Clinical trial NCT03829319
Conditions: Nonsquamous Non-small Cell Lung Cancer
Keywords: programmed cell death 1 (PD-1, PD1) programmed cell death-ligand 1 (PD-L1, PDL1) programmed cell death-ligand 2 (PD-L2, PDL2)
Sponsor: Merck Sharp & Dohme LLC
Start date: 2019-03-25; Completion date: 2024-08-30
Enrollment: 761 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the safety and efficacy of pemetrexed + platinum chemotherapy + pembrolizumab (MK-3475) with or without lenvatinib (MK-7902/E7080) as first-line intervention in adults with metastatic nonsquamous non-small cell lung cancer.

The primary study hypotheses state that: 1) the combination of lenvatinib + platinum doublet chemotherapy + pembrolizumab prolongs Progression-free Survival (PFS) as assessed by blinded independent central review (BICR) per modified Response Evaluation Criteria in Solid Tumors version 1.1 (RESIST 1.1) compared to matching placebo + platinum doublet chemotherapy + pembrolizumab, and 2) the combination of lenvatinib + platinum doublet chemotherapy + pembrolizumab prolongs Overall Survival (OS) compared to matching placebo + platinum doublet chemotherapy + pembrolizumab.

Detailed description:

Arms: arm 1: Participants receive carboplatin Area Under Curve 5 mg/mL/min (AUC5) or cisplatin 75 mg/m\^2 via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) for 4 cycles PLUS pemetrexed 500 mg/m\^2 via IV infusion Q3W for 4 cycles PLUS pembrolizumab via IV infusion Q3W for up to 35 cycles (up to 2 years) PLUS lenvatinib via oral capsule once daily. arm 2: In Parts 1 and 2: Participants receive carboplatin AUC5 or cisplatin 75 mg/m\^2 via IV infusion Q3W for 4 cycles PLUS pemetrexed 500 mg/m\^2 via IV infusion Q3W for 4 cycles PLUS pembrolizumab via IV infusion Q3W for up to 35 cycles (up to 2 years) PLUS (Part 2 only) placebo matching lenvatinib via oral capsule once daily.
Interventions: intervention 1: Pembrolizumab intervention 2: Carboplatin intervention 3: Cisplatin intervention 4: Pemetrexed intervention 5: Lenvatinib intervention 6: Placebo matching lenvatinib
Intervention descriptions: intervention 1: IV infusion Q3W intervention 2: IV infusion Q3W intervention 3: IV infusion Q3W intervention 4: IV infusion Q3W intervention 5: Oral capsule once daily intervention 6: Oral capsule once daily

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 3 Randomized, Placebo-controlled Study to 
Evaluate the Safety and
Efficacy of Pemetrexed + Platinum Chemotherapy + 
Pembrolizumab (MK-3475) with or without Lenvatinib 
(E7080/MK-7902) as First-line Intervention in Participants 
with Metastatic Nonsquamous Non small Cell Lung Cancer 
(LEAP-006)
NCT03829319
27-October-2023


