SmPC for additional guidance on management of 
immune-related AEs associated with pembrolizumab.
Please refer to the current lenvatinib SmPC for additional guidance on management of AEs 
associated with lenvatinib administration and other contraindications.
10.7.7
Portugal-specific Requirements
1. Exclusion Criterion 21: HIV testing is mandatory.
2. Exclusion Criterion 22: Hepatitis B and C testing is mandatory.
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10.8
Appendix 8: Description of the iRECIST Process for Assessment of Disease 
Progression
Assessment at Screening and Prior to 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 evidence of radiologic PD by RECIST 1.1 as determined by the 
investigator, the investigator will decide whether to continue a participant on study 
intervention until repeat imaging is obtained (using iRECIST for participant management see
Table 6 and Figure 3). This decision by the investigator should be based on the participant’s 
overall clinical condition**.
**Clinical stability is defined as:
•
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 
imaging for confirmation of PD by iRECIST.
If the investigator decides to continue study intervention, 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. Images should continue to be sent to 
the CIV for retrospective BICR.
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:
•
Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir.
•
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).
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iRECIST defines new response categories, including iRECIST-unconfirmed progressive 
disease (iUPD) and iRECIST-confirmed progressive disease (iCPD). For purposes of 
iRECIST assessment, the first visit showing progression according to RECIST 1.1 will be 
assigned a visit (overall) response of iUPD, regardless of which factors caused the 
progression.
At this visit, target and 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.
Assessment at Confirmatory Imaging
At confirmatory imaging, the participant will be classified as progression confirmed (with an 
overall response of iCPD), or as showing persistent unconfirmed progression (with an overall 
response of iUPD), or as showing disease stability or response (iRECIST-confirmed stable 
disease [iSD]/iRECIST-confirmed partial response [iPR]/iRECIST-confirmed complete 
response [iCR]).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:
•
Any of the factors that were the basis for the iUPD at the previous visit show worsening
-
For target lesions, worsening is a further increase in the sum of diameters of ≥5 mm, 
compared to any prior iUPD time point
-
For nontarget lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the “unequivocal” 
standard of RECIST 1.1
-
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
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Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:
•
None of the progression-confirming factors identified above occurs AND
•
The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging at
which iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation imaging proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:
•
None of the progression-confirming factors identified above occurs, AND
•
The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold. 
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be 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 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 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 in the SoA (Section 1.3).
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Detection of Progression at Visits After Pseudoprogression 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 progression, their doing so for the 
first time results in iUPD.
-
If nontarget lesions have shown previous unequivocal progression, and this 
progression 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 Confirmatory Imaging above) is repeated. Progression 
must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with
one exception: if new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve 
to iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication [Seymour, L., et 
al 2017].
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10.9
Appendix 9: Eastern Cooperative Oncology Group (ECOG) Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry out all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% of 
waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry out any self-care. 
Totally confined to bed or chair.
5
Dead.