PRODUCT: MK-7902 006-08
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PROTOCOL/AMENDMENT NO.: MK-7902-006-08 (E7080-G000-315)
MK-7902-006-08 FINAL PROTOCOL
27-OCT-2023
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3 Randomized, Placebo-controlled Study to Evaluate the Safety and 
Efficacy of Pemetrexed + Platinum Chemotherapy + Pembrolizumab (MK-3475) with or 
without Lenvatinib (E7080/MK-7902) as First-line Intervention in Participants with 
Metastatic Nonsquamous Non-small Cell Lung Cancer (LEAP-006)
Protocol Number: MK-7902-006-08 (E7080-G000-315)
Compound Number: MK-7902 (E7080/lenvatinib) and MK-3475 (pembrolizumab)
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
The study is cofunded by MSD and Eisai.
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
EudraCT
140221
2018-003824-35
Approval Date:  27 October 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
7902-006-08
27-OCT-2023
The study is to be discontinued based on the observation that the combination of pembrolizumab 
+ platinum chemotherapy + lenvatinib versus pembrolizumab + platinum chemotherapy 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 IA3.
7902-006-07
06-OCT-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.
7902-006-06
03-SEP-2021
Country-specific clarifications were added to address the sourcing of pembrolizumab in the UK 
and to clarify pembrolizumab dose modification and toxicity management in Canada.
7902-006-05
30-APR-2021
The protocol was amended to update the assumptions and timing of the analyses in the SAP to 
allow sufficient duration of follow-up based on updated enrollment period and the long-term 
survival data from the reference study KEYNOTE-189. 
7902-006-04 –
China-Specific
03-MAR-2020
The protocol was amended to extend the enrollment period beyond the global study to achieve 
required exposure and number of events to investigate efficacy and safety in participants with 1L 
NSCLC enrolled in China.
7902-006-03
09-AUG-2019
The study protocol was amended to correct significant clerical errors inadvertently introduced 
into study amendment 02 that altered the study protocol inclusion/exclusion criteria and 
contraceptive language.
7902-006-02
02-JUL-2019
Amended text to address health authority feedback and to align with the Sponsor’s newly 
released lenvatinib and pembrolizumab (LEAP) program protocol template.
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Document
Date of Issue
Overall Rationale
7902-006-01
16-JAN-2019
The protocol was amended in response to the feedback from the regulatory agency (FDA) 
regarding a potential hold comment related to permanent discontinuation of lenvatinib for Grade 
3 thromboembolic events since CTCAE V5 classifies Grade 3 as “Urgent medical intervention 
indicated”.
7902-006-00
08-NOV-2018
Original protocol
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 08
Overall Rationale for the Amendment:
The study is to be discontinued based on the observation that the combination of 
pembrolizumab + platinum chemotherapy + lenvatinib versus pembrolizumab + platinum 
chemotherapy 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 IA3.
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 
pembrolizumab monotherapy. Upon study 
termination, participants are discontinued 
and may be enrolled in a pembrolizumab 
extension study, if available.
This change addresses new data that recently 
became available. The combination of 
pembrolizumab + platinum chemotherapy + 
lenvatinib versus pembrolizumab + platinum 
chemotherapy 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 IA3..
Section Number and 
Name
Description of Change
Brief Rationale
Additional Changes
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.
Section 1.1, Synopsis
Table: Intervention Groups and Duration:
To clarify that hat 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 pembrolizumab 
monotherapy. Upon study termination, 
participants are discontinued and may be 
enrolled in a pembrolizumab extension 
study, if available.
Refer to Section 1.1 rationale .
Section 1.3, Schedule of 
Activities
Clarify which activities will or will not be 
performed during the study for participants 
who are still on study treatment.
Refer to Section 1.1 rationale.
Section 4.3.1, Maximum 
Dose/Exposure for This 
Study
Note on study-specific investigator letter 
has been added.
Refer to Section 1.1 rationale.
Section 4.4, Beginning and 
End of Study Definition
Participants may be enrolled in an 
extension study.
Refer to Section 1.1 rationale.
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Section Number and 
Name
Description of Change
Brief Rationale
Section 6.1, Study 
Intervention(s) 
Administered
Note on study-specific investigator letter 
has been added.
Refer to Section 1.1 rationale.
Section 6.3.3, Blinding
Study unblinded due to result of FA.
Refer to Section 1.1 rationale.
Section 6.6, Dose 
Modification 
(Escalation/Titration/Other)
Treatment of participants with study 
interventions is clarified. Note on study-
specific investigator letter has been added.
Refer to Section 1.1 rationale.
Section 7.1.1, Second 
Course Treatment
Clarify that participants will be considered 
for Second Course treatment following 
investigator assessment of PD.
Refer to Section 1.1 rationale.
Section 8.1.10, Participant 
Blinding/Unblinding
Study unblinded due to results of final 
analysis
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 8.2.1.3, 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.
Section 8.9, Biomarkers
Sample collection will be discontinued.
Refer to Section 1.1 rationale.
Section 8.12.2, Treatment 
Period
BICR verification was removed.
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 ............................................................................................17
1.1
Synopsis.................................................................................................................17
1.2
Schema ..................................................................................................................25
1.3
Schedule of Activities (SoA)................................................................................26
1.3.1
Initial Treatment Phase - Parts 1 and 2 ........................................................26
1.3.2
Second Course Treatment (Retreatment) - Parts 1 and 2.............................36
2
INTRODUCTION..........................................................................................................40
2.1
Study Rationale....................................................................................................40
2.2
Background ..........................................................................................................40
2.2.1
Pharmaceutical and Therapeutic Background .............................................41
2.2.1.1
Lenvatinib ..........................................................................................41
2.2.1.2
Pembrolizumab ..................................................................................42
2.2.1.3
Lung Cancer: Epidemiology and Current Therapeutic Options ........42
2.2.1.4
Lenvatinib Activity in Non-small Cell Cancer..................................43
2.2.1.5
Scientific Rationale for the Combination of Lenvatinib and 
Pembrolizumab ..................................................................................44
2.2.2
Preclinical and Clinical Studies ...................................................................45
2.2.3
Ongoing Clinical Studies of Lenvatinib and Pembrolizumab .....................45
2.2.4
Information on Other Study-related Therapy ..............................................46
2.3
Benefit/Risk Assessment......................................................................................46
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................46
4
STUDY DESIGN............................................................................................................50
4.1
Overall Design......................................................................................................50
4.2
Scientific Rationale for Study Design.................................................................53
4.2.1
Rationale for Endpoints ...............................................................................54
4.2.1.1
Efficacy Endpoints.............................................................................54
4.2.1.1.1
Primary Efficacy Endpoints.....................................................54
4.2.1.1.2
Secondary Efficacy Endpoints.................................................55
4.2.1.1.3
RECIST 1.1..............................................................................55
4.2.1.1.4
Modified RECIST 1.1 for Immune-based Therapeutics 
(iRECIST)................................................................................55
4.2.1.2
Safety Endpoints................................................................................55
4.2.1.3
Rationale for Patient-Reported Outcomes .........................................56
4.2.1.3.1
EORTC QLQ-C30 ...................................................................56
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4.2.1.3.2
EORTC QLQ-LC13.................................................................56
4.2.1.3.3
EuroQoL EQ-5D......................................................................56
4.2.1.4
Pharmacokinetic Endpoints ...............................................................57
4.2.1.5
Planned Exploratory Biomarker Research.........................................57
4.2.2
Rationale for the Use of Comparator/Placebo .............................................59
4.3
Justification for Dose...........................................................................................59
4.3.1
Maximum Dose/Exposure for This Study ...................................................59
4.3.2
Lenvatinib Dosing........................................................................................59
4.3.3
Pembrolizumab Dosing................................................................................60
4.3.4
Chemotherapy Dosing .................................................................................61
4.4
Beginning and End of Study Definition .............................................................61
4.4.1
Clinical Criteria for Early Study Termination .............................................61
5
STUDY POPULATION ................................................................................................62
5.1
Inclusion Criteria.................................................................................................62
5.2
Exclusion Criteria................................................................................................66
5.3
Lifestyle Considerations......................................................................................69
5.3.1
Meals and Dietary Restrictions....................................................................69
5.3.2
Contraception...............................................................................................69
5.3.3
Pregnancy.....................................................................................................69
5.3.4
Use in Nursing Women................................................................................70
5.4
Screen Failures.....................................................................................................70
5.5
Participant Replacement Strategy......................................................................70
6
STUDY INTERVENTION............................................................................................70
6.1
Study Intervention(s) Administered...................................................................70
6.2
Preparation/Handling/Storage/Accountability .................................................73
6.2.1
Dose Preparation..........................................................................................73
6.2.2
Handling, Storage, and Accountability........................................................73
6.3
Measures to Minimize Bias: Randomization and Blinding..............................74
6.3.1
Intervention Assignment..............................................................................74
6.3.2
Stratification.................................................................................................74
6.3.3
Blinding........................................................................................................75
6.4
Study Intervention Compliance..........................................................................75
6.5
Concomitant Therapy..........................................................................................75
6.5.1
Allowed Concomitant Medications .............................................................76
6.5.2
Prohibited Concomitant Medications ..........................................................77
6.5.3
Drug Interactions .........................................................................................77
6.5.4
Rescue Medications and Supportive Care ...................................................78
6.5.4.1
Systemic Corticosteroid Use..............................................................78
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6.5.4.2
Antiemetic Use...................................................................................78
6.5.4.3
Colony-stimulating Factors................................................................78
6.5.4.4
Cisplatin Premedication.....................................................................79
6.5.4.5
Pemetrexed Premedication.................................................................79
6.6
Dose Modification (Escalation/Titration/Other)...............................................79
6.6.1
Lenvatinib ....................................................................................................80
6.6.1.1
Management of Hypertension............................................................81
6.6.1.2
Management of Proteinuria................................................................83
6.6.1.3
Management of Diarrhea ...................................................................84
6.6.1.4
Management of Hepatotoxicity..........................................................84
6.6.1.5
Management of Thromboembolic Events..........................................84
6.6.1.6
Management of Posterior Reversible Encephalopathy 
Syndrome/Reversible Posterior Leukoencephalopathy Syndrome....85
6.6.1.7
Management of Hypocalcemia ..........................................................85
6.6.1.8
Management of Hemorrhage .............................................................85
6.6.1.9
Management of Gastrointestinal Perforation or Fistula Formation...85
6.6.1.10
Management of QT Prolongation ......................................................86
6.6.1.11
Management of Osteonecrosis of the Jaw .........................................86
6.6.1.12
Other Allowed Dose Interruptions for Lenvatinib.............................86
6.6.2
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................86
6.6.2.1
Dose Modification and Toxicity Management for Immune-related 
AEs Associated with Pembrolizumab................................................86
6.6.2.2
Dose Modification and Toxicity Management of Infusion-
Reactions Related to Pembrolizumab................................................91
6.6.2.3
Other Allowed Dose Interruption(s) for Pembrolizumab ..................94
6.6.3
Chemotherapy..............................................................................................94
6.6.4
Dose Modifications for Overlapping Toxicities ..........................................96
6.7
Intervention After the End of the Study............................................................97
6.8
Clinical Supplies Disclosure................................................................................97
6.9
Standard Policies..................................................................................................97
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................97
7.1
Discontinuation of Study Intervention...............................................................97
7.1.1
Second Course Treatment............................................................................99
7.2
Participant Withdrawal From the Study.........................................................100
7.3
Lost to Follow-up ...............................................................................................101
8
STUDY ASSESSMENTS AND PROCEDURES......................................................101
8.1
Administrative and General Procedures .........................................................102
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8.1.1
Informed Consent.......................................................................................102
8.1.1.1
General Informed Consent...............................................................102
8.1.2
Inclusion/Exclusion Criteria ......................................................................103
8.1.3
Participant Identification Card...................................................................103
8.1.4
Medical History .........................................................................................103
8.1.4.1
General Medical History..................................................................103
8.1.4.2
Oncologic Disease Details...............................................................103
8.1.5
Prior and Concomitant Medications Review.............................................103
8.1.5.1
Prior Medications.............................................................................103
8.1.5.2
Prior Oncologic Treatment ..............................................................104
8.1.5.3
Concomitant Medications................................................................104
8.1.6
Assignment of Screening Number.............................................................104
8.1.7
Assignment of Treatment/Randomization Number...................................104
8.1.8
Study Intervention Administration ............................................................105
8.1.8.1
Timing of Dose Administration.......................................................105
8.1.8.1.1
Lenvatinib/Matching Placebo ................................................105
8.1.8.1.2
Pembrolizumab ......................................................................105
8.1.8.1.3
Carboplatin.............................................................................105
8.1.8.1.4
Cisplatin.................................................................................105
8.1.8.1.5
Pemetrexed.............................................................................106
8.1.8.2
Treatment Compliance.....................................................................106
8.1.8.2.1
Lenvatinib/Placebo ................................................................106
8.1.8.2.2
Pembrolizumab/Platinum Doublet Chemotherapy ................106
8.1.9
Discontinuation and Withdrawal ...............................................................106
8.1.10
Participant Blinding/Unblinding................................................................106
8.1.11
Calibration of Equipment...........................................................................107
8.2
Efficacy Assessments .........................................................................................107
8.2.1
Tumor Scans and Response Assessment ...................................................107
8.2.1.1
Initial Tumor Scans..........................................................................108
8.2.1.2
Tumor Scans During the Study........................................................109
8.2.1.3
End of Treatment and Follow-up Tumor Scans...............................109
8.2.1.4
Second Course Treatment Tumor Scans..........................................110
8.2.1.5
RECIST 1.1 Assessment of Disease................................................111
8.2.1.6
iRECIST Assessment of Disease.....................................................112
8.2.1.7
Tumor Tissue Collection for Biomarker Analysis...........................115
8.2.2
Patient-Reported Outcomes .......................................................................116
8.3
Safety Assessments.............................................................................................116
8.3.1
Physical Examinations...............................................................................116
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8.3.2
Vital Signs..................................................................................................116
8.3.3
Electrocardiograms ....................................................................................117
8.3.4
Echocardiograms or Multigated Acquisition Scans...................................117
8.3.5
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 118
8.3.6
Pregnancy Test...........................................................................................118
8.3.7
Clinical Safety Laboratory Assessments ...................................................118
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ..................................................................................118
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................119
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....121
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.121
8.4.4
Regulatory Reporting Requirements for SAE ...........................................122
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................122
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................122
8.4.7
Events of Clinical Interest (ECIs)..............................................................123
8.5
Treatment of Overdose......................................................................................123
8.6
Pharmacokinetics...............................................................................................124
8.6.1
Blood Collection for Lenvatinib................................................................124
8.6.2
Blood Collection for Pembrolizumab........................................................124
8.6.3
Blood Collection for Chemotherapy..........................................................125
8.7
Pharmacodynamics............................................................................................125
8.8
Planned Genetic Analysis Sample Collection..................................................125
8.9
Biomarkers .........................................................................................................125
8.10
Medical Resource Utilization and Health Economics.....................................126
8.11
Treatment Eligibility Assessment.....................................................................126
8.12
Visit Requirements.............................................................................................126
8.12.1
Screening Period ........................................................................................126
8.12.2
Treatment Period........................................................................................127
8.12.3
Discontinued Participants Continuing to be Monitored in the Study ........128
8.12.4
Posttreatment Period..................................................................................128
8.12.4.1
Safety Follow-up Visit.....................................................................128
8.12.4.2
Efficacy Follow-up Visits................................................................128
8.12.4.3
Survival Follow-up Visits................................................................128
9
STATISTICAL ANALYSIS PLAN ...........................................................................129
9.1
Statistical Analysis Plan Summary...................................................................129
9.2
Responsibility for Analyses/In-house Blinding ...............................................131
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9.3
Hypotheses/Estimation ......................................................................................132
9.4
Analysis Endpoints.............................................................................................132
9.4.1
Efficacy Endpoints.....................................................................................132
9.4.2
Safety Endpoints........................................................................................133
9.4.3
Patient-reported Endpoints.........................................................................133
9.5
Analysis Populations..........................................................................................134
9.5.1
Efficacy Analysis Populations...................................................................134
9.5.2
Safety Analysis Populations ......................................................................134
9.5.3
PRO Analysis Population ..........................................................................135
9.5.4
Pharmacokinetic Analysis Population .......................................................135
9.6
Statistical Methods.............................................................................................135
9.6.1
Statistical Methods for Efficacy Analyses.................................................135
9.6.1.1
Progression-free Survival.................................................................135
9.6.1.2
Overall Survival...............................................................................137
9.6.1.3
Objective Response Rate and Duration of Response.......................138
9.6.1.4
Analysis Strategy for Key Efficacy Endpoints................................139
9.6.2
Statistical Methods for Safety Analyses ....................................................139
9.6.3
Statistical Methods for PRO Analyses.......................................................141
9.6.4
Summaries of Baseline Characteristics and Demographics.......................142
9.7
Interim Analyses ................................................................................................142
9.7.1
Interim Analysis for Part 1.........................................................................142
9.7.2
Interim Analysis for Part 2.........................................................................142
9.7.2.1
Efficacy Interim Analyses................................................................142
9.7.2.2
Safety Interim Analyses...................................................................143
9.8
Multiplicity .........................................................................................................144
9.8.1
Multiplicity for Part 1 ................................................................................144
9.8.2
Multiplicity for Part 2 ................................................................................144
9.8.2.1
Objective Response Rate .................................................................145
9.8.2.2
Progression-free Survival.................................................................145
9.8.2.3
Overall Survival...............................................................................146
9.9
Sample Size and Power Calculations ...............................................................148
9.9.1
Sample Size and Power for Efficacy Analyses..........................................148
9.10
Subgroup Analyses.............................................................................................149
9.11
Compliance (Medication Adherence)...............................................................150
9.12
Extent of Exposure.............................................................................................150
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................151
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......151
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10.1.1
Code of Conduct for Clinical Trials...........................................................151
10.1.2
Financial Disclosure...................................................................................153
10.1.3
Data Protection...........................................................................................154
10.1.3.1
Confidentiality of Data ....................................................................154
10.1.3.2
Confidentiality of Participant Records.............................................154
10.1.3.3
Confidentiality of IRB/IEC Information..........................................154
10.1.4
Committees Structure.................................................................................155
10.1.4.1
Steering Committee .........................................................................155
10.1.4.2
Executive Oversight Committee......................................................155
10.1.4.3
External Data Monitoring Committee .............................................155
10.1.5
Publication Policy......................................................................................156
10.1.6
Compliance with Study Registration and Results Posting Requirements .156
10.1.7
Compliance with Law, Audit, and Debarment ..........................................156
10.1.8
Data Quality Assurance .............................................................................157
10.1.9
Source Documents .....................................................................................158
10.1.10
Study and Site Closure...............................................................................158
10.2
Appendix 2: Clinical Laboratory Tests............................................................159
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................161
10.3.1
Definition of AE ........................................................................................161
10.3.2
Definition of SAE ......................................................................................162
10.3.3
Additional Events Reported in the Same Manner as SAE.........................163
10.3.4
Recording AE and SAE .............................................................................163
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................167
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................169
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................170
10.5.1
Definitions..................................................................................................170
10.5.2
Contraception Requirements......................................................................171
10.6
Appendix 6: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................173
10.7
Appendix 7: Country-specific Requirements..................................................177
10.7.1
Germany-specific Requirements................................................................177
10.7.2
UK-specific Requirements.........................................................................177
10.7.3
Japan-specific Requirements .....................................................................177
10.7.4
Argentina-specific Requirements...............................................................178
10.7.5
France-specific Requirements....................................................................178
10.7.6
Canada-specific Requirements...................................................................178
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10.8
Appendix 8: Abbreviations ...............................................................................179
10.9
Appendix 9: MASCC 2016 Guidelines.............................................................183
11
REFERENCES.............................................................................................................184
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LIST OF TABLES
Table 1
Dose-limiting Toxicities ............................................................................51
Table 2
Adequate Organ Function Laboratory Values ...........................................65
Table 3
Study Treatments .......................................................................................71
Table 4
Dose Modification Guidelines for Lenvatinib-related Adverse Events.....81
Table 5
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations .........................................................88
Table 6
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ..................................................................................................92
Table 7
Chemotherapy Dose Level Definitions......................................................94
Table 8
Recommended Dose Modifications for Chemotherapy-related 
Hematological Toxicities...........................................................................95
Table 9
Recommended Dose Modifications for Chemotherapy-related 
Nonhematological Toxicities.....................................................................95
Table 10
Summary of Imaging and Treatment Requirements After First 
Radiologic Evidence of Disease Progression ..........................................114
Table 11
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events...............................................................120
Table 12
Censoring Rules for Primary and Sensitivity Analyses of 
Progression-free Survival.........................................................................137
Table 13
Censoring Rules for Duration of Response .............................................138
Table 14
Analysis Methods for Key Efficacy Endpoints .......................................139
Table 15
Analysis Strategy for Safety Parameters..................................................141
Table 16
Summary of Interim and Final Analyses Strategy...................................143
Table 17
Possible Alpha-levels and Approximate ORR Difference Required to 
Demonstrate Efficacy for ORR at IA1.....................................................145
Table 18
Efficacy Boundaries and Properties for Progression-free Survival 
Analyses...................................................................................................146
Table 19
Efficacy Boundaries and Properties for Overall Survival Analyses........147
Table 20
Protocol-required Safety Laboratory Assessments..................................160
Table 21
Highly Effective Contraception Methods................................................171
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LIST OF FIGURES
Figure 1
Study Schema.............................................................................................25
Figure 2
Imaging and Treatment for Clinically Stable Participants After First 
Radiologic Evidence of Progressive Disease Assessed by the 
Investigator ..............................................................................................115
Figure 3
Type I Error Reallocation Strategy Following Closed Testing Principle144
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3 Randomized, Placebo-controlled Study to Evaluate the Safety and 
Efficacy of Pemetrexed + Platinum Chemotherapy + Pembrolizumab (MK-3475) with or 
without Lenvatinib (E7080/MK-7902) as First-line Intervention in Participants with 
Metastatic Nonsquamous Non-small Cell Lung Cancer (LEAP-006)
Short Title: A Phase 3 Study of Pemetrexed + Platinum Chemotherapy + Pembrolizumab 
with or without Lenvatinib in Participants with NSCLC
Acronym: Protocol 006
Hypotheses, Objectives, and Endpoints:
The objectives of the study are as follows, in participants with nonsquamous non-small cell 
lung cancer (NSCLC), who are at least 18 years of age.
NOTE: Based on the data from the final safety and efficacy analysis for LEAP-006 (data 
cutoff 11-AUG-2023), the combination of pembrolizumab + platinum chemotherapy + 
lenvatinib versus pembrolizumab + platinum chemotherapy did not meet the pre-specified 
criteria for the primary endpoint of OS at the final analysis and the second dual primary 
endpoint of PFS at IA3. Based upon these data, the study was unblinded as of 20-SEP-2023. 
Safety analysis will be performed at the end of the study; there will be no further analyses for 
efficacy and ePRO endpoints.
NOTE: In alignment with the study-specific investigator letter dated 20-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 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 08, participants who are still on study treatment will no longer require 
tumor response assessments by BICR to be performed. Scans will no longer be submitted to 
the iCRO. Participants who are still on study medication should continue tumor imaging 
assessment as assessed by investigator per protocol. Biomarker and PK specimen collection 
is discontinued.
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Primary Objectives
Primary Endpoints
- Part 1: To evaluate the safety and 
tolerability of treatment with lenvatinib + 
platinum doublet chemotherapy + 
pembrolizumab.
- Dose-limiting toxicities (DLTs), adverse 
events (AEs) and study intervention 
discontinuations due to AEs.
- Part 2: To compare progression free 
survival (PFS) as assessed by blinded 
independent central review (BICR) according 
to Response Evaluation Criteria in Solid 
Tumors, version 1.1 (RECIST 1.1 ) for 
lenvatinib + platinum doublet chemotherapy 
+ pembrolizumab versus matching placebo + 
platinum doublet chemotherapy + 
pembrolizumab.
- Hypothesis (H1): The combination of 
lenvatinib +platinum doublet chemotherapy 
+ pembrolizumab prolongs PFS per 
RECIST 1.1 by BICR compared to matching 
placebo + platinum doublet chemotherapy + 
pembrolizumab.
- PFS, defined as the time from 
randomization to the date of the first 
documentation of disease progression or 
death from any cause, whichever is earlier.
- Part 2: To compare overall survival (OS) 
for the combinations of lenvatinib + platinum 
doublet chemotherapy + pembrolizumab 
versus matching placebo + platinum doublet 
chemotherapy + pembrolizumab.
- Hypothesis (H2): The combination of 
lenvatinib + platinum doublet chemotherapy 
+ pembrolizumab prolongs OS compared to 
matching placebo + platinum doublet 
chemotherapy + pembrolizumab.
- OS, defined as the time from 
randomization to the date of death from 
any cause.
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Secondary Objectives
Secondary Endpoints
- Part 2: To compare objective response rate 
(ORR) as assessed by BICR according to 
RECIST 1.1 for the combinations of 
lenvatinib + platinum doublet chemotherapy 
+ pembrolizumab versus matching placebo + 
platinum doublet chemotherapy + 
pembrolizumab.
- Hypothesis (H3): The combination of 
lenvatinib + platinum doublet chemotherapy 
+ pembrolizumab has superior ORR per 
RECIST 1.1 by BICR compared to matching 
placebo + platinum doublet chemotherapy + 
pembrolizumab.
- Objective response (OR), defined as a 
confirmed complete response (CR) or 
partial response (PR).
- Part 2: To evaluate duration of response 
(DOR) per RECIST 1.1 by BICR for the 
combinations of lenvatinib + platinum 
doublet chemotherapy + pembrolizumab and 
matching placebo + platinum doublet 
chemotherapy + pembrolizumab.
- DOR, defined as the time from the first 
documented evidence of CR or PR until 
disease progression or death due to any 
cause (whichever is earlier), for 
participants who demonstrate a confirmed 
CR or PR.
- Part 2: To evaluate the safety and 
tolerability for the combinations of lenvatinib 
+ platinum doublet chemotherapy + 
pembrolizumab and matching placebo + 
platinum doublet chemotherapy + 
pembrolizumab.
- Adverse events (AEs) and study 
intervention discontinuations due to AEs.
- Part 2: To evaluate the mean change from 
baseline in global health status/quality of life 
(QoL), cough, chest pain, dyspnea, and 
physical functioning for the combinations of 
lenvatinib + platinum doublet chemotherapy 
+ pembrolizumab and matching placebo + 
platinum doublet chemotherapy + 
pembrolizumab.
- Change from baseline for the following 
patient-reported outcomes (PRO) 
scales/items: global health status/QoL 
(EORTC QLQ-C30 Items 29 and 30), 
cough (EORTC QLQ-LC13 Item 31), 
chest pain (EORTC QLQ-LC13 Item 40), 
dyspnea (EORTC QLQ-C30 Item 8), and 
physical functioning (EORTC QLQ-C30 
Items 1 through 5).
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- Part 2: To evaluate the time to true 
deterioration (TTD) in global health 
status/QoL, cough, chest pain, dyspnea, and 
physical functioning for the combinations of 
lenvatinib + platinum doublet chemotherapy 
+ pembrolizumab and matching placebo + 
platinum doublet chemotherapy + 
pembrolizumab.
- TTD, defined as the time from baseline to 
the first onset of a ≥10-point deterioration 
from baseline with confirmation by the 
subsequent visit of a ≥10-point 
deterioration from baseline in global health 
status/QoL (EORTC QLQ-C30 Items 29 
and 30), cough (EORTC QLQ-LC13 
Item 31), chest pain (EORTC QLQ-LC13 
Item 40), dyspnea (EORTC QLQ-C30 
Item 8), and physical functioning (EORTC 
QLQ-C30 Items 1 through 5).
- TTD in the composite endpoint 
(combination of cough [QLQ-LC13 item 
31], chest pain [QLQ-LC13 item 40], or 
dyspnea [QLQ-C30 item 8]) defined as the 
time to first onset of a ≥10-point 
deterioration from baseline in any one of 3 
scale items with confirmation by the 
subsequent visit of a ≥10-point 
deterioration from baseline in the same 
scale as the first onset 
Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
First-line treatment of metastatic NSCLC
Population
Adult participants with treatment-naïve, metastatic 
nonsquamous NSCLC
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
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Type of Control
Placebo control
Study Blinding
Double-blind
Masking
Investigator
Participant
Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 5 years from the time the first participant 
(or their legally acceptable representative) provides 
documented informed consent until the last participant’s 
last study-related contact.
Extension Study in China: The Sponsor estimates that 
the study will require approximately 1 additional year 
(beyond the global study’s last participant last study-
related contact) from the time the first participant (or 
their legally acceptable representative) provides
informed consent until the last participant’s last study-
related contact. 
Number of Participants:
Global Study: The planned sample size for Part 1 (safety run-in) is approximately 
12 participants. The planned sample size for Part 2 (Phase 3 study) is approximately 
714 participants with approximately 357 participants in each treatment arm.
Extension Study in China: Approximately 200 participants overall will be enrolled in China, 
including participants enrolled in either the global study or the extension study.
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group 
Name
Drug
Dose 
Strength
Dose 
Freq
uency
Route 
of 
Admin-
istration
Regimen/ 
Treatment 
Period
Use
Part 1 and 
Part 2: 
Arms 1 and 2
Carboplatin or
Cisplatin
AUC 5
mg/mL/min
(carboplatin)
75 mg/m2
(cisplatin)
Q3W
IV
4 cycles
Standard of care
Pemetrexed
500 mg/m2
Q3W
IV
4 cycles with 
possibility of 
maintenance 
therapy until 
reaching a 
discontinuation 
criterion1
Standard of care
Pembrolizumab
200 mg
Q3W
IV
Up to 35 cycles
Standard of 
care/Experimental
Part 1 and 
Part 2: Arm 1
Lenvatinib
8 mg
Once 
daily
Oral
Until reaching 
a 
discontinuation 
criterion1
Experimental
Part 2: Arm 2
Matching 
placebo
N/A
Once 
daily
Oral
Until reaching 
a 
discontinuation 
criterion1
Placebo
Abbreviations: AUC = area under the plasma drug concentration-time curve; BICR = blinded independent 
central review; iRECIST = Response Evaluation Criteria in Solid Tumors version 1.1 for immune-based 
therapeutics; IV = intravenous(ly); N/A = not applicable; Q3W = once every 3 weeks; RECIST = Response 
Evaluation Criteria in Solid Tumors
1. Radiographically documented disease progression verified by BICR per RECIST 1.1, and only when 
clinically appropriate, confirmed by the site per iRECIST, unacceptable toxicity, intercurrent illness that 
prevents further administration of treatment, investigator’s decision to withdraw treatment, participant 
withdrawal of consent, pregnancy, noncompliance with study intervention or procedure requirements, or 
administrative reasons requiring cessation of treatment.
Total 
Number
2 (Part 2)
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Duration of 
Participation
Each participant will participate in the study from the time the participant
provides documented informed consent through the final study-related 
contact.
After a screening phase of 28 days, each participant will be assigned to 
receive study intervention until one of the conditions for discontinuation of 
study intervention is met.
Participants treated with pembrolizumab who complete 35 cycles of 
treatment with stable disease (SD) or better or participants who attain an 
investigator-determined CR and have received at least 8 cycles of 
pembrolizumab may be eligible for retreatment with up to an additional 
17 cycles (approximately 1 year) of pembrolizumab if they experience 
radiographic disease progression after stopping treatment in the initial 
treatment phase. This retreatment is termed Second Course Treatment. 
Participants may also continue treatment with lenvatinib/matching placebo
during Second Course Treatment at the discretion of the investigator until 
meeting one of the criteria for treatment discontinuation.
Participants will be permitted to continue study intervention beyond 
RECIST 1.1-defined disease progression as long as the treating investigator 
considers that the participant may experience clinical benefit with 
continued treatment per iRECIST, and the participant is tolerating study 
intervention. All decisions to continue treatment beyond 2 consecutive 
scans (at least 4 weeks apart) showing progression must be approved by the 
Sponsor.
After study intervention completion/discontinuation, each participant will 
be followed for safety as described in Section 8.4.
Participants who complete or discontinue study intervention in the absence 
of radiographic disease progression will have posttreatment follow-up 
imaging for disease status 6 weeks, 12 weeks, 18 weeks, 27 weeks, 
36 weeks, 45 weeks, and 54 weeks from the day of randomization, as 
applicable, and every 12 weeks thereafter until disease progression is 
documented radiographically per RECIST 1.1 and verified by BICR, 
initiating a new anticancer therapy, participant withdrawal of consent, 
pregnancy, becoming lost to follow-up, death, or the end of the study, 
whichever is earlier.
After confirmed disease progression or initiation of a new anticancer 
therapy, each participant will be contacted by telephone every 12 weeks to 
assess survival status until participant withdrawal of consent, becoming 
lost to follow-up, death, or the end of the study, whichever is earlier. The 
end of the study will be when the last participant completes the last 
study-related telephone call or visit, withdraws from the study, or is lost to 
follow-up (ie, the participant is unable to be contacted by the investigator).
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The study is to be discontinued based on the observation that the 
combination of pembrolizumab + platinum chemotherapy + lenvatinib
versus pembrolizumab + platinum chemotherapy 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 IA3. Upon study 
termination, participants are discontinued and may be enrolled in a 
pembrolizumab extension study, if available.
Study Governance Committees:
Steering Committee
Yes
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 8.
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1.2
Schema
The study design is depicted in Figure 1.
Abbreviations: ALK = anaplastic lymphoma kinase; DLT = dose-limiting toxicity; ECOG = Eastern Cooperative Oncology 
Group; EGFR = epidermal growth factor receptor; NSCLC = non-small cell lung cancer; PD-L1 = programmed death 
ligand 1; PS = performance status; Q3W = once every 3 weeks; qd = once daily; ROS1 = c-ros oncogene 1; TPS = tumor 
proportion score
Figure 1
Study Schema
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1.3
Schedule of Activities (SoA)
1.3.1
Initial Treatment Phase - Parts 1 and 2
Study Period
Screen-
ing
Treatment
Cycle = 21 days
EOT
Post treatment
Notes
Safety2
Follow-up3
Survival
Visit Timing1/Cycle 
Number
-28 to 
-1
1
2
3
4
5
6-35
>36
30 Days
post last 
dose
Every 
6/9/12 
Weeks
Every 
12 Weeks
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8.11 for 
visit details.
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling Window 
(Days)
+ 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At 
D/C
+ 7
± 7
± 14
Administrative Procedures
Informed Consent 
Form
X
The ICF must be documented prior 
to any protocol-specific procedures
are performed. Additional consent is 
required at disease progression.
Inclusion/Exclusion 
Criteria
X
Participant ID Card
X
X
Update at C1D1.
Demographics and 
Medical History
X
Prior/Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior medications taken within 
30 days before the first dose of study 
intervention and concomitant 
medications taken during the study 
and for 30 days after the last dose of 
study intervention (or 90 days if 
used to treat an SAE) will be 
recorded.
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Study Period
Screen-
ing
Treatment
Cycle = 21 days
EOT
Post treatment
Notes
Safety2
Follow-up3
Survival
Visit Timing1/Cycle 
Number
-28 to 
-1
1
2
3
4
5
6-35
>36
30 Days
post last 
dose
Every 
6/9/12 
Weeks
Every 
12 Weeks
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8.11 for 
visit details.
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling Window 
(Days)
+ 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At 
D/C
+ 7
± 7
± 14
Contact
X
Participants will be contacted on 
C1D8 to assess for development of 
early toxicity. If early toxicity is 
suspected, an unscheduled visit can 
occur prior to C1D15 if deemed 
necessary by the investigator.
New Anticancer 
Therapy Status
X
X
X
X
All anticancer therapy will be 
recorded until time of death or 
termination of Survival Follow-up. 
If a clinic visit is not feasible, 
follow-up information may be 
obtained via telephone or e-mail.
Survival Status
X
Participants may be contacted for 
survival status at any time during the 
course of the study.
Treatment Eligibility 
Assessment (TEA)
X
The investigator must complete the 
eCRF and provide rationale to 
document the choice of (or potential 
treatment with) cisplatin prior to 
randomization.
Study Intervention – Per Randomized Assignment
Treatment 
Randomization
X
Dose within 3 days of 
randomization.
Lenvatinib Dispensed
X
X
X
X
X
X
X
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Study Period
Screen-
ing
Treatment
Cycle = 21 days
EOT
Post treatment
Notes
Safety2
Follow-up3
Survival
Visit Timing1/Cycle 
Number
-28 to 
-1
1
2
3
4
5
6-35
>36
30 Days
post last 
dose
Every 
6/9/12 
Weeks
Every 
12 Weeks
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8.11 for 
visit details.
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling Window 
(Days)
+ 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At 
D/C
+ 7
± 7
± 14
Lenvatinib 
Administration
Dose of lenvatinib will be 
administered in the clinic on Day 1 
of each cycle and Day 15 of Cycle 1, 
0 to 4 hours after completion of 
pembrolizumab administration and 
before chemotherapy. 
Self-administer on all other days.
Pembrolizumab 
Administration
X
X
X
X
X
X
Administered as the first study 
intervention on Day 1 of each 
21-day cycle.
Carboplatin or 
Cisplatin 
Administration
X
X
X
X
Pemetrexed 
Administration
X
X
X
X
X
X
X
Pemetrexed should be administered 
at least 30 minutes prior to 
carboplatin or cisplatin during those 
treatment cycles.
Premedication should be dosed per 
the approved product labels.
Clinical Procedures/Assessments
Adverse Event 
Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Report AEs occurring within 30 
days after the last dose of study 
intervention. Report SAEs occurring 
within 90 days after the last dose of 
study intervention, or 30 days after 
the last dose of study intervention if 
a new anticancer therapy is initiated,
whichever is earlier.
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PRODUCT: MK-7902 006-08
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PROTOCOL/AMENDMENT NO.: MK-7902-006-08 (E7080-G000-315)
MK-7902-006-08 FINAL PROTOCOL
27-OCT-2023
Study Period
Screen-
ing
Treatment
Cycle = 21 days
EOT
Post treatment
Notes
Safety2
Follow-up3
Survival
Visit Timing1/Cycle 
Number
-28 to 
-1
1
2
3
4
5
6-35
>36
30 Days
post last 
dose
Every 
6/9/12 
Weeks
Every 
12 Weeks
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8.11 for 
visit details.
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling Window 
(Days)
+ 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At 
D/C
+ 7
± 7
± 14
Full Physical 
Examination
X
X
At Screening, perform within 7 days 
prior to C1D1.
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
Height
X
Vital Signs and 
Weight
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs must be taken in the 
clinic.
Refer to Section 6.6.1.1 for 
hypertension management BP 
monitoring guidelines.
D15 visit is mandatory in C1 and 
C2. During C3 and subsequent 
cycles, participants may return for 
the D15 visit if BP monitoring is 
required as specified in Section
6.6.1.1.
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PRODUCT: MK-7902 006-08
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PROTOCOL/AMENDMENT NO.: MK-7902-006-08 (E7080-G000-315)
MK-7902-006-08 FINAL PROTOCOL
27-OCT-2023
Study Period
Screen-
ing
Treatment
Cycle = 21 days
EOT
Post treatment
Notes
Safety2
Follow-up3
Survival
Visit Timing1/Cycle 
Number
-28 to 
-1
1
2
3
4
5
6-35
>36
30 Days
post last 
dose
Every 
6/9/12 
Weeks
Every 
12 Weeks
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8.11 for 
visit details.
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling Window 
(Days)
+ 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At 
D/C
+ 7
± 7
± 14
12-Lead ECG with 
QTc Measurement
X
X
X
X
X
X
X
ECG at Screening , C1D1, C2D1, 
D1 of every fourth cycle thereafter 
(eg, C6, C10, C14, etc.), EOT, and 
Safety Follow-up. 
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 ECG 
monitoring every cycle.
If lenvatinib/matching placebo is 
discontinued, ECG is only required
at EOT and Safety Follow-up visits.
ECHO/MUGA
X
X
Additional assessments may be 
performed as clinically indicated.
ECOG Performance 
Status
X
X
X
X
X
X
X
X
X
X
At Screening, perform within 7 days 
prior to C1D1 but before 
randomization.
Brain MRI
X
Required at Screening.
Follow-up MRI is required as
clinically indicated, and at 
subsequent suspected CR.
If MRI is contraindicated or cannot 
be performed CT head with contrast 
is acceptable. 
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PRODUCT: MK-7902 006-08
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PROTOCOL/AMENDMENT NO.: MK-7902-006-08 (E7080-G000-315)
MK-7902-006-08 FINAL PROTOCOL
27-OCT-2023
Study Period
Screen-
ing
Treatment
Cycle = 21 days
EOT
Post treatment
Notes
Safety2
Follow-up3
Survival
Visit Timing1/Cycle 
Number
-28 to 
-1
1
2
3
4
5
6-35
>36
30 Days
post last 
dose
Every 
6/9/12 
Weeks
Every 
12 Weeks
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8.11 for 
visit details.
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling Window 
(Days)
+ 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At 
D/C
+ 7
± 7
± 14
Laboratory Procedures/Assessments: LOCAL
Serum HCG or urine 
pregnancy test 
(WOCBP only)
X
X
X
X
X
X
X
X
X
WOCBP require negative test prior 
to randomization. If more than 24 
hours have elapsed prior to first dose 
of study intervention, another 
pregnancy test is required prior to 
starting study intervention.
A serum or urine pregnancy test will 
be performed per Appendix 2.
Hepatitis B and C 
Serology
X
Not required unless mandated by 
local health authorities.
HIV Testing
X
Not required unless mandated by 
local health authorities.
PT/INR and 
aPTT/PTT
X
Perform eligibility labs within 
10 days prior to C1D1. Additional 
testing to be conducted as clinically 
indicated for participants taking 
anticoagulant therapy.
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PRODUCT: MK-7902 006-08
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PROTOCOL/AMENDMENT NO.: MK-7902-006-08 (E7080-G000-315)
MK-7902-006-08 FINAL PROTOCOL
27-OCT-2023
Study Period
Screen-
ing
Treatment
Cycle = 21 days
EOT
Post treatment
Notes
Safety2
Follow-up3
Survival
Visit Timing1/Cycle 
Number
-28 to 
-1
1
2
3
4
5
6-35
>36
30 Days
post last 
dose
Every 
6/9/12 
Weeks
Every 
12 Weeks
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8.11 for 
visit details.
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling Window 
(Days)
+ 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At 
D/C
+ 7
± 7
± 14
CBC with Differential
X
X
X
X
X
X
X
X
X
X
At Screening, perform within 
10 days prior to C1D1. After 
Cycle 1, may collect up to 3 days 
prior to dosing.
Chemistry Panel
X
X
X
X
X
X
X
X
X
X
Thyroid Function 
(T3, FT4, and TSH)
X
X
X
X
X
X
X
At Screening, C2D1, then every 2 
cycles thereafter.
Screening samples to be collected 
within 10 days before first dose.
Participants may be dosed in 
subsequent cycles after C1D1 while 
thyroid function tests are pending.
After C1, collect within 3 days 
before dosing.
May use central laboratory only if 
local laboratory is not capable.
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PRODUCT: MK-7902 006-08
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PROTOCOL/AMENDMENT NO.: MK-7902-006-08 (E7080-G000-315)
MK-7902-006-08 FINAL PROTOCOL
27-OCT-2023
Study Period
Screen-
ing
Treatment
Cycle = 21 days
EOT
Post treatment
Notes
Safety2
Follow-up3
Survival
Visit Timing1/Cycle 
Number
-28 to 
-1
1
2
3
4
5
6-35
>36
30 Days
post last 
dose
Every 
6/9/12 
Weeks
Every 
12 Weeks
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8.11 for 
visit details.
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling Window 
(Days)
+ 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At 
D/C
+ 7
± 7
± 14
Urinalysis/Urine 
Dipstick Testing
X
X
X
X
X
X
X
X
X
X
X
Performed locally within 7 days 
before first dose.
After C1, collect within 3 days 
before dosing.
Urinalysis is required at Screening 
and every 4 cycles. At other time 
points, either urinalysis or urine dip 
stick are acceptable.
If lenvatinib/ matching placebo is 
discontinued, urinalysis is required 
every 4 cycles.
For participants with proteinuria >1+ 
during Screening, refer to Exclusion 
Criterion 26.
For management of proteinuria, refer 
to Section 6.6.1.2
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 above.
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PRODUCT: MK-7902 006-08
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PROTOCOL/AMENDMENT NO.: MK-7902-006-08 (E7080-G000-315)
MK-7902-006-08 FINAL PROTOCOL
27-OCT-2023
Study Period
Screen-
ing
Treatment
Cycle = 21 days
EOT
Post treatment
Notes
Safety2
Follow-up3
Survival
Visit Timing1/Cycle 
Number
-28 to 
-1
1
2
3
4
5
6-35
>36
30 Days
post last 
dose
Every 
6/9/12 
Weeks
Every 
12 Weeks
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8.11 for 
visit details.
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling Window 
(Days)
+ 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At 
D/C
+ 7
± 7
± 14
Laboratory Procedures/Assessments: CENTRAL
Plasma Sample for 
Lenvatinib PK
X
X
X
C1D1: 0.5 to 4 and 6 to 10 hours
postdose
C1D15: predose, and 2 to 12 hours
postdose
C2D1: predose, 0.5 to 4 and 6 to 
10 hours postdose
All predose samples should be 
collected within 2 hours of 
lenvatinib administration.
Postdose samples not needed if 
lenvatinib administration is skipped.
Serum for 
Pembrolizumab PK
X
X
Prior to pembrolizumab infusion on 
C1D1, C2D1, and C8D1.
Antipembrolizumab 
Antibodies
X
X
Tumor Tissue Collection
Newly 
Obtained/Archival 
Tissue Sample for 
Biomarker Analysis
X
May use archival tissue sample that 
was obtained prior to Screening 
period as part of the participant’s 
SOC.
EGFR, ALK, and 
ROS1 Molecular 
Status
X
Not required for participants with 
KRAS mutation. May send tumor 
tissue to central lab for molecular 
testing if status is unknown and 
cannot be determined locally.
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PRODUCT: MK-7902 006-08
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PROTOCOL/AMENDMENT NO.: MK-7902-006-08 (E7080-G000-315)
MK-7902-006-08 FINAL PROTOCOL
27-OCT-2023
Study Period
Screen-
ing
Treatment
Cycle = 21 days
EOT
Post treatment
Notes
Safety2
Follow-up3
Survival
Visit Timing1/Cycle 
Number
-28 to 
-1
1
2
3
4
5
6-35
>36
30 Days
post last 
dose
Every 
6/9/12 
Weeks
Every 
12 Weeks
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8.11 for 
visit details.
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling Window 
(Days)
+ 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At 
D/C
+ 7
± 7
± 14
Efficacy Assessments
Tumor Imaging and 
Response Assessment
(Thorax, Abdomen, 
Pelvis)
X
X
X*
Perform imaging at Screening, 6, 12, 
and 18 weeks from the day of 
randomization, then Q9W through 
Week 54, and Q12W thereafter; ie, 
6, 12, 18, 27, 36, 45, 54, 66, 78, 90, 
etc. weeks from the day of 
randomization. Schedule should be 
followed regardless of treatment
delays. If imaging was obtained 
within 4 weeks prior to EOT, scan at 
EOT is not mandatory.
*The visit window at the 6-week 
time point is + 7 days.
Abbreviations: AE = adverse event; ALK = anaplastic lymphoma kinase; aPTT = activated partial thromboplastin time; BICR = blinded independent central (imaging) review; CBC = 
complete blood count; CR = complete response; CXDX = Cycle X, Day X; D/C = discontinuation; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECHO = echocardiogram; 
ECOG = Eastern Cooperative Oncology Group; eCRF = electronic Case Report Form; EGFR = epidermal growth factor receptor; EORTC = European Organisation for Research and 
Treatment of Cancer; EOT = end of treatment; ePRO = electronic patient-reported outcome; EQ-5D-5L = EuroQoL 5-dimension, 5-level Questionnaire; FT4 = free thyroxine; hr = hours; 
HBV/HCV = Hepatitis B/C virus; HCG = human chorionic gonadotropin; HIV = human immunodeficiency virus; ICF = informed consent form; ID = identification; INR = international 
normalized ratio; IRB/IEC = Institutional Review Board/Independent Ethics Committee; min = minute(s); MRI = magnetic resonance imaging; MUGA = multigated acquisition; NSCLC = 
non-small cell lung cancer; PD = progressive disease; PK = pharmacokinetics; PT = prothrombin time; PTT = partial thromboplastin time; Q = every; QLQ-C30 = Quality of Life 
Questionnaire Core 30; QLQ-LC13 = Quality of Life Questionnaire and Lung Cancer Module 13; QTc = corrected QT interval; RNA = ribonucleic acid; ROS1 = c-ros oncogene 1; SAE = 
serious adverse event; SoA = schedule of activities; SOC = standard of care; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid stimulating- hormone; W = weeks; WOCBP = woman of 
childbearing potential; WONCBP = woman of nonchildbearing potential
1.
At Screening, visit timing is in relation to the first dose of study intervention.
2.
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the last dose of study intervention or before initiation of new anticancer therapy, whichever is 
earlier. If the End of Treatment Visit occurs ≥30 days from last dose of study intervention, a Safety Follow-up Visit is not required.
3.
For participants who D/C study intervention for reasons other than BICR-verified PD, follow-up visits to monitor disease status continue until BICR-verified PD or initiation of a new 
anticancer therapy. Participants who D/C study intervention with BICR-verified PD proceed directly to Survival Follow-up.
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PRODUCT: MK-7902 006-08
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PROTOCOL/AMENDMENT NO.: MK-7902-006-08 (E7080-G000-315)
MK-7902-006-08 FINAL PROTOCOL
27-OCT-2023
1.3.2
Second Course Treatment (Retreatment) - Parts 1 and 2
Study Period
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety1
Follow-up2
Survival
Visit Timing/Cycle Number
1
2
3
4
5
≥6
30 (+ 7) 
Days After 
Last Dose 
Every 
12 Weeks
Every 12 
Weeks
All procedures and assessments are to be 
performed prior to administration of study 
intervention unless otherwise indicated.
Scheduling Window (Days)
+ 3
± 3
± 3
± 3
± 3
± 3
At 
D/C
+ 7
± 7
± 14
Administrative and General Procedures
Inclusion/exclusion Criteria
X
Prior/Concomitant Medications
X
X
X
X
X
X
X
X
Prior medications taken within 30 days before 
the first dose of Second Course Treatment and 
concomitant medications taken during the 
study and for 30 days after the last dose of 
Second Course Treatment (or 90 days if used 
to treat an SAE) will be recorded.
New Anticancer Therapy Status
X
X
X
X
Survival Status
X
Participants may be contacted for survival 
status at any time during the course of the 
study.
Study Intervention – Per Randomized Assignment
Lenvatinib Dispensed
X
X
X
X
X
X
The decision of whether or not to continue 
lenvatinib during Second Course will be at the 
discretion of the investigator if the patient was 
receiving lenvatinib in First Course. If 
continued, the dose of lenvatinib will be given 
in clinic on Day 1 of each SC Cycle, 0 to 
4 hours after completion of pembrolizumab 
administration; it will be self-administered on 
all other days. Treatment with lenvatinib will 
continue until meeting at least 1 of the D/C 
criteria listed in Section 7.1.
Lenvatinib Administration for patients 
who received lenvatinib in First 
Course
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PRODUCT: MK-7902 006-08
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PROTOCOL/AMENDMENT NO.: MK-7902-006-08 (E7080-G000-315)
MK-7902-006-08 FINAL PROTOCOL
27-OCT-2023
Study Period
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety1
Follow-up2
Survival
Visit Timing/Cycle Number
1
2
3
4
5
≥6
30 (+ 7) 
Days After 
Last Dose 
Every 
12 Weeks
Every 12 
Weeks
All procedures and assessments are to be 
performed prior to administration of study 
intervention unless otherwise indicated.
Scheduling Window (Days)
+ 3
± 3
± 3
± 3
± 3
± 3
At 
D/C
+ 7
± 7
± 14
Pembrolizumab Administration
X
X
X
X
X
X
Participants who are eligible for Second 
Course may receive up to an additional 
17 cycles of treatment with pembrolizumab. 
Pembrolizumab will be administered as the 
first study intervention on Day 1 of each 
21-day SC Cycle.
Clinical Procedures/Assessments
Adverse Event Monitoring
X
X
X
X
X
X
X
X
X
Report AEs occurring within 30 days after the 
last dose of study intervention. Report SAEs 
occurring within 90 days after the last dose of 
study intervention, or 30 days after the last 
dose of study intervention if a new anticancer 
therapy is initiated, whichever is earlier.
Full Physical Examination
X
X
Directed Physical Examination
X
X
X
X
X
X
Vital Signs, Weight
X
X
X
X
X
X
X
X
Vital signs must be taken in the clinic.
Refer to Section 6.6.1.1 for hypertension 
management BP monitoring guidelines.
Participants may return for the D15 visit if BP 
monitoring is required as specified in Section
6.6.1.1.
12-Lead ECG with QTc Measurement
X*
X
X*
X
X
If lenvatinib/ matching placebo is 
discontinued, ECG is only required at EOT
and Safety Follow-up visits.
*Every fourth cycle beginning with Cycle 5 
(eg, C5, C9, C13, etc.).
ECOG Performance Status
X
X
X
X
X
X
X
X
Perform within 7 days prior to SC Cycle 1.
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PRODUCT: MK-7902 006-08
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PROTOCOL/AMENDMENT NO.: MK-7902-006-08 (E7080-G000-315)
MK-7902-006-08 FINAL PROTOCOL
27-OCT-2023
Study Period
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety1
Follow-up2
Survival
Visit Timing/Cycle Number
1
2
3
4
5
≥6
30 (+ 7) 
Days After 
Last Dose 
Every 
12 Weeks
Every 12 
Weeks
All procedures and assessments are to be 
performed prior to administration of study 
intervention unless otherwise indicated.
Scheduling Window (Days)
+ 3
± 3
± 3
± 3
± 3
± 3
At 
D/C
+ 7
± 7
± 14
Laboratory Procedures/Assessments: LOCAL
Serum HCG or urine pregnancy test 
(WOCBP only)
X
X
X
X
X
X
X
X
WOCBP require negative test prior to 
randomization. If more than 24 hours have 
elapsed prior to first dose of study intervention 
in SC C1, another pregnancy test is required 
prior to starting study intervention.
A serum or urine pregnancy test will be 
performed per Appendix 2.
PT/INR and aPTT/PTT
X
Additional testing to be conducted as clinically 
indicated for participants taking anticoagulant 
therapy.
CBC with Differential
X
X
X
X
X
X
X
X
Perform within 10 days prior to SC Cycle 1. 
After SC Cycle 1, may collect up to 3 days 
prior to dosing.
Chemistry Panel
X
X
X
X
X
X
X
X
Thyroid Function (T3, FT4, and TSH)
X*
X
X*
X
X
*Thyroid function tests will be performed at 
C1 and every 2 cycles thereafter.
Perform within 10 days before SC C1. After 
SC C1, collect within 3 days before dosing.
Participants may be dosed in subsequent 
cycles after SC C1 while thyroid function tests 
are pending.
May use central laboratory only if local 
laboratory is not capable.
08LT9R


PRODUCT: MK-7902 006-08
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PROTOCOL/AMENDMENT NO.: MK-7902-006-08 (E7080-G000-315)
MK-7902-006-08 FINAL PROTOCOL
27-OCT-2023
Study Period
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety1
Follow-up2
Survival
Visit Timing/Cycle Number
1
2
3
4
5
≥6
30 (+ 7) 
Days After 
Last Dose 
Every 
12 Weeks
Every 12 
Weeks
All procedures and assessments are to be 
performed prior to administration of study 
intervention unless otherwise indicated.
Scheduling Window (Days)
+ 3
± 3
± 3
± 3
± 3
± 3
At 
D/C
+ 7
± 7
± 14
Urinalysis/Urine Dipstick Testing
X
X
X
X
X
X
X
X
Performed locally within 7 days before SC 
Cycle 1. After SC Cycle 1, collect within 
3 days before dosing.
If lenvatinib/ matching placebo is 
discontinued, urinalysis is required every 
4 cycles.
Repeat testing for participants with proteinuria 
≥2+ should be performed as clinically 
indicated until the results have been 1+ or 
negative for 2 consecutive treatment cycles.
Efficacy Assessments
Tumor Imaging and Response 
Assessment (Thorax, Abdomen, 
Pelvis)
X
X
X
X
X
SC baseline imaging within 30 days prior to 
SC Cycle 1. Perform imaging Q12W 
(± 7 days) from SC Cycle 1 (ie, 12, 24, 36, 48, 
etc. weeks after SC Cycle 1). Schedule should 
be followed regardless of treatment delays. If 
imaging was obtained within 4 weeks prior to 
EOT, scan at EOT is not mandatory.
Abbreviations: AE = adverse event; aPTT = activated partial thromboplastin time; HCG = human chorionic gonadotropin; CBC = complete blood count; D/C = discontinuation; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; FT4 = free thyroxine; INR = international normalized ratio; PD = progressive 
disease; PT = prothrombin time; PTT = partial thromboplastin time; Q = every; QTc = corrected QT interval; SAE = serious adverse event; SC = Second Course; T3 = 
triiodothyronine; T4 = thyroxine; TSH = thyroid stimulating hormone; W = weeks; WOCBP = woman of childbearing potential
1.
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the last dose of study intervention or before initiation of new anticancer therapy, 
whichever is earlier. If the End of Treatment Visit occurs ≥30 days from last dose of study intervention, a Safety Follow-up Visit is not required.
2.
For participants who D/C study intervention for reasons other than BICR-verified PD, follow-up visits to monitor disease status continue until BICR-verified PD or initiation 
of a new anticancer therapy. Participants who D/C study intervention with BICR-verified PD proceed directly to Survival Follow-up.
08LT9R