[Oken, M. M., et al 1982]
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10.10 Appendix 10: Abbreviations
Abbreviation
Expanded Term
1L
first-line
2L
second-line
ADA
antidrug antibodies
AE
adverse event 
AJCC
American Joint Committee on Cancer
ALK
anaplastic lymphoma kinase gene
ALT
alanine aminotransferase
APaT
all participants as treated
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
β-HCG
β human chorionic gonadotropin
BICR
blinded independent central review
BP
blood pressure
CI
confidence interval
CIV
central imaging vendor
COVID-19
Coronavirus Disease 2019
CR
complete response
CRF
case report form 
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTFG
Clinical Trials Facilitation and Coordination Group
CYP
cytochrome P450
DCR
disease control rate
DCR12
disease control rate at 12 weeks
DDI
drug-drug interaction
DLT
dose-limiting toxicity
DMC
data monitoring committee 
DNA
deoxyribonucleic acid
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Abbreviation
Expanded Term
DOR
duration of response
ECG
electrocardiogram 
ECHO
echocardiogram
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
eDMC
external data monitoring committee
EEA
European Economic Area
EGFR
epithelial growth factor receptor
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EORTC
European Organization for Research and Treatment of Cancer
ePRO
electronic patient-reported outcome
EQ-5D-5L
European Quality of Life Five-Dimensional Five-Level Questionnaire
EU CTR
European Union Clinical Trials Regulation
FDA
Food and Drug Administration (United States)
FDAAA
Food and Drug Administration Amendments Act
FFPE
formalin-fixed, paraffin-embedded
FGF
fibroblast growth factor
FGFR
fibroblast growth factor receptor
FoxP3
Forkhead box P3
FSH
follicle stimulating hormone
FT3
free triiodothyronine
FU
follow-up
GCP
Good Clinical Practice
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
hazard ratio
HRT
hormone replacement therapy
IA
interim analysis
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Abbreviation
Expanded Term
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
iCPD
iRECIST-confirmed progressive disease
iCR
iRECIST-confirmed complete response
iCRO
imaging contract research organization
IEC
Independent Ethics Committee
INR
international normalized ratio
iPR
iRECIST-confirmed partial response
irAE
immune-related AE
IRB
Institutional Review Board 
iRECIST
Response Evaluation Criteria in Solid Tumors Version 1.1 for immune-
based therapeutics
IRT
interactive response technology
iSD
iRECIST-confirmed stable disease
ITT
intention-to-treat
IUD
intrauterine device
iUPD
iRECIST-unconfirmed progressive disease
IUS
intrauterine hormone-releasing system
IV
intravenous(ly)
LFT
liver function tests
LVEF
left ventricular ejection fraction
mAb
monoclonal antibody
MAPK
mitogen-activated protein kinase
MRI
magnetic resonance imaging
MTD
maximum tolerated dose 
MUGA
multigated acquisition
NCI
National Cancer Institute
NSCLC
non-small cell lung cancer
ONJ
osteonecrosis of the jaw
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Abbreviation
Expanded Term
ORR
objective response rate
OS
overall survival
PD
progressive disease
PD-1
programmed cell death protein 1
PDGF
platelet derived growth factor
PD-L1
programmed cell death ligand 1
PFS
progression-free survival
Pgp
P-glycoprotein
PK
pharmacokinetic(s)
PO
oral(ly)
PopPK
population pharmacokinetics
PR
partial response
PRO
patient-reported outcome
Q3W
every 3 weeks
QD
once daily
QLQ-C30
Quality of Life Questionnaire Core 30 items
QLQ-LC13
Quality of Life Questionnaire Lung Cancer Module 13
QoL
quality of life
QTcF
QT interval corrected with Fridericia’s formula
RCC
renal cell carcinoma
RECIST 1.1
Response Evaluation Criteria in Solid Tumors Version 1.1
RNA
ribonucleic acid
ROS1
c-ros oncogene 1
RP2D
recommended Phase 2 dose
RTKi
receptor tyrosine kinase inhibitor
RUQ
right upper quadrant 
SAE
serious adverse event 
SAP
statistical analysis plan
SD
stable disease
SGOT
serum glutamate oxaloacetate transaminase
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Abbreviation
Expanded Term
SGPT
serum glutamate pyruvate transaminase
SoA
schedule of activities
SOC
standard of care
sSAP
supplemental statistical analysis plan
T3
triiodothyronine
T4
thyroxine
TAM
tumor-associated macrophage
TPS
tumor proportion score
TSH
thyroid-stimulating hormone
TTD
time to true deterioration
ULN
upper limit of normal
UPCR
urine protein/creatinine ratio
VEGF
vascular endothelial growth factor
VEGFR
vascular endothelial growth factor receptor
WBC
white blood cell
WOCBP
woman/women of childbearing potential 
WONCBP
woman/women of non-childbearing potential
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11
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