PRODUCT: MK-7902 006-08
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PROTOCOL/AMENDMENT NO.: MK-7902-006-08 (E7080-G000-315)
MK-7902-006-08 FINAL PROTOCOL
27-OCT-2023
2
INTRODUCTION
2.1
Study Rationale
The standard of care (SOC) for metastatic non-small cell lung cancer (NSCLC) has changed 
in recent years with the development of immunotherapeutic agents. Prior to the advent of 
immune checkpoint inhibitors, platinum-based doublet chemotherapy was considered SOC 
for patients with newly diagnosed, metastatic NSCLC. Despite the benefits of chemotherapy 
in prolonging survival in this group of patients, the outcome remains dismal. The expected 
median survival is about 1 year, and the 5-year survival rate is less than 5% [Cronin, K. A., et 
al 2018]. The arrival of immune checkpoint blockage, particularly the programmed cell death 
protein 1 (PD-1) inhibitors, has changed the treatment paradigm in metastatic lung cancer. 
The United States (US) Food and Drug Administration (FDA) has approved pembrolizumab
as the first anti-PD-1 receptor antibody for the treatment of metastatic nonsquamous NSCLC
either as monotherapy in tumors with high programmed death ligand 1 (PD-L1) expression 
(tumor proportion score [TPS] 50%), or in combination with chemotherapy for all 
nonsquamous NSCLC regardless of PD-L1 expression. With pembrolizumab treatment, the 
median overall survival (OS) in this group is >30 months, with a 1-year OS of ~ 70%, 
compared to a 1-year OS of ~ 50% for patients receiving chemotherapy without 
pembrolizumab [Gandhi, L., et al 2018].
Despite the improvement in OS in patients with metastatic NSCLC treated with checkpoint 
inhibitors, a significant portion of these patients will die of their disease. As such, new 
therapeutics, as well as novel combinations, are needed to improve outcomes. The present 
study is designed to further evaluate the safety and efficacy of combination therapy with
lenvatinib (also known as E7080 or MK-7902), hereafter referred to as lenvatinib,
pembrolizumab, and SOC chemotherapy as a first-line (1L) treatment in adult participants 
with metastatic NSCLC.
2.2
Background
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to the PD-
1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in 
vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an IV immunotherapy for advanced malignancies. Keytruda® (pembrolizumab) is indicated 
for the treatment of patients across a number of indications. For more details on specific 
indications refer to the IB.
Lenvatinib (also known as E7080 or MK-7902; hereafter referred to as lenvatinib) is a 
multiple receptor tyrosine kinase inhibitor (RTKi) with a potentially differentiated profile. It 
inhibits the 3 main vascular endothelial growth factor (VEGF) receptors (VEGFRs), 
VEGFR1, VEGFR2, and VEGFR3, as well as fibroblast growth factor receptors (FGFRs), 
FGFR1, FGFR2, FGFR3, and FGFR4, platelet-derived growth factor receptor (PDGFR) α, 
c-kit, and the RET proto-oncogene, which play roles in tumor angiogenesis, tumor 
progression, and modification of tumor immunity. 
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Refer to the respective Investigator’s Brochure (IB)/approved labeling for detailed 
background information on pembrolizumab and lenvatinib.
2.2.1
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved 
prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and 
pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. 
Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable 
objective tumor responses in cancers such as melanoma [Dudley, M. E., et al 2005] [Hunder, 
N. N., et al 2008].
2.2.1.1
Lenvatinib
Angiogenesis, the formation of new blood vessels from a pre-existing vascular network, is 
essential for tumor growth and metastasis. VEGF and its family of receptors (VEGRs 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 for 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 RTK inhibitor that selectively inhibits VEGF receptors, 
VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), FGFR1-4, PDGFRα, KIT, and 
RET. Among known kinase inhibitors in clinical use, lenvatinib is one of the only inhibitors 
currently labeled with a mechanism of action as an inhibitor of not only VEGFRs but also 
FGFRs, both of which are currently believed to be very important for tumor angiogenesis.
Co-crystal structural analysis demonstrated that lenvatinib has a distinct mode of interaction 
with VEGFR2 or FGFR1, termed Type V, while most of the known kinase inhibitors on the 
market are categorized as Type I or II [Okamoto, K., et al 2015]. Lenvatinib binds to 
ATP-binding sites and neighboring allosteric regions in the kinase domain adopting the 
DFG-in conformation. Most of the known kinase inhibitors are categorized as Type I, 
binding these kinases in the DFG-in configuration and only binding to the ATP-binding site, 
or Type II binding to the kinase in the DFG-out conformation and binding to both the 
ATP-binding site and the neighboring regions.
Lenvatinib inhibited cell free kinase activities for VEGFR1-3 and FGFR1-3 with Ki values
around 1 nmol/L, and 8-22 nmol/L, respectively. In cell-based assays, lenvatinib inhibited 
VEGF-derived and FGF-derived tube formation of HUVEC with IC50 values of 2.1 and 7.3 
nmol/L, respectively. Analysis of the signal transduction molecules revealed that lenvatinib 
inhibited both the MAPK pathway and the mTOR-S6K-S6 pathway in HUVECs triggered by 
activated VEGFR and FGFR. Furthermore, lenvatinib (10, 30 mg/kg) significantly inhibited 
both VEGF- and FGF-driven angiogenesis in a murine in vivo model [Yamamoto, Y., et al 
2014]. In vivo, lenvatinib exhibited antitumor activity against various human tumor 
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xenografts in athymic mice including 5 types of thyroid carcinomas (differentiated [papillary 
and follicular], anaplastic, squamous, and medullary thyroid carcinomas), RCC, HCC, 
melanoma, gastric cancer, NSCLC, ovarian cancer, Ewing’s sarcoma, and osteosarcoma. In 
addition, the antitumor activity of lenvatinib in combination with other anticancer agents in 
several xenograft models was greater than that of lenvatinib or the other agents alone.
In summary, lenvatinib inhibited VEGF-driven VEGFR2 phosphorylation and suppressed 
proliferation and tube formation in human umbilical vein endothelial cell (HUVEC) models. 
Antitumor activity of lenvatinib in vivo has been shown in numerous xenograft animals. 
These results suggest that lenvatinib may be a novel anticancer therapy through inhibition of 
angiogenesis and may be useful as either monotherapy or in combination with other 
anticancer drugs.
2.2.1.2
Pembrolizumab
The PD-1 receptor ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 that has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
[Dudley, M. E., et al 2005] [Hunder, N. N., et al 2008].
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an IgV type domain responsible 
for ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules. 
The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch motif. 
Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to 
the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ, and ZAP70, which are 
involved in the CD3 T-cell signaling cascade [Okazaki, T., et al 2001] [Chemnitz, J. M., et al 
2004] [Sheppard, K-A, et al 2004] [Riley, J. L. 2009]. The mechanism by which PD-1 down 
modulates T-cell responses is similar to, but distinct from, that of CTLA-4, because both 
molecules regulate an overlapping set of signaling proteins [Parry, R. V., et al 2005] 
[Francisco, L. M., et al 2010]. As a consequence, the PD-1/PD-L1 pathway is an attractive 
target for therapeutic intervention in NSCLC.
2.2.1.3
Lung Cancer: Epidemiology and Current Therapeutic Options
The global incidence of lung cancer was 1.8 million in 2012, resulting in an estimated 
1.6 million deaths [World Health Organization 2012]. In the United States, the 2018 
estimated incidence of new diagnoses was 234,030, and the estimated number of deaths 
was 154,050 [National Cancer Institute 2018]. NSCLC represents approximately 80% to 
85% of all lung cancers. Of the patients with NSCLC, tumor histology is approximately 40% 
to 60% adenocarcinoma, 10% to 15% squamous, 5% neuroendocrine, and the rest, “not 
otherwise specified” [Sulpher, J. A., et al 2013].
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Approximately 70% of patients with NSCLC have advanced disease not amenable to surgical 
resection at the time of diagnosis. From 2006 to 2012, the overall 5-year relative survival rate 
for lung cancer was 17.7% in the United States. Five-year relative survival rates were 55% 
for localized, 28% for regional, 4.3% for distant, and 7.4% for unstaged [National 
Comprehensive Cancer Network 2017].
In the Phase 3 study KEYNOTE-024, pembrolizumab, a PD-1 inhibitor, showed statistically 
significant increases in OS and progression-free survival (PFS) compared to SOC 
platinum-based chemotherapy for treatment-naïve participants with metastatic NSCLC 
whose tumors expressed high levels of PD-L1 (TPS ≥50%) with no epidermal growth factor 
receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations, leading 
to regulatory approval for this indication in the US and other countries around the world. 
Approximately 30% of patients with newly diagnosed, advanced NSCLC highly express 
PD-L1 to a TPS ≥50% [Reck, M., et al 2016].
In the Phase 2 study KEYNOTE-021 Cohort G, pembrolizumab plus pemetrexed and 
carboplatin showed statistically significant increases in objective response rate ([ORR]; 55% 
vs. 29%) and PFS (8.9 vs. 13.0 months, HR 0.53 [95% confidence interval [CI] 0.31 to 0.91]) 
compared to pemetrexed and carboplatin alone in participants with nonsquamous advanced 
NSCLC, regardless of PD-L1 status [Langer, C. J., et al 2016]. Moreover, a recent update of 
data from KEYNOTE-021 showed that an OS benefit has also been seen when 
pembrolizumab is added to chemotherapy (hazard ratio [HR] 0.59; 95% CI 0.34 to 1.05; 
p=0.03) [Borghaei, H., et al 2017]. These findings were confirmed in the Phase 3 
randomized, double-blinded KEYNOTE-189 study of pemetrexed and a platinum-based
chemotherapy with or without pembrolizumab in 1L, metastatic, nonsquamous NSCLC. 
KEYNOTE-189 showed that treatment with pembrolizumab plus pemetrexed and 
platinum-based chemotherapy (carboplatin or cisplatin) significantly prolonged OS (HR 
0.49; 95% CI 0.38 to 0.64; p<0.001) and PFS (HR 0.52; 95% CI 0.43 to 0.64; p<0.001) 
compared with SOC chemotherapy. These results established pembrolizumab plus 
chemotherapy as an efficacious option for 1L treatment in patients with nonsquamous
NSCLC [Gandhi, L., et al 2018].
Taken together, strong efficacy data from randomized KEYNOTE studies have established 
an important role for pembrolizumab either as monotherapy or in combination with 
chemotherapy in patients with NSCLC.
2.2.1.4
Lenvatinib Activity in Non-small Cell Cancer
Lenvatinib has been studied in advanced NSCLC. As a single agent, a randomized Phase 2 
study (E7080703) 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 lenvatinib qd and 
46 received placebo; all participants received best supportive care in addition to study 
intervention. Median OS was 38.4 weeks for lenvatinib and 24.1 weeks for placebo, median 
PFS was 20.9 weeks for lenvatinib and 7.9 weeks for placebo, ORR was 10.1% for lenvatinib 
and 2.2% for placebo, and DCR was 42.7% for lenvatinib and 19.6% for placebo. The 
toxicities were manageable. Grade 3/4 AEs occurred in 69% of lenvatinib recipients, and in 
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50% of placebo recipients. Grade 3/4 AEs were dyspnea and pneumonia in both treatment 
groups, as well as hypertension in the lenvatinib group [Havel, L., et al 2014].
In a Phase 1/2 study (Study E7080-J081-110), lenvatinib at 4 mg BID was examined in 
combination with carboplatin AUC 6 and paclitaxel 200 mg/m2 in Japanese participants with 
NSCLC. The ORR was 61% (95% CI: 41% to 79%) and was composed of 1 CR and 16 PRs. 
The median PFS was reported as 9 months. In this study, the most frequently reported
Grade 3 and Grade 4 toxicities were neutropenia (95%), leukopenia (50%), hypertension 
(36%), thrombocytopenia (27%), and febrile neutropenia (23%)[Nishio, M., et al 2013]. In 
the Four-Arm Cooperative Group Study (FACS), 4 common platinum doublets as first-line 
intervention were compared in Japanese participants with NSCLC. The Grade 3 and Grade 4 
events observed in the carboplatin and paclitaxel arm were neutropenia (88%), febrile 
neutropenia (18%), and thrombocytopenia (11%). These data suggest that the addition of 
lenvatinib potentially leads to enhanced efficacy without significant enhancement of the 
hematologic toxicities from chemotherapy [Ohe, Y., et al 2007].
2.2.1.5
Scientific Rationale for the Combination of Lenvatinib and Pembrolizumab
Early studies have shown that lenvatinib has antitumor activity in many solid tumors. 
LENVIMA® (lenvatinib) is a kinase inhibitor that is indicated for differentiated thyroid 
cancer (DTC) as a single agent for patients with locally recurrent or metastatic, progressive, 
radioactive iodine-refractory DTC and for RCC in combination with everolimus for patients 
with advanced RCC following one prior antiangiogenic therapy [U.S. Prescribing 
Information 2018]. In both tumor types, lenvatinib statistically significantly prolonged PFS. 
Lenvatinib monotherapy is also approved for the first-line treatment of patients with 
unresectable HCC.
In preclinical models, lenvatinib decreased the tumor-associated macrophage (TAM) 
population, which is known as an immune regulator in the tumor microenvironment. By 
decreasing TAMs, expression levels of cytokines and immune-regulating receptors were 
changed to increase immune activation. 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 anti-PD-1/PD-L1 inhibitors has been investigated in the CT26 
colorectal cancer syngeneic model (anti-PD-L1 inhibitor) and the LL/2 lung cancer 
syngeneic model (anti-PD-1 mAb). Combination treatment with lenvatinib and either an 
anti-PD-1 or anti-PD-L1 inhibitor showed significant and superior antitumor effects 
compared with either compound alone, in these 2 syngeneic models [Kato, Y., et al 2015].
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 
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 given 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 (NSCLC, renal cell 
carcinoma [RCC], endometrial cancer, urothelial carcinoma, melanoma, and squamous cell 
carcinoma of the head and neck).
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2.2.2
Preclinical and Clinical Studies
Refer to the respective IBs for preclinical and clinical study data on pembrolizumab and 
lenvatinib.
2.2.3
Ongoing Clinical Studies of Lenvatinib and Pembrolizumab
Pembrolizumab is under evaluation in patients with NSCLC as monotherapy and in 
combination with chemotherapy, immunotherapy, and targeted therapies. Lenvatinib is being 
studied in patients with different types of solid tumors, including NSCLC, and in 
combination with other therapies, including PD-1-targeted therapies. A full list of ongoing 
studies can be found in the respective IBs of pembrolizumab [IB Edition 16 2018] and 
lenvatinib [IB Edition 15-Eisai 2018]. Details of the ongoing study 111/KEYNOTE-146 are 
outlined below.
Study 111/KEYNOTE-146
Study 111/KEYNOTE-146, is a multicenter, open-label, Phase 1b/2 clinical study to evaluate 
the efficacy and safety of lenvatinib in combination with pembrolizumab. The primary 
objective of the Phase 1b portion of the study is to determine the MTD in participants with 
unresectable solid tumors (endometrial cancer, melanoma, NSCLC, RCC, squamous cell 
carcinoma of the head and neck, and urothelial cancer) who have progressed after treatment 
with approved therapies or for which there are no standard effective therapies available. The 
primary endpoint of the initial part of Phase 2 is ORR after 24 weeks of treatment, with select 
secondary endpoints, including ORR, disease control rate, PFS, and duration of response 
(DOR).
As of the data cutoff of 01-DEC-2017, 20 participants with NSCLC were enrolled (data on 
file). Of the enrolled participants, 9 (45%) were PD-L1(+) (TPS ≥1%), 5 (25%) were PD-
L1(), and 6 (30%) were not tested; 3 (15%) were treatment-naïve; and 6 (30%), 9 (45%), 
and 2 (10%) had 1, 2, and ≥3 prior lines of systemic therapy, respectively. The primary 
endpoint of ORR at Week 24 was 30.0% (95% CI, 11.9% to 54.3%). Grade 3 and 4 
treatment-related AEs occurred in 11 participants (55%) and 1 participant (5%), respectively 
(ie, increased aspartate aminotransferase [AST]). There was 1 fatal treatment-related AE 
(exsanguination that was deemed “possibly related” to study intervention). The most 
common Grade 3 treatment-related AEs were hypertension (30% [6 of 20 participants]) and 
fatigue, diarrhea, and hyponatremia (15% [3 of 20 subjects]). These findings indicate that the 
combination of lenvatinib with pembrolizumab shows promising clinical activity with a 
manageable safety profile in previously treated patients with metastatic NSCLC who were 
not preselected for PD-L1 status.
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2.2.4
Information on Other Study-related Therapy
Study participants will receive concomitant chemotherapy with either carboplatin or cisplatin 
and pemetrexed as per their product labels. Refer to their respective package inserts for more 
information.
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.
While there are options for patients with metastatic NSCLC, a significant percentage of these 
patients will die from their cancer. As such, there is a continual need for novel therapies in 
this setting. Moreover, as discussed in the previous section, both lenvatinib and 
pembrolizumab combination therapy alone and given concomitantly with chemotherapy have 
shown activity in NSCLC. The most common Grade 3 treatment-emergent AEs were 
hypertension (24%), fatigue (14%), diarrhea (14%), proteinuria (10%), and arthralgia (10%)
(Data on file). Toxicities were manageable with dose interruption and/or modification and no 
new safety signals were found. Existing data suggest that inhibiting angiogenesis in 
combination with PD-1 blockade is a promising therapeutic strategy and the benefit: risk
assessment for participants included in this study is considered to be favorable.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IBs and ICF documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
The objectives of the study are as follows, in participants with nonsquamous non-small cell 
lung cancer (NSCLC), who are at least 18 years of age:
Throughout this protocol, the term RECIST 1.1 refers to the modification of RECIST 1.1 to 
include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Refer 
to Section 4.2.1.1.3 for further details.
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Objectives
Endpoints
Primary
•
Part 1: To evaluate the safety and 
tolerability of treatment with 
lenvatinib + platinum doublet 
chemotherapy + pembrolizumab.
•
Dose-limiting toxicities (DLTs), adverse 
events (AEs) and study intervention
discontinuations due to AEs.
•
Part 2: To compare progression free 
survival (PFS) as assessed by blinded 
independent central review (BICR) 
according to Response Evaluation 
Criteria in Solid Tumors, version 1.1 
(RECIST 1.1) for lenvatinib +
platinum doublet chemotherapy + 
pembrolizumab versus matching 
placebo + platinum doublet 
chemotherapy + pembrolizumab.
•
Hypothesis (H1): The combination of 
lenvatinib +platinum doublet 
chemotherapy + pembrolizumab
prolongs PFS per RECIST 1.1 by
BICR compared to matching placebo 
+ platinum doublet chemotherapy + 
pembrolizumab.
•
PFS, defined as the time from 
randomization to the date of the first 
documentation of disease progression or 
death from any cause, whichever is 
earlier.
•
Part 2: To compare overall survival 
(OS) for the combinations of 
lenvatinib + platinum doublet 
chemotherapy + pembrolizumab 
versus matching placebo + platinum 
doublet chemotherapy + 
pembrolizumab.
•
Hypothesis (H2): The combination of 
lenvatinib + platinum doublet 
chemotherapy + pembrolizumab 
prolongs OS compared to matching 
placebo + platinum doublet 
chemotherapy + pembrolizumab.
•
OS, defined as the time from 
randomization to the date of death from 
any cause.
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Objectives
Endpoints
Secondary
•
Part 2: To compare objective response 
rate (ORR) as assessed by BICR 
according to RECIST 1.1 for the 
combinations of lenvatinib + platinum 
doublet chemotherapy + 
pembrolizumab versus matching 
placebo + platinum doublet 
chemotherapy + pembrolizumab.
•
Hypothesis (H3): The combination of 
lenvatinib + platinum doublet 
chemotherapy + pembrolizumab has 
superior ORR per RECIST 1.1 by
BICR compared to matching placebo 
+ platinum doublet chemotherapy + 
pembrolizumab.
•
Objective response (OR), defined as a 
confirmed complete response (CR) or 
partial response (PR).
•
Part 2: To evaluate duration of 
response (DOR) per RECIST 1.1 by 
BICR for the combinations of 
lenvatinib + platinum doublet 
chemotherapy + pembrolizumab and
matching placebo + platinum doublet 
chemotherapy + pembrolizumab.
•
DOR, defined as the time from the first 
documented evidence of CR or PR until 
disease progression or death due to any 
cause (whichever is earlier), for 
participants who demonstrate a confirmed 
CR or PR.
•
Part 2: To evaluate the safety and 
tolerability for the combinations of
lenvatinib + platinum doublet 
chemotherapy + pembrolizumab and
matching placebo + platinum doublet 
chemotherapy + pembrolizumab.
•
Adverse events (AEs) and study 
intervention discontinuations due to AEs.
•
Part 2: To evaluate the mean change 
from baseline in global health 
status/quality of life (QoL), cough, 
chest pain, dyspnea, and physical 
functioning for the combinations of 
lenvatinib + platinum doublet 
chemotherapy + pembrolizumab and
matching placebo + platinum doublet 
chemotherapy + pembrolizumab.

Change from baseline for the following 
patient-reported outcomes (PRO) 
scales/items: global health status/QoL 
(EORTC QLQ-C30 Items 29 and 30), 
cough (EORTC QLQ-LC13 Item 31), 
chest pain (EORTC QLQ-LC13 Item 40), 
dyspnea (EORTC QLQ-C30 Item 8), and 
physical functioning (EORTC QLQ-C30 
Items 1 through 5).
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Objectives
Endpoints
•
Part 2: To evaluate the time to true 
deterioration (TTD) in global health 
status/QoL, cough, chest pain, 
dyspnea, and physical functioning for 
the combinations of lenvatinib + 
platinum doublet chemotherapy + 
pembrolizumab and matching placebo 
+ platinum doublet chemotherapy +
pembrolizumab.
•
TTD, defined as the time from baseline to 
the first onset of a ≥10-point deterioration
from baseline with confirmation by the 
subsequent visit of a ≥10-point 
deterioration from baseline in global 
health status/QoL (EORTC QLQ-C30 
Items 29 and 30), cough (EORTC 
QLQ-LC13 Item 31), chest pain (EORTC 
QLQ-LC13 Item 40), dyspnea (EORTC 
QLQ-C30 Item 8), and physical 
functioning (EORTC QLQ-C30 Items 1
through 5).
•
TTD in the composite endpoint 
(combination of cough [QLQ-LC13 item 
31], chest pain [QLQ-LC13 item 40], or 
dyspnea [QLQ-C30 item 8]) defined as 
the time to first onset of a ≥10-point 
deterioration from baseline in any one of 3 
scale items with confirmation by the 
subsequent visit of a ≥10-point 
deterioration from baseline in the same 
scale as the first onset.
Tertiary/Exploratory
•
Part 2: To evaluate the 
pharmacokinetics (PK) of lenvatinib 
when co-administered with 
pembrolizumab following treatment 
with lenvatinib + platinum doublet 
chemotherapy + pembrolizumab.
•
Plasma concentration of lenvatinib versus 
time.
•
Part 2: To evaluate and compare 
participants’ health status as assessed 
by the 5-level version of the European 
Quality of Life (EuroQoL) 
5-dimension Questionnaire 
(EQ-5D-5L) to generate utility scores 
for use in economic models.
•
Health utilities assessed using the 
EQ-5D-5L.
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Objectives
Endpoints
•
Part 2: 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 lenvatinib in all 
participants.
•
Molecular (genomic, metabolic, and/or 
proteomic) determinants of response or 
resistance to treatments, using blood 
and/or tumor tissue.
4
STUDY DESIGN
4.1
Overall Design
This is a Phase 3, randomized, double-blind, active-control with placebo, parallel-group, 
multisite study of lenvatinib versus matching placebo in combination with pembrolizumab 
and platinum doublet chemotherapy in participants with treatment-naïve metastatic 
nonsquamous NSCLC. Eligible participants will have measurable disease based on 
RECIST 1.1, an ECOG performance status of 0 or 1, and a cancer that is EGFR, ALK, and 
ROS proto-oncogene 1 (ROS1) negative.
Currently there is no data available examining the safety profile of lenvatinib with 
pembrolizumab and chemotherapy. As such, this study will include an open-label safety run-
in (Part 1). In Part 1, approximately 12 participants will be treated with lenvatinib in 
combination with pembrolizumab and platinum doublet chemotherapy to ensure that at least 
6 participants will be treated with lenvatinib in combination with pembrolizumab, 
carboplatin, and pemetrexed, and at least 6 participants will be treated with lenvatinib in 
combination with pembrolizumab, cisplatin, and pemetrexed. Participants will be closely 
followed for unacceptable toxicities for 21 days after the first dose of study intervention (the 
dose-limiting toxicity [DLT] evaluation period) for occurrence of specific AEs that are 
deemed dose-limiting according to Table 1. If after all Part 1 participants complete the 
21-day DLT period, less than 3 DLTs in 6 participants in each platinum-containing arm have 
occurred, enrollment to Part 2 will begin without delay. If 3 or more DLTs occur in 
6 participants in each platinum-containing arm during this safety run-in, enrollment to Part 2 
may be delayed to further examine safety data and consider study design changes.
Participants in Part 1 will continue to receive study intervention and be followed in the 
posttreatment period as applicable. Safety data from this population will be reported 
separately from data in the blinded Phase 3 portion of the study.
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Table 1
Dose-limiting Toxicities
Toxicity Category
Toxicity CTCAE Grade
Hematologic

Grade 4 neutropenia lasting for ≥7 days

Grade 3 or Grade 4 febrile neutropeniaa

Thrombocytopenia <25,000/mm3 associated with bleeding and/or which 
requires platelet transfusion
Other nonhematologic
toxicity

Any other Grade 4 or a Grade 5 toxicity

Grade 3 toxicities lasting >3 days excluding:
o
Nausea, vomiting, and diarrhea controlled by medical intervention 
within 72 hours
o
Grade 3 rash in the absence of desquamation, no mucosal involvement, 
does not require steroids, and resolves to Grade 1 by the next scheduled 
dose of pembrolizumab

Grade 3 hypertension not able to be controlled by medication

Grade 3 or above gastrointestinal perforation

Grade 3 or above wound dehiscence requiring medical or surgical 
intervention

Any grade thromboembolic event
Any Grade 3 nonhematologic laboratory value if:
o
Medical intervention is required to treat the participant, or
o
The abnormality leads to hospitalization
Abbreviations: ANC = absolute neutrophil count; CTCAE = Common Terminology Criteria for Adverse Events v4.0.
a
Febrile neutropenia Grade 3 or Grade 4
o
Grade 3 is defined as ANC <1000/mm3 with a single temperature of >38.3ºC (101ºF) or a sustained temperature 
of ≥38ºC (100.4ºF) for more than 1 hour.
o
Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3ºC (101ºF) or a sustained temperature 
of ≥38ºC (100.4ºF) for more than 1 hour, with life-threatening consequences and urgent intervention indicated.
In Part 2, participants will be randomized 1:1 to Arm 1 (lenvatinib + pembrolizumab +
platinum doublet chemotherapy) or Arm 2 (matching placebo + pembrolizumab + platinum
doublet chemotherapy). Randomization will be stratified by PD-L1 TPS (<50% vs. ≥50%), 
geographical site (East Asian vs. non-East Asian), and ECOG performance status at 
Screening (0 vs. 1). The planned sample size is approximately 714 participants with
approximately 357 participants in each treatment arm.
The study design is depicted in Figure 1.
Study interventions include oral lenvatinib, 8 mg qd (Arm 1) or matching placebo (Arm 2), 
and pembrolizumab, 200 mg, carboplatin (AUC 5 mg/mL/min) or cisplatin (75 mg/m2), and 
pemetrexed, 500 mg/m2 all given by intravenous (IV) infusion on Day 1 of a 21-day cycle.
Lenvatinib/matching placebo, pembrolizumab, carboplatin/cisplatin, and pemetrexed 
combination treatment will be given for up to the first 4 cycles, after which participants may 
receive maintenance treatment with lenvatinib/matching placebo, pembrolizumab, and 
pemetrexed. Pembrolizumab may be given for up to a total of 35 cycles; there is no treatment 
duration limit for lenvatinib/matching placebo or pemetrexed. The study has no planned 
treatment cross-over.
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Participants will be evaluated with radiographic imaging to assess response to treatment 
6 weeks, 12 weeks, and 18 weeks from the day of randomization, then every 9 weeks through 
Week 54, and subsequently every 12 weeks until disease progression is documented 
radiographically per RECIST 1.1 and verified by BICR, initiating a new anticancer therapy, 
participant withdrawal of consent, pregnancy, becoming lost to follow-up, death, or the end 
of the study, whichever is earlier.
All imaging obtained on study will be submitted to the imaging vendor for BICR, which will 
assess the images using RECIST 1.1 (see Section 8.2.1.5) for determination of PFS, ORR, 
and DOR. Initial tumor imaging showing site-assessed progressive disease (PD) should be 
submitted immediately for verification by BICR before treatment discontinuation. 
Treatment-based decisions may use site-assessed iRECIST as described in Section 8.2.1.6, 
which allows participants with initial site-assessed PD to continue treatment until PD is 
confirmed by the site 4 to 8 weeks later.
Adverse event monitoring will be ongoing throughout the study and graded in severity 
according to the guidelines outlined in the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), Version 4.0.
An external Data Monitoring Committee (DMC) will evaluate the safety, tolerability, and 
efficacy of study intervention. The first DMC review will be triggered once at least 
10 participants are treated with at least 2 cycles of each of the following regimens: 
(i) lenvatinib, pembrolizumab, carboplatin, pemetrexed; (ii) placebo, pembrolizumab, 
carboplatin, pemetrexed; (iii) lenvatinib, pembrolizumab, cisplatin, pemetrexed; and (iv) 
placebo, pembrolizumab, cisplatin, pemetrexed. Refer to Section 10.1.4 and the DMC 
Charter for further details.
Study interventions will continue until reaching a discontinuation criterion (Section 7.1), 
examples of which include disease progression which is radiographically documented and
verified by BICR per RECIST 1.1, and only when clinically appropriate, confirmed by the 
site per iRECIST; unacceptable toxicity; intercurrent illness that prevents further 
administration of treatment; investigator’s decision to withdraw treatment; participant 
withdrawal of consent; pregnancy; noncompliance with study intervention or procedure 
requirements; administrative reasons requiring cessation of treatment; or, for carboplatin, 
cisplatin, and pembrolizumab ONLY, treatment completion (4 cycles of carboplatin or 
cisplatin/35 cycles of pembrolizumab). There is no treatment duration limit for 
lenvatinib/matching placebo or pemetrexed.
Participants treated with pembrolizumab who complete 35 cycles of treatment with stable 
disease (SD) or better or participants who attain an investigator-determined CR and have 
received at least 8 cycles of pembrolizumab may be eligible for retreatment with up to an 
additional 17 cycles (approximately 1 year) of pembrolizumab if they experience 
radiographic disease progression after stopping treatment in the initial treatment phase. This 
retreatment is termed Second Course Treatment and is only available if the study remains 
open and the participant meets the criteria listed in Section 7.1.1. Participants will also 
continue treatment with lenvatinib/placebo at the discretion of the investigator until meeting 
one of the criteria for treatment discontinuation. Responses or events of progression that 
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occur during Second Course Treatment will not be counted towards the ORR and PFS 
endpoints in this study.
The study will be conducted in conformance with Good Clinical Practices (GCP).
Extension Study in China
Approximately 200 participants in China will be randomized overall in the global study and
the extension study. After enrollment of the global study is closed, participants in China will 
continue to be enrolled and randomized in a 1:1 ratio in an extension study designed to meet 
local regulatory requirements. The extension study will be identical to the global study (eg,
double-blinded, with identical inclusion and exclusion criteria, study endpoints, primary and 
secondary objectives, and study procedures), with the exception of an additional 
supplemental statistical analysis plan (sSAP) for participants enrolled in China. Details of the 
analysis will be provided in the separate China-specific sSAP document.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
Further improvements can be made on the therapeutic options available for patients with 
previously untreated metastatic nonsquamous NSCLC, notwithstanding the progress made 
with the use of molecularly targeted agents in patients with actionable mutations and with the 
use of the use of the anti-PD1/anti-PD-L1 antibodies to inhibit suppression of the immune 
system, which have begun to change outcomes in this patient population.
Pembrolizumab, in particular, has led to a paradigm shift from standard platinum-based 
doublets utilizing both monotherapy and combination approaches in the first-line treatment 
of NSCLC. KEYNOTE-024 and KEYNOTE-042 showed that pembrolizumab monotherapy 
leads to a statistically significant OS benefit in participants with PD-L1-positive metastatic 
NSCLC compared with chemotherapy, including in participants with squamous histology.
However, about 30% of patients with NSCLC have tumors that do not express PD-L1.
Therapeutic approaches to expand on the efficacy of pembrolizumab monotherapy have led 
to combination strategies with chemotherapy. The efficacy of the combination of 
pembrolizumab with chemotherapy is expected to be at least additive, and possibly 
synergistic, due to the immunomodulatory effects of pembrolizumab and induction of PD-L1 
expression by cytotoxic chemotherapeutics. Chemotherapy has been shown to augment the 
antitumor immune response by inducing immunogenic cell death, enhancing the maturation 
and activation of dendritic cells, increasing T-cell penetrance and function in the tumor,
improving the presentation of tumor antigens, and eliminating immunosuppressive cells 
(T-regulatory cells, myeloid derived suppressor cells, and M2 macrophages) [Apetoh, L., et 
al 2015].
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KEYNOTE-189 demonstrated that treatment with pembrolizumab in combination with 
pemetrexed/platinum chemotherapy (cisplatin or carboplatin) provided a clinically 
meaningful and significant improvement in OS [OS HR 0.49; p<0.00001; median OS not 
reached vs. 11.3 months], PFS [PFS HR of 0.52; p<0.00001; median PFS 8.8 months vs.
4.9 months] and ORR [47.6% vs. 18.9%; p<0.0001] for previously untreated patients with 
metastatic nonsquamous NSCLC. Importantly, all subgroups benefited from pembrolizumab 
in combination with pemetrexed and platinum-based chemotherapy, including patients whose 
tumors did not express PD-L1; therefore, extending the benefit of pembrolizumab to those 
with PD-L1 negative tumors.
A potential opportunity to improve upon the current therapeutic strategy in nonsquamous 
NSCLC is by adding an RTKi to pembrolizumab in the maintenance setting. This two-part 
Phase 3 study is being conducted to evaluate the efficacy and safety of lenvatinib versus 
matching placebo in combination with pembrolizumab and platinum doublet chemotherapy
in participants with treatment-naïve metastatic nonsquamous NSCLC. If the study shows 
acceptable safety and efficacy profiles with this combination of experimental intervention + 
SOC and improves outcomes, the study could support the regulatory approval of 
pembrolizumab + lenvatinib + SOC in patients with metastatic NSCLC.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
4.2.1.1.1
Primary Efficacy Endpoints
This study will use PFS based on RECIST 1.1 criteria adjusted to follow a maximum of 
10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR as the
primary endpoint and [OS/ORR] as the secondary endpoint. Progression-free survival and 
ORR are acceptable measures of clinical benefit for a late-stage study that demonstrates 
superiority of a new antineoplastic therapy, especially if the magnitude of the effect is large 
and the therapy has an acceptable risk/benefit profile. The use of BICR and RECIST 1.1 to 
assess PFS and ORR are typically considered acceptable by regulatory authorities. Images 
will be read by a central imaging vendor blinded to treatment assignment to minimize bias in 
the response assessments. In addition, the final determination of radiologic progression will 
be based on the central assessment of progression, rather than a local site 
investigator/radiology assessment. Real time determination of radiologic progression as 
determined by central review will be communicated to the site.
Overall survival has been recognized as the gold standard for the demonstration of 
superiority of a new antineoplastic therapy in randomized clinical studies.
For additional details about assessing efficacy endpoints using RECIST 1.1 and iRECIST, 
see Appendix 6.
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4.2.1.1.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints of this study are ORR and DOR based on RECIST 1.1 and 
assessed by BICR; both are accepted by regulatory authorities and the oncology community.
4.2.1.1.3
RECIST 1.1
RECIST 1.1 will be used by the BICR when assessing images for efficacy measures and by 
the local site when determining eligibility (Section 8.2.1.5). Although traditional RECIST 1.1 
references a maximum of 5 target lesions in total and 2 per organ, this protocol has 
implemented an adjustment to RECIST 1.1 to allow a maximum of 10 target lesions in total 
and 5 per organ. Refer to Sec. 8.2.1.5 for additional detail. 
4.2.1.1.4
Modified RECIST 1.1 for Immune-based Therapeutics (iRECIST)
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
following treatment with pembrolizumab (Section 8.2.1.6). Immunotherapeutic agents such 
as pembrolizumab may produce antitumor effects by potentiating endogenous cancer-specific 
immune responses. The response patterns seen with such an approach may extend beyond the 
typical time course of responses seen with cytotoxic agents, and patients treated with 
pembrolizumab may manifest a clinical response after an initial increase in tumor burden or 
even the appearance of new lesions. Thus, standard RECIST 1.1 may not fully capture the 
treatment benefits from immunotherapeutic agents such as pembrolizumab. Based on an 
analysis of participants with melanoma enrolled in KEYNOTE-001 (KN001), 7% of 
evaluable participants experienced delayed or early tumor pseudo-progression. Of note, 
participants who had PD by RECIST 1.1 but not by the immune-related response criteria
[Wolchok, J. D., et al 2009] had longer OS than participants with PD by both criteria [Hodi, 
F. S., et al 2014]. Additionally, the data suggest that RECIST 1.1 may underestimate the 
benefit of pembrolizumab in approximately 15% of participants. These findings support the 
need to apply a modification to RECIST 1.1 that takes into account the unique patterns of 
atypical responses in immunotherapy and enables treatment beyond initial radiographic 
progression, if the participant is clinically stable.
iRECIST assessment has been developed and published by the RECIST Working Group, 
with input from leading experts from industry and academia, along with participation from 
the US Food and Drug Administration and the European Medicines Agency [Seymour, L., et 
al 2017]. The unidimensional measurement of target lesions, qualitative assessment of 
nontarget lesions, and response categories are identical to RECIST 1.1, until progression is 
seen by RECIST 1.1. However, if a participant is clinically stable, additional imaging may be 
performed to confirm radiographic progression. iRECIST will be used by investigators to 
assess tumor response and progression and make treatment decisions as well as for 
exploratory efficacy analyses where specified.
4.2.1.2
Safety Endpoints
Safety parameters commonly used for evaluating investigational systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
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causality, and outcome of AEs/serious adverse events (SAEs); and changes in vital signs and 
laboratory values. Adverse events will be assessed as defined by CTCAE, Version 4.0.
4.2.1.3
Rationale for Patient-Reported Outcomes
Assessment of symptoms is considered clinically important and accepted by health 
authorities. Participants will provide information regarding their HRQoL via the following 
assessment tools: EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D. These measures are 
not pure efficacy or safety endpoints because they are affected by both disease progression 
and treatment tolerability.
4.2.1.3.1
EORTC QLQ-C30
EORTC QLQ-C30 is the most widely used cancer specific health related quality of life 
(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), 
6 single items (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial 
impact), and a global health and QoL scale [Aaronson, N. K., et al 1993]. The EORTC QLQ-
C30 is a psychometrically and clinically validated instrument appropriate for assessing QoL 
in oncology studies [Aaronson, N. K., et al 1993].
4.2.1.3.2
EORTC QLQ-LC13
The EORTC Quality of Life Questionnaire and Lung Cancer Module 13 (QLQ-LC13), a 
supplemental lung cancer-specific module used in combination with QLQ-C30, is composed
of multi-item and single-item measures of lung cancer-associated symptoms (cough, 
hemoptysis, dyspnea, and site-specific pain) and treatment-related symptoms (sore mouth, 
dysphagia, peripheral neuropathy, and alopecia) [Bergman, B., et al 1994]. It is scored on a 
4-point scale (1 = not at all, 2 = a little, 3 = quite a bit, and 4 = very much) and has been 
translated and validated into more than 60 languages.
The EORTC QLQ-C30 and QLQ-LC13 are the most frequently used and reported PRO 
measures in lung cancer clinical studies. The reliability, validity, and practicality of these 
instruments have been reported [Aaronson, N. K., et al 1993a] [Bergman, B., et al 1994].
4.2.1.3.3
EuroQoL EQ-5D
The EuroQoL-5D (EQ-5D) is a standardized instrument for use as a measure of health 
outcome and will provide data to develop health utilities for use in health economic analyses 
[Rabin, R. and de Charro, F. 2001]Rabin, 2001. The 5 health state dimensions in the EQ-5D 
include the following: mobility, selfcare, usual activities, pain/discomfort, and 
anxiety/depression. Each dimension is rated on a 5-point scale from 1 (no problem) to 5 
(unable to/extreme problems). The EQ-5D also includes a graded (0 to 100) vertical visual 
analog scale on which the participant rates his or her general state of health at the time of the 
assessment. This instrument has been used extensively in cancer studies and published results 
from these studies support its validity and reliability [Pickard, A. S., et al 2007].
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4.2.1.4
Pharmacokinetic Endpoints
Standard PK parameters of clearance and volume of distribution at steady state are planned to 
be calculated for lenvatinib when co-administered with pembrolizumab in this study using 
the accepted mixed effects modeling approach. PK data obtained 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 patient 
population.
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  and growth factor related signaling pathways related to 
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lenvatinib and pembrolizumab 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.
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, 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.
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4.2.2
Rationale for the Use of Comparator/Placebo
No comparator/placebo will be used in Part 1 (safety run-in). In Part 2, participants will be 
randomized to receive lenvatinib or matching placebo. Both treatment arms will receive 
platinum doublet chemotherapy and pembrolizumab.
Based on the results of KEYNOTE-021G and KEYNOTE-189, standard 1L therapy for 
nonsquamous NSCLC, without activating mutations such as EGFR mutations or ALK fusion,
is chemotherapy in combination with pembrolizumab, which has shown a 1-year OS of 70% 
compared to 50% with chemotherapy alone. For patients with high PD-L1 expression, 
pembrolizumab is given as monotherapy, with an expected 2-year OS of 52% [Brahmer, J. 
R., et al 2017]. The results from KEYNOTE studies establish pembrolizumab plus 
chemotherapy as an efficacious option for 1L treatment in patients with NSCLC and a valid 
comparator that new treatment combinations will need to surpass. The use of 
lenvatinib/matching placebo in combination with pembrolizumab and chemotherapy will 
ensure the objectivity of the local investigators’ treatment decisions and AE causality 
assessments, while still providing participants SOC treatment.
4.3
Justification for Dose
4.3.1
Maximum Dose/Exposure for This Study
NOTE: In alignment with the study-specific investigator letter dated 20-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 can continue treatment per investigator’s
discretion. Participants who are potential candidates for Second Course treatment will 
continue in Efficacy Follow up.
In this study, the maximum doses for lenvatinib and pemetrexed are 8 mg qd and 500 mg/m2
Q3W, respectively. There is no maximum number of administrations for either lenvatinib or 
pemetrexed. The maximum dose and exposure for pembrolizumab in this study is 200 mg 
Q3W for up to 35 administrations (~ 2 years); however, participants may be eligible for an 
additional 17 administrations (~ 1 year; See Section 7.1.1). The maximum dose/exposure for 
carboplatin and cisplatin is 4 administrations (AUC 5 mg/mL/min for carboplatin, 75 mg/m2
for cisplatin both given Q3W).
4.3.2
Lenvatinib Dosing
The dosing regimen of lenvatinib was selected based on the results of a Phase 1 dose-finding 
study (Study E7080-J081-110) conducted in Japan with chemotherapy-naïve NSCLC, in 
which lenvatinib was tested in combination with carboplatin (AUC 6 mg/mL/min) and 
paclitaxel 200 mg/m2 to establish an MTD. The MTD of lenvatinib was determined to be 
4 mg BID after DLTs were experienced at 6 mg BID (febrile neutropenia/gingival infection 
[n=2]). A dose-expansion cohort was added, and 28 participants were dosed in total: 12 in the 
dose-finding cohort and 16 participants in the dose-expansion cohort. In total, 22 participants 
were dosed at 4 mg BID with 6 dosed at 6 mg BID. The most frequent Grade 3 and Grade 4 
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toxicities were neutropenia (95%), leukopenia (50%), hypertension (36%), thrombocytopenia 
(27%), and febrile neutropenia (23%) [Nishio, M., et al 2013]. The rate of hematologic 
toxicities was not deemed to be significantly different from this chemotherapy regimen alone 
[Ohe, Y., et al 2007].
In a small Phase 2 study (HOT 0902) by the Hokkaido Lung Cancer Clinical Study Group, 
carboplatin (AUC 5 mg/mL/min) and pemetrexed (500 mg/m2) were examined for efficacy 
and toxicity. Only 29.3% and 2.4% of patients developed Grade 3 or Grade 4 neutropenia 
and febrile neutropenia, respectively. Grade 3 and Grade 4 thrombocytopenia was seen in 
17% of patients [Kanazawa, K., et al 2014]. These data suggest that some hematologic 
toxicities seen with the combination of lenvatinib plus carboplatin and paclitaxel in Study 
E7080-J081-110 can be mitigated by the use of carboplatin and pemetrexed.
Modeling of PK data from Phase 1 lenvatinib studies examining BID versus qd dosing
demonstrated that higher drug exposure from qd dosing correlated with improved PFS or 
tumor response compared to BID dosing. Since there were no differences between the 
2 dosing regimens in term of safety or tolerability, qd dosing was recommended for ongoing 
and future studies of lenvatinib [Gupta, A., et al 2010]. As such, lenvatinib dosing for this 
study will be 8 mg qd.
4.3.3
Pembrolizumab Dosing
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based 
on the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab for adults across all indications and regardless of tumor 
type. As outlined below, this dose is justified by: 

Clinical data from 8 randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W), 

Clinical data showing meaningful improvement in benefit-risk including OS at 200 
mg Q3W across multiple indications, and

Pharmacology data showing full target saturation in both systemic circulation 
(inferred from pharmacokinetic [PK] data) and tumor (inferred from physiologically-
based PK [PBPK] analysis) at 200 mg Q3W.
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and NSCLC, covering different disease settings (treatment-naïve, previously 
treated, PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and 
in combination with chemotherapy). Five studies compared 2 mg/kg Q3W versus 10 mg/kg 
Q3W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies 
compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and 
KN006). All of these studies demonstrated flat dose- and exposure-response relationships 
across the doses studied representing an approximate 5- to 7.5-fold difference in exposure. 
The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to the highest doses 
studied. Subsequently, flat dose-exposure-response relationships were also observed in other 
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tumor types including head and neck cancer, bladder cancer, gastric cancer and classical 
Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of the 
tumor type. These findings are consistent with the mechanism of action of pembrolizumab, 
which acts by interaction with immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W. Second, a PBPK analysis was conducted to predict tumor PD-1 saturation over a wide 
range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that the fixed-dosing 
provides similar control of PK variability as weight-based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed-dose and 2 mg/kg Q3W dose.
Supported by these PK characteristics, and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across all pembrolizumab protocols.
4.3.4
Chemotherapy Dosing
The dosing regimens of chemotherapy represent the SOC per the approved product labels. 
Chemotherapy may be reduced, interrupted, or discontinued as outlined in Table 8 and 
Table 9, at the investigator’s discretion, or according to applicable local label 
recommendations, if more stringent.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consen, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
Upon study termination, participants are discontinued and may be enrolled in a 
pembrolizumab extension study, if available.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or 
other applicable regulatory requirements, procedure-related problems, or the number of 
discontinuations for administrative reasons is too high.
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5
STUDY POPULATION
Male/female participants with metastatic NSCLC, who have not received systemic anticancer 
therapy for their metastatic disease and are at least 18 years of age may be enrolled in this 
study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
1. Have a histologically or cytologically confirmed diagnosis of Stage IV (American Joint 
Committee on Cancer [AJCC], version 8 or current version) nonsquamous NSCLC.
Note: Mixed tumors will be categorized by the predominant cell type; if small cell 
elements are present, the participant is ineligible.
2. Have confirmation that EGFR-, ALK-, or ROS1-directed therapy is not indicated as 
primary treatment (documentation of absence of tumor-activating EGFR mutations AND 
absence of ALK and ROS1 gene rearrangements OR presence of a KRAS mutation).
3. Have measurable disease per RECIST 1.1.
Note: Lesions that appear measurable, but are situated in a previously irradiated area, can 
be considered measurable (eligible for selection as target lesions) if they have shown 
documented growth since the completion of irradiation.
4. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy 
of a tumor lesion not previously irradiated. FFPE tissue blocks are preferred to slides. 
Newly obtained biopsies are preferred to archived tissue. Formalin fixed specimens after 
the participant has been diagnosed with metastatic disease are preferred. Biopsies 
obtained prior to receipt of adjuvant/neoadjuvant chemotherapy are permitted if recent 
biopsy is not feasible.
Demographics
5. Be male or female ≥18 years of age inclusive, at the time of signing the informed consent
form (ICF).
6. Have a life expectancy of at least 3 months.
7. Have an ECOG performance status of 0 or 1 within 7 days prior to the first dose of study 
intervention but before randomization.
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Male Participants
Contraceptive use by men should be consistent with local regulations regarding the methods 
of contraception for those participating in clinical studies. If the contraception requirements 
in the local label for any of the study interventions is more stringent than the requirements 
above, the local label requirements are to be followed.
8. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 7 days after the last dose of lenvatinib/matching 
placebo and up to 180 days after the last dose of chemotherapeutic agents:
• Refrain from donating sperm
PLUS either:
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent
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.
Note:  7 days after lenvatinib/matching placebo is stopped, if the participant is on 
pembrolizumab only and is greater than 180 days post chemotherapy, no male
contraception measures are needed.
Female Participants
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
9. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:
-
Is not a WOCBP
OR
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-
Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), with low user dependency, or be abstinent from heterosexual 
intercourse as their preferred and usual lifestyle (abstinent on a long term and 
persistent basis), as described in Appendix 5 during the intervention period and for at 
least 120 days post pembrolizumab and 30 days post-lenvatinib/matching placebo, 
and up to 180 days post last dose of chemotherapeutic agents, whichever occurs last. 
The investigator should evaluate the potential for contraceptive method failure (ie, 
noncompliance, recently initiated) in relationship to the first dose of study 
intervention.
-
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 24 hours before the first dose of study 
intervention.
-
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.

Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 2.

The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
Informed Consent
10. The participant (or legally acceptable representative) has provided documented informed 
consent for the study.
Laboratory Values
11. Have adequate organ function as defined in the following table (Table 2). Specimens 
must be collected and reviewed within 10 days prior to the start of study intervention.
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Table 2
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematologic
Absolute neutrophil count (ANC)
≥1500/µL
Platelet count
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/L1
Renal
Serum Creatinine OR
Measured or calculated CrCl2
(GFR can also be used in place of creatinine or 
CrCl)
≤1.5 × ULN OR
≥60 mL/min for participant with creatinine 
levels >1.5 × the institutional ULN
Hepatic
Total bilirubin OR Direct bilirubin
Total 
bilirubin 
≤1.5 ×ULN 
OR 
direct 
bilirubin ≤ULN for participants with total 
bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with 
liver metastases)
Coagulation
INR or PT
Activated partial thromboplastin time (aPTT)3
≤1.5 × ULN unless the participant is 
receiving anticoagulant therapy as long as PT 
or aPTT is within therapeutic range of 
intended use of anticoagulants
Abbreviations: aPTT = activated partial thromboplastin time; ALT (SGPT)=alanine aminotransferase (serum 
glutamic pyruvic transaminase); 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.
1 Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.
2 CrCl should be calculated per institutional standard.
3.PTT may be performed if the local laboratory is unable to perform aPTT.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of 
specific chemotherapies.
12. Have adequately controlled blood pressure (BP) with or without antihypertensive 
medications, defined as BP ≤150/90 mm Hg and no change in antihypertensive 
medications within 1 week prior to randomization.
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5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has known untreated central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Participants with previously treated brain metastases may participate provided 
they are radiologically stable (ie, without evidence of progression for at least 4 weeks by 
repeat imaging [the repeat imaging must be performed during the screening period]),
clinically stable, and have not required steroids for at least 14 days prior to the first dose 
of study intervention.
2. Has a history of (noninfectious) pneumonitis that required systemic steroids or current 
pneumonitis/interstitial lung disease.
3. Radiographic evidence of intratumoral caviations, 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).
4. Has a known history of an additional malignancy, except if the participant has undergone 
potentially curative therapy with no evidence of that disease recurrence for at least 
3 years since initiation of that therapy.
-
Note: The time requirement for no evidence of disease for at least 3 years does 
not apply to the NSCLC for which a participant is enrolled in the study. The time 
requirement also does not apply to participants who underwent successful 
definitive resection of basal cell carcinoma of the skin, superficial bladder cancer, 
squamous cell carcinoma of the skin, in situ cervical cancer, or other in situ 
cancers.
5. Has an active autoimmune disease that has required systemic treatment in the past 2 years 
(ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is allowed.
6. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 
(doses exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of study intervention.
7. Has had an allogeneic tissue/solid organ transplant.
8. Has a known history of human immunodeficiency virus (HIV) infection. HIV testing is 
not required unless mandated by the local health authority.
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9. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] 
reactive or HBV-DNA detected) or known active Hepatitis C virus (defined as HCV 
RNA [qualitative] detected or HCV antibody reactive, if HCV-RNA is not the local SOC) 
infection. No testing for Hepatitis B or Hepatitis C is required unless mandated by the 
local health authority.
10. Has a history of a gastrointestinal condition or procedure that in the opinion of the 
investigator may affect oral drug absorption.
11. Has active hemoptysis (at least 0.5 tsp of bright red blood) within 2 weeks prior to the 
first dose of study intervention.
12. Has significant cardiovascular impairment within 12 months prior to the first dose of 
study intervention, including history of congestive heart failure greater than New York 
Heart Association (NYHA) Class II, unstable angina, myocardial infarction, 
cerebrovascular accident (CVA)/stroke, or cardiac arrhythmia associated with 
hemodynamic instability.
13. Has a known history of active tuberculosis.
14. Has an active infection requiring systemic therapy.
15. Has had major surgery within 3 weeks prior to first dose of study interventions. Note: 
Adequate wound healing after major surgery must be assessed clinically, independent of 
time elapsed for eligibility.
16. Has known psychiatric or substance abuse disorders that would interfere with the 
participant’s cooperation to meet with the requirements of the study.
17. Previously had a severe hypersensitivity reaction to treatment with a monoclonal 
antibody or has a known sensitivity to any component of lenvatinib or pembrolizumab, or 
as applicable, carboplatin, cisplatin, or pemetrexed.
18. A WOCBP who has a positive urine pregnancy test within 24 hours prior to
randomization or treatment allocation (see Appendix 5). If the urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required.
Note: In the event that 24 hours have elapsed between the Screening pregnancy test and 
the first dose of study intervention, another pregnancy test (urine or serum) must be 
performed and must be negative in order for the participant to start receiving study 
medication.
19. Has preexisting ≥Grade 3 gastrointestinal or non-gastrointestinal fistula.
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Prior/Concomitant Therapy
20. Has received prior systemic chemotherapy or other targeted or biological antineoplastic 
therapy for their metastatic NSCLC.
Note: Prior treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant 
therapy is allowed as long as therapy was completed at least 6 months prior to the 
diagnosis of metastatic NSCLC.
21. Has received prior treatment with pembrolizumab or any other anti-PD-1, anti-PD-L1, 
anti-PD-L2 agent, with lenvatinib or any other RTKi, or with an agent directed to another 
stimulatory or co-inhibitory T cell receptor (eg, CTLA-4, OX-40, CD137, GITR).
22. Has received radiotherapy within 14 days prior to the first dose of study intervention or 
received lung radiation therapy of >30 Gy within 6 months prior to the first dose of study 
intervention.
Note: Participants must have recovered from all radiation-related toxicities to Grade ≤1, 
not required corticosteroids, and not have had radiation pneumonitis. A 1-week washout 
is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
23. Has received systemic steroid therapy (in doses exceeding 10 mg daily of prednisone 
equivalent) within 7 days prior to the first dose of study intervention.
24. Has received a live or live attenuated vaccine within 30 days prior to the first dose of 
study intervention. Note: killed vaccines are allowed.
Prior/Concurrent Clinical Study Experience
25. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 
4 weeks prior to the first dose of study intervention.
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been >4 weeks after the last dose of the previous 
investigational agent.
Diagnostic Assessments
26. Participants with proteinuria >1+ on urine dipstick testing/urinalysis will undergo 
24-hour urine collection for quantitative assessment of proteinuria. Participants with 
urine protein ≥1 g/24 hours will be ineligible.
27. Has a prolongation of QTc interval (calculated using Fridericia’s formula) of >480 msec
28. Has left ventricular ejection fraction (LVEF) below the institutional (or local laboratory)
normal range as determined by multigated acquisition scan (MUGA) or echocardiogram 
(ECHO).
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Other Exclusions
29. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant’s ability to 
participate for the full duration of the study, or make it not in the best interest of the 
participant to participate, in the opinion of the treating investigator.
Note: Country-specific requirements are listed in Appendix 7.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participant should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea, or vomiting.
5.3.2
Contraception
Lenvatinib and pembrolizumab may have adverse effects on a fetus in utero. Refer to 
Appendix 5 for approved methods of contraception.
Based on its mechanism of action, lenvatinib can cause fetal harm when administered to a 
pregnant woman. Lenvatinib may also result in reduced fertility in females of reproductive 
potential and may result in damage to male reproductive tissues leading to reduced fertility of 
unknown duration. In animal reproduction studies, oral administration of lenvatinib during 
organogenesis at doses below the recommended human dose resulted in embryotoxicity, 
fetotoxicity, and teratogenicity in rats and rabbits.
Participants should be informed that taking study intervention may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in 
the study, participants of childbearing potential must adhere to the contraception 
requirements (Appendix 5) from the first day of study intervention initiation (or 14 days prior 
for oral contraception) throughout the treatment period and up to 120 days post
pembrolizumab and/or 30 days post-lenvatinib/matching placebo and up to 180 days after last 
dose of chemotherapeutic agents. If there is any question that a participant of childbearing 
potential will not reliably comply with the requirements for contraception, that participant 
should not be entered into the study.
5.3.3
Pregnancy
If a participant inadvertently becomes pregnant while on treatment with lenvatinib or 
pembrolizumab, the participant will be immediately discontinued from study intervention. 
The site will contact the participant at least monthly and document the participant’s status 
until the pregnancy has been completed or terminated. The outcome of the pregnancy will be 
reported to the Sponsor without delay and within 24 hours if the outcome is an SAE (eg, 
death, abortion, congenital anomaly, or other disabling or life-threatening complication to the
mother or newborn). The study investigator will make every effort to obtain permission to 
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follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
Sponsor. If a male participant impregnates his female partner, the study personnel at the site 
must be informed immediately and the pregnancy must be reported to the Sponsor and 
followed as described above.
5.3.4
Use in Nursing Women
It is unknown whether lenvatinib or pembrolizumab are excreted in human milk. Since many 
drugs are excreted in human milk, and because of the potential for serious adverse reactions 
in the nursing infant, participants who are breastfeeding are not eligible for enrollment.
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 OR withdraws consent will not be 
replaced.
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 will be packaged to support enrollment and will be affixed with a clinical 
label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 3.
NOTE: In alignment with the study-specific investigator letter dated 20-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 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 3
Study Treatments
Arm 
Name
Arm Type
Study 
Treatment 
Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admin-
istration
Regimen/
Treatment 
Period
Use
IMP/
NIMP
Sourcing
Part 1 
and 
Part 2: 
Arm 1
Experimental
Lenvatinib
Drug
Capsule
4 mg and 
1 mg
8 mg
Oral
Once daily; 
no treatment 
duration 
limit
Experimental
IMP
Central
Part 2: 
Arm 2
Placebo 
comparator
Matching 
placebo
Drug
Capsule
N/A
N/A
Oral
Once daily; 
no treatment 
duration 
limit
Placebo
IMP
Central
Part 1 
and 
Part 2: 
Arms 1 
and 2
Experimental/
Placebo 
comparator
Pembro-
lizumab
(MK-3475)
Drug
Solution for 
infusion
25 mg/mL
200 mg
IV 
infusion
Once every 
3 weeks; up 
to a total of 
35 cycles
Standard of 
care/
Experimental
IMP
Central
Part 1 
and 
Part 2: 
Arms 1 
and 21
Experimental/
Placebo 
comparator
Carboplatin
Drug
Solution for 
infusion
10 mg/mL
AUC 5
mg/mL/min
IV 
infusion
Once every 
3 weeks; up 
to the first 
4 cycles of 
treatment
Standard of 
care
NIMP
Local or 
Central
Part 1 
and 
Part 2: 
Arms 1 
and 21
Experimental/
Placebo 
comparator
Cisplatin
Drug
Solution for 
infusion
1 mg/mL
75 mg/m2
IV 
infusion
Once every 
3 weeks; up 
to the first 
4 cycles of 
treatment
Standard of 
care
NIMP
Local or 
Central
Part 1 
and 
Part 2: 
Arms 1 
and 21
Experimental/
Placebo 
comparator
Cisplatin
Drug
Lyophilized 
Powder
20 mg
75 mg/m2
IV 
infusion
Once every 
3 weeks; up 
to the first 
4 cycles of 
treatment
Standard of 
care
NIMP
Local or 
Central
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Arm 
Name
Arm Type
Study 
Treatment 
Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admin-
istration
Regimen/
Treatment 
Period
Use
IMP/
NIMP
Sourcing
Part 1 
and 
Part 2: 
Arms 1 
and 21
Experimental/
Placebo 
comparator
Pemetrexed
Drug
Lyophilized 
powder
500 mg/
vial
500 mg/m2
IV 
infusion
Once every 
3 weeks; no 
treatment 
duration 
limit
Standard of 
care
NIMP
Local or 
Central
Abbreviations: AUC = area under the plasma drug concentration-time curve; IMP = Investigational Medicinal Product; IV = intravenous; 
NIMP = Non-Investigational Medicinal Product
Definitions of Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) are based on guidance issued by the European 
Commission. Regional and/or country differences in the definitions may exist. In these circumstances, local legislation is followed.
1 Clinical supply concentration and formulation of chemotherapy may vary by local sourcing.
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All supplies indicated in Table 3 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number 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.
The investigator will select one of the following platinum doublet chemotherapy regimens 
prior to randomization:

Pemetrexed 500 mg/m2 + carboplatin AUC 5 mg/mL/min Q3W for 4 cycles followed by 
maintenance therapy with pemetrexed 500 mg/m2 Q3W until reaching a discontinuation 
criterion listed in Section 7.1

Pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 for 4 cycles followed by maintenance 
therapy with pemetrexed 500 mg/m2 Q3W until reaching a discontinuation criterion listed 
in Section 7.1
All participants will also receive pembrolizumab 200 mg Q3W for up to a total of 35 cycles 
and lenvatinib (Part 1 and Part 2: Arm 1)/matching placebo (Part 2: Arm 2) until reaching a 
discontinuation criterion listed in Section 7.1. There is no treatment duration limit for 
lenvatinib/matching placebo or pemetrexed.
Part 1 will be an unblinded, open-label, safety run-in. In Part 2, treatment with 
lenvatinib/matching placebo will be double-blinded. Matching placebo was created by the 
Sponsor to match the active product.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Chemotherapy should be prepared per the approved product labels. Details on preparation 
and administration of pembrolizumab are provided in the Pharmacy Manual.
Participants/caregivers will be given instructions on how to handle and store lenvatinib 
capsules at home.
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 IVRS/IWRS. Participants 
in Part 1 (safety run-in) will receive lenvatinib in combination with pembrolizumab and 
platinum doublet chemotherapy without randomization. In Part 2 (Phase 3 study), 
participants will be assigned randomly in a 1:1 ratio to lenvatinib in combination with 
platinum doublet chemotherapy plus pembrolizumab (Arm 1) or matching placebo in 
combination with platinum doublet chemotherapy plus pembrolizumab (Arm 2).
6.3.2
Stratification
Part 1 (safety run-in):
There are no stratification factors for Part 1.
Part 2 (Phase 3 Study):
Treatment assignment in Part 2 will be stratified by the following factors:
1. PD-L1 TPS (<50% vs. ≥50%)
2. Geographic site (East Asian vs. non-East Asian)
3. ECOG performance status at Screening (0 vs. 1)
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6.3.3
Blinding
As of the final analysis, the study was unblinded. Original protocol text that is contained in 
this section has been retained for reference.
Part 1 (safety run-in):
Part 1 of this study is being conducted as an open-label study, ie, participants, investigators, 
and Sponsor personnel will be aware of study intervention assignments.
Part 2 (Phase 3 Study):
In Part 2, a double-blinding technique with in-house blinding will be used.
Lenvatinib/matching placebo will be packaged identically for Arms 1 and 2 so that the blind 
is maintained. The participant, the investigator, the Sponsor, and delegate(s) who are 
involved in study intervention administration or the clinical evaluation of participants will be
unaware of treatment assignments.
The treatment identity of pembrolizumab and chemotherapy will be open-label; the identity 
of those treatments will be known by the participant, the investigator, the Sponsor, and
delegate(s) who are involved in study intervention administration or the clinical evaluation of 
participants.
See Section 8.1.10 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
The central vendor PD-L1 TPS results of participants will be blinded to the investigator. The 
Sponsor acknowledges that due to the commercial availability of PD-L1 testing assays, it is 
possible that the investigator may know a participant’s TPS prior to Screening. This risk is 
seen as acceptable, as the treatment interventions are hypothesized to provide benefit 
regardless of TPS.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment for >28 days (lenvatinib), >6 weeks 
(chemotherapy), or >12 weeks (pembrolizumab) require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the treatment period. If there is a clinical indication for any medication or vaccination 
specifically prohibited, discontinuation from study intervention may be required. The 
investigator is to discuss prohibited medication/vaccination with the Sponsor’s Clinical 
Director. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician but the decision to continue the 
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participant on study intervention requires the mutual agreement of the investigator, the 
Sponsor, and the participant.
All prior medications (including over-the-counter medications) administered within 30 days 
prior to the first dose of study intervention and any concomitant therapy administered to the 
participant during the course of the study (starting at the date of informed consent) until 
30 days after the final dose (or 90 days if used to treat an SAE) of study intervention will be 
recorded. Additionally, all diagnostic, therapeutic, or surgical procedures relating to 
malignancy should be recorded. Any medication that is considered necessary for the 
participant’s health and that is not expected to interfere with the evaluation of or interact with 
the study interventions may be continued during the study.
6.5.1
Allowed Concomitant Medications
Treatment of complications or AEs, or therapy to ameliorate symptoms (including blood 
products, blood transfusions, fluid transfusions, antibiotics, and antidiarrheal drugs), may be 
given at the discretion of the investigator, unless it is expected to interfere with the evaluation 
of (or to interact with) the study interventions. Antiemetic drugs or any other prophylaxis 
treatment should be considered in accordance with institutional guidelines.
The following concomitant medications are also allowed:

Hormone replacement therapy

Thyroid hormone suppressive therapy

Anticoagulants including low molecular-weight heparin (LMWH), 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)

Colony-stimulating factors
Use of colony-stimulating factors (CSFs) for primary prophylaxis is permitted at the 
investigator’s discretion. Refer to the American Society of Clinical Oncology 
guidelines for use of CSFs [Smith, T. J., et al 2006].
Any additional procedural or participant-specific particularities should be discussed with the 
Sponsor.
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6.5.2
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 debulking of tumor, etc.), or cancer 
immunotherapy not specified in this protocol
Note: Topical anticancer agents to treat skin lesions (eg, in situ melanoma or squamous 
cell carcinoma) are allowed, excluding skin metastasis of melanoma.
•
Other concurrent investigational drugs
•
Live or live attenuated vaccines within 30 days prior to the first dose of study 
intervention and while participating in the study. 
Note: killed vaccines are allowed. 
•
Systemic glucocorticoids for any purpose other than listed in Section 6.5.4.1.
•
Radiation therapy for disease control.
Note: Palliative radiotherapy is permitted for nontarget lesions if considered medically 
necessary by the treating physician and upon discussion with the Sponsor.
•
Phenytoin during treatment with carboplatin/cisplatin
For participants who, at the discretion of the investigator, require the use of any of the 
aforementioned treatments for clinical management, continuation of the study interventions
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 disease progression, and study interventions will be discontinued. These 
participants should complete all end of treatment assessments and continue to be followed for 
survival as outlined in the SoA.
Country-specific requirements are listed in Appendix 7.
6.5.3
Drug Interactions
A clinical drug-drug interaction (DDI) study in cancer patients showed that plasma 
concentrations of midazolam (a sensitive CYP3A and Pgp substrate) were not altered in a 
clinically meaningful manner in the presence of lenvatinib. No significant DDI is therefore 
expected between lenvatinib and other CYP3A4/Pgp substrates.
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Nonclinical studies identify CYP3A4 as the important CYP isozyme responsible for human 
hepatic metabolism of lenvatinib. However, clinical studies conducted showed that 
coadministration of lenvatinib with either inducers or inhibitors of CYP3A4/P-glycoprotein 
(P gp) are not of clinical concern.
No drug interaction is expected between pembrolizumab and lenvatinib because of divergent 
metabolic pathways. Pembrolizumab is a monoclonal antibody and is primarily catabolized 
like other proteins, while lenvatinib is metabolized by enzymatic (CYP3A and aldehyde 
oxidase) and non-enzymatic processes (lenvatinib IB).
6.5.4
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 6.6.2.
Note: If after 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.
6.5.4.1
Systemic Corticosteroid Use
Systemic corticosteroids are permitted in the following situations:
•
To mediate potential immune-related AEs as guided in Table 5.
•
As premedication/post medication to prevent AEs associated with chemotherapy or
IV contrast.
•
Brief, limited use of systemic corticosteroids (≤7 days) is permitted where such use is 
considered SOC (eg, for chronic obstructive pulmonary disease exacerbation).
•
Replacement doses of steroids (ie, ≤10 mg daily of prednisone equivalent) and the use 
of local steroid injections and topical steroids are permitted while on study.
6.5.4.2
Antiemetic Use
For participants receiving chemotherapy, antiemetic therapy should follow Multinational 
Association of Supportive Care in Cancer ([MASCC]; Appendix 9) or appropriate local 
guidelines and should, for the first 4 cycles, include a 5-HT3 receptor antagonist, 
dexamethasone (or equivalent), and aprepitant (or equivalent NK-1 receptor antagonist) as 
per the guideline followed.
6.5.4.3
Colony-stimulating Factors
For participants receiving chemotherapy, the American Society of Clinical Oncology 
(ASCO) guidelines for use of CSFs, or local equivalent, should be used for patient 
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management [Smith, T. J., et al 2006]. Use of CSFs for primary prophylaxis is permitted at 
the investigator’s discretion.
6.5.4.4
Cisplatin Premedication
Hydration is necessary to cause sufficient diuresis during and after treatment with cisplatin. 
All participants should receive adequate hydration from 2 to 12 hours before administration 
until a minimum of 6 hours after administration of cisplatin per the local label.
6.5.4.5
Pemetrexed Premedication
All participants must receive the appropriate supplementation of vitamin B12, folic acid, and 
corticosteroid prophylaxis as listed below or per the local label:
•
Folic acid, 350 μg to 1000 μg orally: At least 5 doses of folic acid must be taken 
during the 7 days preceding the first dose of pemetrexed, through the full course of 
therapy, and for 21 days after the last dose of pemetrexed.
•
Vitamin B12, 1000 μg by intramuscular (IM) injection: vitamin B12 must be given in 
the week preceding the first dose of pemetrexed and once every 3 cycles thereafter. 
Subsequent vitamin B12 injections may be given on the same day as pemetrexed.
•
Dexamethasone prophylaxis, 4 mg orally twice per day (or equivalent):
Dexamethasone may be taken the day before, day of, and day after pemetrexed 
administration. Higher or additional doses are permitted for antiemetic prophylaxis 
during Cycles 1 through 4 but are not to exceed doses in MASCC guidelines (or local 
equivalent) (Appendix 9).
6.6
Dose Modification (Escalation/Titration/Other)
NOTE: In alignment with the study-specific investigator letter dated 20-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 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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6.6.1
Lenvatinib
Lenvatinib dose reduction and interruption for participants who experience 
lenvatinib/pembrolizumab combination therapy-related toxicity will be in accordance with 
the dose modification guidelines described in Table 4. An interruption of study intervention 
for more than 28 days will require Sponsor approval before treatment can be resumed.
Adverse events will be graded using NCI CTCAE, Version 4.0. Investigators will decide the 
probability of the event being related to one or both drugs as to whether dose modification is 
required.
The starting dose of lenvatinib is 8 mg/day. Dose reductions of lenvatinib occur in succession 
based on the previous dose level as outlined in Table 4. Any dose reduction below 2 mg/day 
must be discussed with the Sponsor. Once the dose of lenvatinib/matching placebo 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 subsections below for management of hypertension (Section 6.6.1.1), 
proteinuria (Section 6.6.1.2), diarrhea (Section 6.6.1.3), hepatotoxicity (Section 6.6.1.4), 
thromboembolic events (Section 6.6.1.5), posterior reversible encephalopathy syndrome
(PRES)/reversible posterior leukoencephalopathy syndrome ([RPLS]; Section 6.6.1.6), 
hypocalcemia (Section 6.6.1.7), hemorrhage (Section 6.6.1.8), gastrointestinal 
perforation or fistula formation (Section 6.6.1.9), QT prolongation (Section 6.6.1.10), 
and osteonecrosis of the jaw (Section 6.6.1.11), as appropriate, before consulting the 
dose modification table (Table 4). For overlapping toxicities of pembrolizumab and 
lenvatinib/matching placebo, please refer to Section 6.6.4.
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Table 4
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,g
First occurrence
Interrupt lenvatinib until resolved 
to Grade 0-1, or tolerable Grade 2
Reduce lenvatinib dose to 
6 mg/day
Second occurrence (same 
toxicity or new toxicity)
Interrupt lenvatinib until resolved 
to Grade 0-1, or tolerable Grade 2
Reduce lenvatinib dose to 
4 mg/day
Third occurrence (same 
toxicity or new toxicity)
Interrupt lenvatinib until resolved 
to Grade 0-1, or tolerable Grade 2
Reduce lenvatinib dose to 
2 mg/day
Fourth occurrence (same 
toxicity or new toxicity)
Interrupt lenvatinib
Discuss with Sponsor
Grade 4f : Discontinue Study Treatment 
Abbreviations: AE = adverse event; BMI = body mass index; CTCAE = Common Terminology Criteria for Adverse 
Events
Note: For grading, see CTCAE, version 4.0. Collect all AE grades (ie, decreasing and increasing CTCAE grades).
a.
An interruption of lenvatinib/placebo for more than 28 days will require Sponsor approval before treatment can be 
resumed.
b.
Initiate optimal medical management for nausea, vomiting, hypertension, hypothyroidism, and/or diarrhea prior to 
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 within 10% of their 
baseline weight (ie, Grade 1 weight loss). These participants may restart study treatment 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 study intervention should be discussed with the 
Sponsor.
f.
Excluding laboratory abnormalities judged to be nonlife-threatening, in which case manage as Grade 3.
g.
For Grade 3 thromboembolic event, permanently discontinue lenvatinib/matching placebo. See Sections 6.6.1.2 and 
6.6.1.5.
6.6.1.1
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 treatment with 
lenvatinib have a BP of ≤150/90 mm Hg at the time of study entry and, if known to be 
hypertensive, have been on a stable dose of antihypertensive medication for at least 1 week 
prior to C1D1. Early detection and effective management of hypertension are important to 
minimize the need for lenvatinib dose interruptions and reductions.
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Regular assessment of BP should be as detailed in the SoA (Section 1.3.1 and Section 1.3.2). 
Hypertension will be graded using the NCI CTCAE, v4.0, based on BP measurements only 
(and not on the number of antihypertensive medications). 
If the participant’s initial BP measurement 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) is elevated (ie, 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 on 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 on 2 assessments at least 
30 minutes apart. For participants already on antihypertensive medication, treatment 
modification may be necessary if hypertension persists.
Lenvatinib/matching placebo should be withheld in any instance where a participant is at 
imminent risk to develop 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 co-morbidities). Once the 
participant has been on the same antihypertensive medications for at least 48 hours and the 
BP is controlled, lenvatinib/matching placebo 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 (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 the Day 15 evaluation until systolic BP has been ≤150 mm Hg and 
diastolic BP has been ≤95 mm Hg for 2 consecutive treatment cycles. A diary will be 
provided to the participant to capture the BP evaluations between study visits.
The following guidelines should be followed for the management of systolic BP
≥160 mm Hg or diastolic BP ≥100 mm Hg confirmed on 2 BP assessments at least 
30 minutes apart:
1. Continue study intervention and institute antihypertensive therapy for participants not 
already receiving this.
2. For those participants already on antihypertensive medication, the dose of the current 
agent may be increased, if appropriate, or 1 or more agents of a different class of 
antihypertensive should be added. Study treatment can be continued without dose 
modification.
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3. If systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg persists despite maximal 
antihypertensive therapy, then lenvatinib administration should be interrupted and 
restarted at a lower dose only when systolic BP ≤150 mm Hg and diastolic 
BP ≤95 mm Hg and the participant has been on a stable dose of antihypertensive 
medication for at least 48 hours.
-
If systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg recurs on the first dose 
reduction despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or the addition of a different class of 
antihypertensive), then lenvatinib/matching placebo 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 on a stable 
dose of antihypertensive medication for at least 48 hours.
-
If systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg recurs on the second dose 
reduction despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or the addition of a different class of 
antihypertensive), then lenvatinib/matching placebo 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 on 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 the management of Grade 4 hypertension 
(life-threatening consequences):
1. Institute appropriate medical management.
2. Discontinue lenvatinib/matching placebo.
6.6.1.2
Management of Proteinuria
Regular assessment of proteinuria should be conducted 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 testing per the SoA (Section 1.3).
2. A 24-hour urine collection initiated as soon as possible and at least within 72 hours 
(or an immediate spot urine protein-to-creatinine ratio [UPCR] test) is required in the 
following situations:
The first (initial) occurrence of proteinuria ≥2+ on urine dipstick/urinalysis while 
on lenvatinib/matching placebo
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A subsequent increase in severity of urine dipstick proteinuria occurring on the 
same lenvatinib/matching placebo dose level
When there has been a lenvatinib/matching placebo dose reduction, and at the new 
dose level, the urine protein dipstick result is ≥2+
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 the NCI CTCAE, v4.0 will be based on the 24-hour urinary 
protein result if one has been obtained. Management of lenvatinib administration 
will be based on the grade of proteinuria according to Table 4.
Monitoring
Urine dipstick testing for participants with proteinuria ≥2+ 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.
Proteinuria monitoring can be performed at the local laboratory or investigator site 
but must be managed by the site physician.
In the event of nephrotic syndrome, lenvatinib/placebo must be discontinued.
6.6.1.3
Management of Diarrhea
An anti-diarrheal agent should be recommended to the participant 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 anti-diarrheal agent 
should be individualized to the participant’s clinical circumstances and follow standard 
medical practice. If signs/symptoms of diarrhea persist despite optimal medical management, 
instructions contained in Table 4, Table 5, and/or Table 9 should be followed.
6.6.1.4
Management of Hepatotoxicity
Liver function tests (alanine transaminase [ALT], aspartate transaminase [AST], bilirubin 
levels) should be conducted as detailed in the SoA (Section 1.3) and as clinically indicated. If 
signs/symptoms indicating liver injury occur, instructions contained in Table 4, Table 5, 
and/or Table 9 should be followed. Appropriate supportive care should be provided together 
with close monitoring. If hepatic failure occurs, study intervention must be discontinued.
6.6.1.5
Management of Thromboembolic Events
Participants should be advised to pay attention to symptoms suggestive of venous 
thromboembolic events which include acute onset of shortness of breath, dyspnea, chest pain, 
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cough, hemoptysis, tachypnea, tachycardia, cyanosis, DVT signs including lower extremity 
swelling, and warmth to touch or tenderness. In case any of these symptoms appear, 
participants should be instructed to report their symptoms promptly to the treating physician. 
If a thromboembolic event is confirmed, instructions contained in Table 4 should be 
followed. Appropriate supportive care should be provided together with close monitoring. If 
a participant experiences a Grade 3 or a life-threatening (Grade 4) thromboembolic reaction, 
including pulmonary embolism, lenvatinib/placebo must be discontinued. 
Arterial thromboembolic events (eg, new onset, worsening, or unstable angina, myocardial 
infarction, transient ischemic attack, and cerebrovascular accident) of any grade require study 
intervention discontinuation.
6.6.1.6
Management of Posterior Reversible Encephalopathy Syndrome/Reversible 
Posterior Leukoencephalopathy Syndrome
Posterior Reversible Encephalopathy Syndrome/Reversible Encephalopathy Syndrome/ 
Reversible Posterior Leukoencephalopathy Syndrome (PRES/RPLS) is a neurological 
disorder that can present with headache, seizure, lethargy, confusion, altered mental function, 
blindness, and other visual or neurological 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, 
instructions in Table 4 should be followed.
6.6.1.7
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 CTCAE, v4.0, using the following 
formula: 
Corrected calcium = ([4 – serum albumin in g/dL] × 0.8 + serum calcium)
The formula is not applicable when serum albumin concentration is normal (˃4 g/dL); in
such cases, total (uncorrected) serum calcium should be used.
Hypocalcemia should be treated per institutional guidelines (eg, using appropriate calcium, 
magnesium, and vitamin D supplementation) until resolution.
6.6.1.8
Management of Hemorrhage
Instructions in Table 4 should be followed for the management of hemorrhage. Either resume 
at a reduced dose or discontinue lenvatinib depending on the severity and persistence of 
hemorrhage.
6.6.1.9
Management of Gastrointestinal Perforation or Fistula Formation
Lenvatinib should be discontinued in any participants who develop gastrointestinal 
perforation of any grade or Grade 4 fistula.
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6.6.1.10
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.
6.6.1.11
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 patients 
at higher risk. For patients 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 6.6.4).
6.6.1.12
Other Allowed Dose Interruptions for Lenvatinib
If the participant is receiving treatment with lenvatinib and requires surgery during the study, 
the stop time and restart time of lenvatinib should be as follows:
For minor procedures: stop lenvatinib at least 2 days before the procedure and restart it at 
least 2 days after, once there is evidence of adequate healing and no risk of bleeding.
For major procedures: stop lenvatinib at least 1 week (5 half-lives) prior to surgery and 
then restart it at least 2 weeks after, once there is evidence of adequate healing and no risk 
of bleeding.
6.6.2
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
6.6.2.1
Dose Modification and Toxicity Management for Immune-related AEs 
Associated with Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
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.
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Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 5.
For overlapping toxicities of pembrolizumab and lenvatinib/matching placebo, please refer to 
Section 6.6.4.
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Table 5
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if the irAEs are not 
controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not 
≤10 mg/day within 12 weeks of the last treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 after corticosteroid 
taper.
irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants for signs and symptoms of 
pneumonitis
Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate corticosteroid 
treatment
Add prophylactic antibiotics for opportunistic 
infections
Recurrent Grade 2 
or Grade 3 or 4 
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) and of bowel 
perforation (ie, peritoneal signs and ileus)
Participants with ≥Grade 2 diarrhea suspecting colitis 
should consider GI consultation and performing 
endoscopy to rule out colitis
Participants with diarrhea/colitis should be advised to 
drink liberal quantities of clear fluids. If sufficient 
oral fluid intake is not feasible, fluid and electrolytes 
should be substituted via IV infusion.
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST / ALT 
Elevation or 
Increased 
Bilirubin
Grade 2
Withhold
Administer corticosteroids 
(initial dose of 0.5-1 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor with liver function tests (consider weekly or 
more frequently until liver enzyme value returned to 
baseline or is stable)
Grade 3 or 4 
Permanently 
discontinue
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure
Withhold a
Initiate insulin replacement 
therapy for participants with 
T1DM
Administer anti-
hyperglycemic in participants 
with hyperglycemia
Monitor participants for hyperglycemia or other signs 
and symptoms of diabetes
Hypophysitis
Grade 2
Withhold
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated
Monitor for signs and symptoms of hypophysitis
(including hypopituitarism and adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue a
Hyperthyroidism 
Grade 2
Continue
Treat with non-selective 
beta-blockers (eg, 
propranolol) or thionamides 
as appropriate
Monitor for signs and symptoms of thyroid disorders
Grade 3 or 4
Withhold or 
Permanently 
discontinue a
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidism
Grade 2-4
Continue
Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care
Monitor for signs and symptoms of thyroid disorders
Nephritis and 
renal dysfunction
Grade 2
Withhold
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper
Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1 
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
All Other irAEs
Persistent Grade 2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold or 
discontinue b
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 
diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
b
Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically important irAEs (eg, 
vasculitis and sclerosing cholangitis).
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6.6.2.2
Dose Modification and Toxicity Management of Infusion-Reactions Related 
to Pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion.
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 6. Management guidelines for toxicities deemed
related to both pembrolizumab and lenvatinib are outlined in Section 6.6.4.
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Table 6
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grade 1
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires therapy or infusion 
interruption but responds promptly 
to symptomatic treatment (eg, 
antihistamines, NSAIDs, narcotics, 
IV fluids); prophylactic medications 
indicated for ≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (eg, from 100 
mL/hr to 50 mL/hr). Otherwise dosing will be held 
until symptoms resolve and the participant should 
be premedicated for the next scheduled dose.
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further study 
drug treatment
Participant may be premedicated 1.5h (± 
30 minutes) prior to infusion of  study 
intervention with:
Diphenhydramine 50 mg po (or equivalent 
dose of antihistamine).
Acetaminophen 500-1000 mg po (or 
equivalent dose of analgesic).
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NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization 
indicated for other clinical sequelae 
(eg, renal impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Participant is permanently discontinued from 
further study drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug 
administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov
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6.6.2.3
Other Allowed Dose Interruption(s) for Pembrolizumab
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical/surgical events or logistical reasons not related to study therapy. Participants should 
be placed back on pembrolizumab 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.
Interruptions from the protocol-specified treatment plan for more than 12 weeks between 
pembrolizumab doses for nondrug-related or administrative reasons require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on participant management.
6.6.3
Chemotherapy
Recommended dose modifications for key chemotherapy toxicities are outlined in Table 7, 
Table 8, and Table 9. These serve only as a guide and do not replace investigator judgment 
and applicable local label recommendations, if more stringent.
Table 7
Chemotherapy Dose Level Definitions
Dose Level 0
Dose Level -1
Dose Level -2
Dose Level -3
Carboplatin
AUC 5 mg/mL/min
Maximum dose 
750 mg
AUC 3.75
mg/mL/min
Maximum dose 
562.5 mg
AUC 2.5
mg/mL/min
Maximum dose 
375 mg
Discontinue 
treatment
Cisplatin
75 mg/m2
56 mg/m2
38 mg/m2
Discontinue 
treatment
Pemetrexed
500 mg/m2
375 mg/m2
250 mg/m2
Discontinue 
treatment
Abbreviation: AUC = area under the plasma drug concentration-time curve
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Table 8
Recommended Dose Modifications for Chemotherapy-related Hematological 
Toxicities
Platelets
ANC
Carboplatin/Cisplatin
Pemetrexed
Dose level from Table 7
≥50,000/mcL
AND
≥500/mcL
DL 0
DL 0
≥50,000/mcL
AND
<500/mcL
DL -1
DL -1
<50,000/mcL without 
bleeding
AND
ANY
DL -1
DL -1
<50,000/mcL with 
Grade ≥2 bleeding
AND
ANY
DL -2
DL -2
ANY
AND
<1,000/mcL + fever 
≥38.5°C (101°F)
DL -1
DL -1
Abbreviation: ANC = absolute neutrophil count; DL = dose level
Table 9
Recommended Dose Modifications for Chemotherapy-related Nonhematological 
Toxicities
Event
CTCAE Grade
Carboplatin
Cisplatin
Pemetrexed
Dose level from Table 7
Nausea or vomiting
Grade 3 or 4
DL 0
DL 0
DL 0
Diarrhea
Grade 3 or 4
DL 0
DL -1
DL -1
Mucositis
Grade 3 or 4
DL 0
DL 0
DL -2
Neurotoxicity
Grade 2
DL 0
DL -2
DL 0
Grade 3 or 4
DL -1
Discontinue 
treatment
DL -1
Transaminase elevation
Grade 3
DL -1
DL -1
DL -1
Grade 4
Discontinue 
treatment
Discontinue 
treatment
Discontinue 
treatment
Other nonhematological
toxicities
Grade 3 or 4
DL -1
DL -1
DL -1
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; DL = dose level
Creatinine clearance (CrCl): CrCl will be based on the original weight-based Cockcroft 
and Gault formula or institutional standard. CrCl must be ≥45 mL/min prior to the 
administration of chemotherapy. Platinum chemotherapy and/or pemetrexed may be delayed 
for up to 42 days to allow the participant time to recover from the toxicity. If a participant’s
CrCl value has not returned to ≥45 mL/min within 42 days after the previous dose, platinum
chemotherapy and/or pemetrexed must be discontinued.
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6.6.4
Dose Modifications 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 
for lenvatinib treatment, while immune-related AEs are risks for pembrolizumab treatment. 
However, certain AEs, such as such as diarrhea, hypothyroidism, and liver enzyme elevation, 
may be initially considered attributable to either study drug. 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 dosed daily and continuously due to a relatively short half-life 
(28 hours), and pembrolizumab is dosed 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:
o
If an AE is identified during a treatment cycle (ie, between 2 pembrolizumab 
doses), only lenvatinib dose interruption is needed.
o
If an AE is identified at the beginning of a treatment cycle, lenvatinib can be 
interrupted and dosing of pembrolizumab should be held.
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 immune-related AE 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 is rapidly worsened, action including interrupting both drugs and initiating 
treatment with a corticosteroid (with exception of hypothyroidism, T1DM) 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 X ULN for more than 2 weeks.
Pembrolizumab will have already been permanently discontinued per [Table 5], but 
lenvatinib may be administered at a reduced dose by the time this criterion is met and 
must be permanently discontinued immediately.
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b) ALT or AST >3 X ULN and (TBL >2 X ULN or INR >1.5).
Although [Table 5] advises pembrolizumab to be withheld (interrupted), and 
[Table 4] advises lenvatinib to have no dose modification or a reduction, if this 
criterion is met, both drugs must be permanently discontinued immediately.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
Treatment with pembrolizumab and chemotherapy in this study is open-label; therefore, the 
participant, the investigator, the Sponsor, and delegate(s) who are involved in study 
intervention administration or the clinical evaluation of participants are not blinded. Study 
intervention (name, strength, or potency) is included in the label text; random code/disclosure 
envelopes or lists are not provided.
The emergency unblinding call center will use the treatment/randomization schedule for the 
study to unblind participants and to unmask study intervention identity of lenvatinib or 
matching placebo. In the event that the emergency unblinding call center is not available for 
a given site in this study, the central electronic treatment allocation/randomization system 
(IVRS/IWRS) should be used in order to unblind participants and to unmask study 
intervention identity. The Sponsor will not provide random code/disclosure envelopes or lists 
with the clinical supplies.
See Section 8.1.10, Participant Blinding/Unblinding, for a description of the method of 
unblinding a participant during the study, should such action be warranted.
6.9
Standard Policies
At the close of the study after treatment unblinding, a letter is to be sent by the investigator to 
those participants who received placebo in the image of the competitor’s product to provide 
the following information:
“You have participated in a study conducted by MSD. This is to advise you that you were 
among those who received a look-alike tablet created by the Sponsor to resemble the drug 
lenvatinib as much as possible. You did not receive the active drug lenvatinib manufactured 
by Eisai Co., Ltd.”
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.
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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 and 
Section 8.11.3.
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 and 
Section 8.12.3.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
The participant interrupts study intervention administration of lenvatinib for more than 
28 days, except if agreed to by the Sponsor.
•
The participant interrupts study intervention administration of pembrolizumab for more 
than 12 weeks, except if agreed to by the Sponsor.
•
Participants receiving the combination therapy (pembrolizumab + lenvatinib) must 
discontinue study therapy if any of the following occur:
o
ALT or AST >5 × ULN for more than 2 weeks
Pembrolizumab will have already been permanently discontinued per [Table 5], 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 >3 × ULN and (TBL >2 × ULN or INR >1.5)
Although [Table 5] advises pembrolizumab to be withheld (interrupted), and [Table 4]
advises lenvatinib to have no dose modification or a reduction, if this criterion is met, both 
drugs must be permanently discontinued immediately.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or the 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.
•
Disease progression is radiographically documented and verified by BICR per 
RECIST 1.1 (after obtaining informed consent addendum and Sponsor communication, 
the investigator may elect to continue treatment beyond confirmed PD per iRECIST).
•
Intercurrent illness that prevents further administration of treatment.
•
The participant has any progression or recurrence of any malignancy, or occurrence of 
another malignancy that requires active treatment. Exceptions to secondary malignancies 
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 treatment or remaining in follow-up.
•
Unacceptable toxicity.
•
Investigator’s decision to discontinue treatment.
•
Administrative reasons requiring cessation of treatment.
•
For carboplatin, cisplatin, and pembrolizumab ONLY: Treatment completion (4 cycles of 
carboplatin or cisplatin/35 cycles of pembrolizumab).
Note: The number of treatments is calculated starting with the first dose. Participants who 
stop the combination or pembrolizumab after receiving 35 doses may be eligible for 
retreatment if they progress after stopping study treatment provided they meet the 
requirements detailed in Section 7.1.1. Participants may be retreated in the Second 
Course Phase (Retreatment) for up to an additional 17 cycles (approximately 1 year).
•
Any study intervention-related toxicity specified as a reason for permanent 
discontinuation as defined in the guidelines for dose modification due to AEs in 
Section 6.6.
7.1.1
Second Course Treatment
Participants are allowed to start Second Course Treatment with investigator assessed PD.
Original protocol text that is contained in this section has been retained for reference.
All participants who stop study intervention with SD or better may be eligible for up to an 
additional 17 cycles (approximately 1 year) of pembrolizumab treatment if they progress 
after stopping study intervention from the initial treatment phase. This retreatment is termed 
the Second Course Phase of this study and is only available if the study remains open and the 
participant meets the following conditions:
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Either

Stopped initial study intervention after attaining an investigator-determined 
confirmed CR based on RECIST 1.1, and
o
Was treated with at least 8 cycles of study intervention before discontinuing 
treatment, and
o
Received at least 2 treatments with pembrolizumab beyond the date when the 
initial CR was declared
OR

Had SD, PR, or CR and stopped study intervention after completion of 35 
administrations (approximately 2 years) of study intervention for reasons other than 
disease progression or intolerability
AND

Experienced an investigator-determined radiographic disease progression by RECIST 
1.1 after stopping initial treatment, and
o
No new anticancer treatment was administered after the last dose of study 
intervention, and
o
The participant meets all of the safety parameters listed in the inclusion criteria 
and none of the safety parameters listed in the exclusion criteria, and
o
The study is ongoing.
Participants who have experienced an initial disease progression by RECIST 1.1 and have an 
iSD, iPR, or iCR per iRECIST after completion of 35 administrations of study intervention 
for reasons other than disease progression or intolerability may be considered for the Second 
Course Phase after consultation with the Sponsor.
The decision of whether or not to continue lenvatinib/placebo during Second Course will be 
at the discretion of the investigator. If continued, participants will be retreated at the same 
dose level and frequency as when they last received the combination of pembrolizumab and 
lenvatinib/placebo. Treatment with lenvatinib/placebo will continue until meeting at least 
1 of the discontinuation criteria listed in Section 7.1.
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.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
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If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study are outlined in Section 8.1.9. The procedures to be performed should a participant 
repeatedly fail to return for scheduled visits and/or if the study site is unable to contact the 
participant are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (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.
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•
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.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant or their legally 
acceptable representative prior to participating in this clinical study. If there are changes to 
the participant’s status during the study (eg, health or age of majority requirements), the 
investigator or medically qualified designee must ensure the appropriate documented 
informed consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the trial protocol number, trial 
protocol title, dated signature, and agreement of the participant (or their legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the Institutional Review Board/Independent Ethics Committee’s 
(IRB/IEC’s) approval/favorable opinion in advance of use. The participant or their 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 a the study and the study population are to be included in the study informed 
consent form.
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The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator who is a qualified 
physician to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
allocation/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
8.1.4.1
General Medical History
A medical history will be obtained by the investigator or qualified designee.
Medical history will include all active conditions, drug allergies, significant medical 
procedures, smoking status, and any condition diagnosed within the previous 10 years that is
considered to be clinically important by the investigator. Any cancer, other than the cancer 
under study, will be recorded as medical history, even if diagnosed greater than 10 years 
before enrollment. Details regarding the cancer under study will be recorded separately and 
not listed as medical history.
8.1.4.2
Oncologic Disease Details
The investigator or qualified designee will obtain historic and current details of the 
participant’s cancer under study. This information will include, but is not limited to, date of 
diagnosis, stage, histology, location(s) of primary lesions, and location(s) of metastases, if 
applicable.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
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within 30 days prior to the first dose of study intervention. Treatment for the disease for 
which the participant has enrolled in the study will be recorded separately and not listed as a 
prior medication.
8.1.5.2
Prior Oncologic Treatment
The investigator or qualified designee will review and record all treatments for the cancer 
under study, including systemic and local treatment, vaccinations, radiation, and surgeries. 
Additional information collected on these treatments will include, but is not limited to, 
reason for discontinuation, best response, and date of progression after each treatment as 
applicable.
8.1.5.3
Concomitant Medications
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 prior to the first dose of Second Course Treatment, 
during Second Course Treatment, and for 30 days after the last dose of Second Course 
Treatment (or 90 days if used to treat an SAE) will be recorded.
Any new anticancer therapy started after the participant’s discontinuation from the treatment 
period will be recorded separately. Additional information collected on this treatment will 
include, but is not limited to, best response and date of progression.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial Screening Visit. Specific details on the Screening/rescreening Visit 
requirements are provided in Section 8.11.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
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The investigator must decide the choice of platinum chemotherapy (carboplatin or cisplatin) 
and provide the rationale prior to randomization.
8.1.8
Study Intervention Administration
Refer to Section 8.1.8.1 for dose and treatment details. Study intervention should begin 
within 3 days of randomization.
8.1.8.1
Timing of Dose Administration
8.1.8.1.1
Lenvatinib/Matching Placebo
Lenvatinib/matching placebo 8 mg (two 4-mg capsules) once daily will be taken orally with 
water (with or without food) at approximately the same time each day in each 21-day cycle. 
However, on Day 1 of each pembrolizumab cycle, lenvatinib/matching placebo will be 
administered in the clinic 0 to 4 hours after completion of pembrolizumab administration. 
During chemotherapy cycles (Cycles 1 to 4), lenvatinib/matching placebo will be 
administered after pembrolizumab and prior to chemotherapy. On Cycle 1 Day 15, lenvatinib 
is to be administered in the clinic to order to obtain PK samples. If a lenvatinib dose is 
missed and cannot be taken within 12 hours, then that dose should be skipped, and the next 
dose should be taken at the usual time of administration.
8.1.8.1.2
Pembrolizumab
Pembrolizumab will be administered by IV infusion over 30 minutes as the first study 
intervention on Day 1 of each 21-day cycle. Sites should make every effort to target infusion 
timing to be as close to 30 minutes as possible, however, given the variability of infusion 
pumps from site to site, a window of -5 minutes and +10 minutes is permitted (ie, infusion 
time is 30 minutes: -5/+10 minutes).
After Cycle 1 Day 1, pembrolizumab may be administered up to 3 days before or after the 
scheduled Day 1 of each cycle for administrative reasons.
8.1.8.1.3
Carboplatin
Participants who will be treated with carboplatin will receive it by IV infusion over 
15-60 minutes (or per approved local label guidelines) after pemetrexed on Day 1 of each 
21-day cycle. Participants should also receive premedication per the approved product label.
After Cycle 1 Day 1, carboplatin may be administered up to 3 days before or after the 
scheduled Day 1 of each cycle for administrative reasons.
8.1.8.1.4
Cisplatin
Participants who will be treated with cisplatin will receive it by IV infusion over 60 minutes
(or per approved local label guidelines) after pemetrexed on Day 1 of each 21-day cycle. 
Participants should also receive premedication per the approved product label.
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After Cycle 1 Day 1, cisplatin may be administered up to 3 days before or after the scheduled 
Day 1 of each cycle for administrative reasons.
8.1.8.1.5
Pemetrexed
Pemetrexed will be administered by IV infusion over 10 minutes (or per approved local label 
guidelines) on Day 1 of each 21-day cycle. Pemetrexed should be administered prior to 
carboplatin or cisplatin during those treatment cycles. Participants should receive 
premedication per the approved product label.
After Cycle 1 Day 1, pemetrexed may be administered up to 3 days before or after the 
scheduled Day 1 of each cycle for administrative reasons.
8.1.8.2
Treatment Compliance
8.1.8.2.1
Lenvatinib/Placebo
During on-site visits, administration of lenvatinib/placebo will be monitored by the 
investigator and/or study staff. The administration, the dose, the time of administration, as 
well as any immediate reactions at the time of intake will be documented in the electronic 
Case Report Form (eCRF).
On all other days, lenvatinib/placebo will be taken at home. When a participant attends a 
study visit, he or she will bring any unused tablets.
8.1.8.2.2
Pembrolizumab/Platinum Doublet Chemotherapy
Administration of pembrolizumab and platinum doublet chemotherapy will be monitored by 
the investigator and/or study staff. The total volume of study intervention infused will be 
compared with the total volume prepared to determine compliance with each dose 
administered.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA and Section 8.11.3.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the End of Treatment Visit should be performed (at the time of withdrawal). 
Any AEs that are present at the time of withdrawal should be followed in accordance with 
the safety requirements outlined in Section 8.4.3.
8.1.10
Participant Blinding/Unblinding
As of the final analysis, the study was unblinded. Original protocol text that is contained in 
this section has been retained for reference.
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Part 1 (safety run-in) of the study will be unblinded, open-label.
In Part 2 (Phase 3 study), STUDY INTERVENTION IDENTIFICATION INFORMATION 
IS TO BE UNMASKED ONLY IF NECESSARY FOR THE WELFARE OF THE 
PARTICIPANT.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity/toxicity grade of the AEs observed, the relation to study intervention, the reason 
thereof, etc., in the medical chart. If it is not possible to record this assessment in the chart 
prior to the unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor’s Clinical Director notified as soon as possible.
Once an emergency unblinding has taken place, the principal investigator, site personnel, and 
Sponsor personnel may be unblinded so that the appropriate follow-up medical care can be 
provided to the participant.
The IRT system should be used for emergency unblinding in the event that this is required 
for participant safety. 
At the end of the study, random code/disclosure envelopes or lists and unblinding logs are to 
be returned to the Sponsor or designee.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy Assessments
8.2.1
Tumor Scans and Response Assessment
As of Amendment 08, participants who are still on study treatment will no longer require 
tumor response assessments by BICR to be performed. Scans will no longer be submitted to 
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the iCRO. Participants who are still on study medication 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.
Throughout this section, the term “scan” refers to any medical imaging data used to assess 
tumor burden and may include cross-sectional imaging (such as CT or MRI), medical 
photography, or other methods as specified in this protocol. 
The process for scan collection and transmission to the central imaging vendor can be found 
in the Site Imaging Manual. Tumor scans by CT is strongly preferred. For the abdomen and 
pelvis, contrast-enhanced magnetic resonance imaging (MRI) may be used when CT with 
iodinated contrast is contraindicated, or when mandated by local practice. MRI is the 
strongly preferred modality for brain scans. The same scan technique regarding modality, 
ideally the same scanner, and the use of contrast should be used in a participant throughout 
the study to optimize the reproducibility of the assessment of existing and new tumor burden 
and improve the accuracy of the assessment of response or progression based on scans. Note: 
For the purposes of assessing tumor scans, the term “investigator” refers to the local 
investigator at the site and/or the radiological reviewer located at the site or at an offsite 
facility.
Participant eligibility will be determined using local assessment (investigator assessment) 
based on RECIST 1.1. All scheduled scans for all study participants from the sites will be 
submitted to the central imaging vendor. In addition, scans (including those obtained via 
other modalities) that are obtained at an unscheduled time point to determine PD, as well as 
scans obtained for other reasons, but which demonstrate radiologic progression, should also 
be submitted to the central imaging vendor.
When the investigator identifies radiographic progression per RECIST 1.1, the central 
imaging vendor will perform expedited verification of radiologic PD and communicate the 
results to the study site and Sponsor (see Section 8.2.1.5 and Figure 2). In clinically stable 
participants, scans should continue until PD has been verified. Once PD is verified centrally, 
subsequent scans (if acquired) should not be submitted to the central imaging vendor.
8.2.1.1
Initial Tumor Scans
Initial tumor scans at Screening must be performed within 28 days prior to the date of 
randomization. Any scans obtained after Cycle 1 Day 1 of treatment cannot be included in 
the screening assessment. The site study team must review screening scans to confirm the 
participant has measurable disease per RECIST 1.1.
The screening scans must be submitted to the central imaging vendor for retrospective 
review.
Tumor scans performed as part of routine clinical management are acceptable for use as 
screening tumor scans if they are of diagnostic quality, performed within 28 days prior to the 
date of randomization, and can be assessed by the central imaging vendor.
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If brain scan is performed to document the stability of existing metastases, MRI should be 
used if possible. If MRI is medically contraindicated, CT with contrast is an acceptable 
alternative.
8.2.1.2
Tumor Scans During the Study
The first on-study scan assessment should be performed at 6 weeks (+7 days) from the day of 
randomization. Subsequent tumor scans should be performed every 6 weeks (±7 days) until 
Week 18, and every 9 weeks (±7 days) or more frequently if clinically indicated. After 
54 weeks, participants who remain on treatment will have scans performed every 12 weeks 
(±7 days). Scan timing should follow calendar days and should not be adjusted for delays in 
cycle starts. Scans should continue to be performed until disease progression is documented 
radiographically per RECIST 1.1 and verified by BICR (unless the investigator elects to 
continue treatment and follow iRECIST), initiating a new anticancer therapy, participant 
withdrawal of consent, pregnancy, becoming lost to follow-up, death, or the end of the study, 
whichever is earlier.
All supplemental scans must be submitted to the central imaging vendor.
Objective response should be confirmed by a repeat scan assessment. Tumor scans to 
confirm PR or CR should be performed at least 4 weeks after the first indication of a 
response is observed. Participants will then return to regular scheduled scans, starting with 
the next scheduled scan time point. Participants who receive additional scans for 
confirmation do not need to undergo the next scheduled tumor scan if it is less than 4 weeks 
later; tumor scans may resume at the subsequent scheduled scan time point. Note: Response 
does not typically need to be verified in real time by the central imaging vendor.
Per iRECIST (Section 8.2.1.6), disease progression 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 who have unconfirmed PD may continue on treatment at the 
discretion of the investigator until progression is confirmed by the site, provided they have 
met the conditions detailed in Section 8.2.1.6. Participants who receive confirmatory scans 
do not need to undergo the next scheduled tumor scan if it is less than 4 weeks later; tumor 
scans may resume at the subsequent scheduled scan time point, if clinically stable. 
Participants who have confirmed PD by iRECIST, as assessed by the site, will discontinue 
study intervention. Exceptions are detailed in Section 8.2.1.6.
8.2.1.3
End of Treatment and Follow-up Tumor Scans
Follow-up tumor imaging is only required for participants who are candidate for Second 
Course treatment.
For participants who discontinue study intervention, tumor scans should be performed at the 
time of treatment discontinuation (±4 weeks). If previous scans were obtained within 4 weeks 
before the date of discontinuation, then scans at treatment discontinuation are not mandatory. 
For participants who discontinue study intervention because of documented disease 
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progression, this is the final required tumor scan if the investigator elects not to implement 
iRECIST.
For participants who discontinue study intervention without documented disease progression, 
every effort should be made to continue monitoring disease status by tumor scans using the 
same scan schedule used while on treatment (every 6 weeks until Week 18, every 9 weeks 
until Week 54, and then every 12 weeks) until disease progression is documented 
radiographically per RECIST 1.1 and verified by BICR (unless the investigator elects to 
continue treatment and follow iRECIST), initiating a new anticancer therapy, participant 
withdrawal of consent, pregnancy, becoming lost to follow-up, death, or the end of the study, 
whichever is earlier.
8.2.1.4
Second Course Treatment Tumor Scans
Before a participant may enter the Second Course Phase, BICR-verification of radiographic
disease progression must have occurred. Tumor scans must be performed within 30 days 
before the first Second Course Treatment. The disease progression scans may also be used as 
the Second Course baseline scans if it is within 30 days before restarting treatment and 
otherwise meets the baseline standards outlined in the Site Imaging Manual. Local reading 
(investigator assessment with site radiology reading) will be used to determine eligibility. All 
Second Course Treatment scans should be submitted to the central imaging vendor for 
quality control, storage, and possible retrospective review. The first on-study scan assessment 
during Second Course Treatment should be performed at 12 weeks (±7 days) after the restart 
of treatment. Subsequent tumor scans should be performed every 12 weeks (±7 days) or more 
frequently, if clinically indicated. Scan timing should follow calendar days and should not be 
adjusted for delays in cycle starts.
Per iRECIST (Section 8.2.1.6), if tumor scans show initial PD, tumor assessment should be 
repeated 4 to 8 weeks later to confirm PD, with the option of continuing treatment while 
awaiting radiologic confirmation of progression. Participants who obtain confirmatory scans 
do not need to undergo scheduled tumor scans if it is less than 4 weeks later and may wait 
until the next scheduled scan time point, if clinically stable.
Scans should continue to be performed until disease progression, initiating a new anticancer 
therapy, participant withdrawal of consent, pregnancy, becoming lost to follow-up, death, or 
the end of the study, whichever is earlier. In clinically stable participants, PD may be 
confirmed by the investigator using iRECIST 4 to 8 weeks after the first tumor scan 
indicating PD.
For participants who discontinue Second Course Treatment, tumor scans should be 
performed at the time of treatment discontinuation (±4 weeks). If previous scans were 
obtained within 4 weeks before the date of discontinuation, then scans at treatment 
discontinuation are not mandatory. For participants who discontinue study intervention 
because of documented disease progression, this is the final required tumor scan.
For participants who discontinue Second Course Treatment without documented disease 
progression, every effort should be made to continue monitoring their disease status by 
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radiologic scans every 12 weeks (±7 days) until disease progression, initiating a new 
anticancer therapy, participant withdrawal of consent, pregnancy, becoming lost to 
follow-up, death, or the end of the study, whichever is earlier.
8.2.1.5
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used by BICR as the primary measure for assessment of tumor response, 
date of disease progression, and as a basis for all protocol guidelines related to disease status 
(eg, discontinuation of study intervention). Initial tumor scans showing site-assessed PD
should be submitted immediately for BICR verification of disease progression. The site will 
be notified if the BICR verifies disease progression using RECIST 1.1. Figure 2 illustrates 
the scan flow involving verification of disease progression for clinically stable participants.
If disease progression is not verified, the process continues as follows:

If participant is clinically stable, continue study intervention per protocol 
-
Resume scans per protocol schedule (≥4 weeks to next scan)
-
Send scans to central imaging vendor
-
Continue local assessment 
-
Do not change investigator assessment of progression
-
If subsequent scan(s) indicate progression, submit scan(s) to central imaging 
vendor to request verification

If the participant is not clinically stable, best medical practice is to be applied
Before stopping study intervention or scans or starting new anticancer therapy in a 
participant who is clinically stable, communication with the Sponsor is required. 
If disease progression is verified, the process continues as follows:

Investigator judgment will determine action

If the participant is clinically stable and study intervention is to continue, 
communication with the Sponsor is required and a reconsent addendum must be 
signed 

Obtain scans locally per original protocol schedule

Do not send scans to central imaging vendor
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For the purpose of this decision process, lack of clinical stability is defined as:

Unacceptable toxicity

Clinical signs or symptoms indicating clinically significant disease progression

Decline in performance status

Rapid disease progression or threat to vital organs or critical anatomical sites (eg, 
CNS metastasis, respiratory failure due to tumor compression, spinal cord 
compression) requiring urgent alternative medical intervention
8.2.1.6
iRECIST Assessment of Disease
iRECIST is based on RECIST 1.1 but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor 
response and progression and make treatment decisions. When clinically stable, participants 
should not be discontinued until disease progression is confirmed by the investigator, 
working with local radiology. This allowance to continue treatment despite initial radiologic 
disease progression takes into account the observation that some participants can have a 
transient tumor flare in the first few months after the start of immunotherapy, and then 
experience subsequent disease response. This data will be captured in the clinical database.
Clinical stability is defined as the following:
•
Absence of symptoms and signs indicating clinically significant disease progression
•
No decline in ECOG performance status
•
No requirement 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 disease progression and is not required to have 
repeat tumor scans for confirmation of disease progression by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study intervention and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
disease progression by iRECIST, per investigator assessment. Scans should continue to be 
sent in to the central imaging vendor for potential retrospective BICR.
If repeat scans do not confirm disease progression per iRECIST, as assessed by the 
investigator, and the participant continues to be clinically stable, study intervention may 
continue and follow the regular scan schedule. If disease progression is confirmed, 
participants will be discontinued from study intervention.
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If a participant has iRECIST-confirmed radiographic progression (iCPD), study intervention 
should be discontinued; however, if the participant is achieving a clinically meaningful 
benefit, an exception to continue study intervention may be considered following 
consultation with the Sponsor. In this case, if study intervention is continued, tumor scans 
should continue to be performed following the intervals outlined in Section 1.3 and submitted 
to the central imaging vendor.
A description of the adaptations and iRECIST process is provided in Appendix 6, with 
additional details in the iRECIST publication [Seymour, L., et al 2017]. A summary of scans 
and treatment requirements after first radiologic evidence of progression is provided in 
Table 10 and illustrated as a flowchart in Figure 2.
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Table 10
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 that has 
been verified by BICR
Repeat imaging at 4 to 
8 weeks to confirm PD.
May continue study intervention 
at the investigator’s discretion 
while awaiting confirmatory 
tumor imaging by site by 
iRECIST.
Repeat imaging at 4 to 
8 weeks to confirm PD at 
the investigator’s 
discretion only.
Discontinue treatment
Repeat tumor imaging 
confirms PD (iCPD) by 
iRECIST per investigator 
assessment
No additional imaging 
required.
Discontinue treatment 
(exception is possible upon 
consultation with Sponsor).
No additional imaging 
required.
Not applicable
Repeat tumor imaging 
shows iUPD by iRECIST 
per investigator assessment
Repeat imaging at 4 to 
8 weeks to confirm PD. 
May occur at next 
regularly scheduled 
imaging visit.
Continue study intervention at 
the investigator’s discretion.
Repeat imaging at 4 to 
8 weeks to confirm PD at 
the investigator’s 
discretion only.
Discontinue treatment
Repeat tumor imaging 
shows iSD, iPR, or iCR by 
iRECIST per investigator 
assessment.
Continue regularly 
scheduled imaging 
assessments.
Continue study intervention at 
the investigator’s discretion.
Continue regularly 
scheduled imaging 
assessments.
May restart study intervention if 
condition has improved and/or 
clinically stable at the 
investigator’s discretion. Next 
tumor imaging should occur 
according to the regular imaging 
schedule.
Abbreviations: BICR = blinded independent central review; iCPD = iRECIST-confirmed progressive disease; iCR = iRECIST complete response; iPR = 
iRECIST partial response; iRECIST = modification of Response Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; iSD = iRECIST 
stable disease; iUPD = iRECIST-unconfirmed progressive disease; PD = progressive disease; RECIST 1.1 = Response Evaluation Criteria in Solid 
Tumors 1.1; VOP = verification of progression.
Note: If progression has been centrally verified, further management is by the site, based on iRECIST. Any further imaging should still be submitted to the 
central imaging vendor, but no rapid review will occur. If RECIST 1.1 PD has not been centrally verified, ideally the site should continue treatment. Whether 
or not treatment continues, imaging should be collected and submitted to the central imaging vendor with VOP request until RECIST 1.1 PD is verified by
BICR.
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Figure 2
Imaging and Treatment for Clinically Stable Participants After First Radiologic 
Evidence of Progressive Disease Assessed by the Investigator
8.2.1.7
Tumor Tissue Collection for Biomarker Analysis
Participation in this study will be dependent upon supplying tumor tissue for biomarker
testing from locations not radiated before biopsy. Formalin-fixed specimens after the 
participant has been diagnosed with metastatic disease but before randomization are 
preferred. Biopsies obtained before receipt of adjuvant/neoadjuvant chemotherapy are
permitted if recent biopsy is not feasible.
All participants should submit either a newly obtained core or excisional biopsy or archival 
tissue (fine-needle aspiration is not adequate for either archival or new tissue samples) to a 
central laboratory for biomarker analysis.
Note: Submission of FFPE tumor tissue sample blocks are preferred; if submitting unstained 
slides, the slides should be freshly cut and submitted to the testing laboratory within 14 days 
from the site slide section date; otherwise, a new specimen will be requested.
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If the sample is determined to be nonevaluable before testing by the central laboratory, a new 
sample should be submitted if available.
8.2.2
Patient-Reported Outcomes
As of Amendment 08, 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.
The EORTC QLQ-C30, EORTC QLQ-LC13, and EuroQoL EQ-5D-5L questionnaires will 
be administered by trained site personnel and completed electronically by participants in the 
following order: EORTC QLQ-C30 first, then EORTC QLQ-LC13, then EuroQoL 
EQ-5D-5L. It is best practice and strongly recommended that electronic PROs (ePROs) be 
administered to randomized participants prior to study intervention administration, AE
evaluation, and disease status notification. If the ePROs are not done at a scheduled time 
point, the MISS_MODE form must be completed to capture the reason the assessment was 
not performed.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
The investigator or qualified designee will perform a full physical examination including oral 
examination during the Screening period and as indicated in the SoA. Clinically significant 
abnormal findings at Screening should be recorded as medical history. After the first dose of 
study intervention, new clinically significant abnormal findings should be recorded as AEs.
For cycles that do not require a full physical examination per the SoA (Section 1.3), the 
investigator or qualified designee will perform a directed physical examination including oral 
examination as clinically indicated.
During the treatment period, physical examinations should be performed prior to dosing. 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
The investigator or qualified designee will take vital signs at Screening, before the 
administration of each dose of study treatment and during the Follow-up Period, as specified 
in the SoA (Section 1.3). Vital signs include temperature, heart rate, respiratory rate, weight, 
and BP. Height will be measured at Screening only.

BP and heart rate 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.
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
Only 1 BP measurement is needed for participants with systolic BP <140 mm Hg and 
diastolic BR <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, 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 
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. Please 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.
MUGA scans or ECHOs should be performed locally in accordance with the institution’s 
standard practice. MUGA scans are the preferred modality, however, whichever modality is 
used for an individual participant at baseline should be repeated for all subsequent LVEF 
assessments for that participant.
LVEF, as assessed by the institution, will be entered in the eCRF. Investigator assessment 
will be based on institutional reports.
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8.3.5
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
8.3.6
Pregnancy Test
All women who are being considered for participation in the study, and who are not 
surgically sterilized or postmenopausal, must be tested for pregnancy within 24 hours of the 
first dose of study intervention. If a urine test is positive or not evaluable, a serum test will be 
required. Participants must be excluded/discontinued from the study in the event of a positive 
test result. Repeated pregnancy test (such as monthly testing) may be conducted if required 
by local regulation.
8.3.7
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 case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
•
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 (90 days if considered an SAE) after the last 
dose of study intervention, every attempt should be made to perform repeat assessments 
until the values return to normal or baseline or if a new baseline is established as 
determined by the investigator.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
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Progression of the cancer under study is not considered an AE as described in Section 8.4.6 
and Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent but before intervention allocation/randomization must be 
reported by the investigator if the participant is receiving placebo run-in or other run-in 
treatment, if the event cause the participant to be excluded from the study, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, or a procedure.
•
All AEs from the time of intervention allocation/randomization through 30 days
following cessation of study intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of intervention allocation/randomization 
through 90 days following cessation of study intervention or 30 days following cessation 
of study intervention if the participant initiates new anticancer therapy, whichever is 
earlier, must be reported by the investigator.
•
All pregnancies and exposure during breastfeeding, from the time of intervention 
allocation/randomization through 120 days after the last dose of pembrolizumab and/or 
30 days after lenvatinib/matching placebo, 180 days after last dose of chemotherapeutic 
agents, or 30 days after the last doses of these agents if the participant initiates new 
anticancer therapy in that timeframe.
•
Additionally, any SAE brought to the attention of an investigator at any time outside of 
the time period specified above must be reported immediately to the Sponsor if the event 
is considered drug-related.
•
Country-specific requirements are listed in Appendix 7.
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Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 11.
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.
Table 11
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through Protocol-
specified Follow-
up Period
Reporting Time Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
Nonserious Adverse 
Event (NSAE) 
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse Event 
(SAE) including Cancer 
and Overdose
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all SAEs, 
cancer, overdose 
associated with 
pembrolizumab 
and overdose 
associated with 
lenvatinib with an 
AE
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
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Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through Protocol-
specified Follow-
up Period
Reporting Time Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
Pregnancy/
Lactation Exposure
Report if:
- participant has 
been exposed to 
any protocol-
specified 
intervention
Exception: A 
positive pregnancy 
test at the time of 
initial screening is 
not a reportable 
event unless the 
participant has 
received study 
intervention.
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- potential drug-
induced liver injury 
(DILI)
- require regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (do not require 
regulatory reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 
calendar days 
of learning of 
event
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events 
including pregnancy and exposure during breastfeeding, events of clinical interest (ECIs), 
cancer, and overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
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8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Any pregnancy complication will be reported as an AE or SAE. 
The medical reason (eg, maternal health or fetal disease) for an elective termination of a 
pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born with 
severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus. 
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints as outlined in Section 3 will not be reported to the Sponsor as AEs/SAEs. 
Specifically, the suspected/actual events covered in this exception include any event that is 
progression of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the study. Any suspected endpoint that upon review is 
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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 nonserious and SAEs are also known as ECIs and must be reported to the Sponsor. 
Events of clinical interest for this study include: 
1.
An overdose of pembrolizumab, as defined in Section 8.5, that is not associated with 
clinical symptoms or abnormal laboratory results.
2.
Any dose over the prescribed dose of lenvatinib associated with an AE.
3.
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose exceeding the prescribed 
dose for:
•
Pembrolizumab: any dose 1000 mg or greater
•
Lenvatinib: any dose above the protocol-prescribed dose if associated with an adverse 
event
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 DTC and RCC.
No specific information is available on the treatment of overdose of pembrolizumab or 
lenvatinib. In the event of overdose, the participant should be observed closely for signs of 
toxicity. Appropriate supportive treatment should be provided if clinically indicated.
If an AE(s) is associated with (“results from”) the overdose of pembrolizumab, the AE(s) is 
reported as an SAE, even if no other seriousness criteria are met. Overdoses associated with 
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lenvatinib should be reported as a nonserious Event of Clinical Interest (ECI), unless the AE 
itself meets criteria for an SAE.
If a dose of pembrolizumab 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.”
All reports of overdose with and without an AE must be reported by the investigator within 
24 hours to the Sponsor either by electronic media or paper.
For chemotherapy, please refer to the local label for the definition of overdose.
8.6
Pharmacokinetics
As of Amendment 08, 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.
8.6.1
Blood Collection for Lenvatinib
Blood samples will be collected as specified in the SoA (Section 1.3). Study sites must have 
appropriately trained staff and adequate equipment for procuring and processing specimens. 
Instructions for the collection, handling, and shipping procedures of PK samples will be 
provided in the Laboratory Manual.
Blood samples will be collected from all participants. Plasma concentrations of lenvatinib 
when co-administered with pembrolizumab will be measured. Lenvatinib will be analyzed 
using a population PK approach.
If at some point during the study, prospective PK blood sample collection is deemed to be 
unnecessary by the Sponsor, it may be reduced or discontinued, and sites will be notified 
accordingly.
8.6.2
Blood Collection for Pembrolizumab
To evaluate pembrolizumab immunogenicity and exposure when administered in 
combination with lenvatinib, sample collections for analysis of antidrug antibodies (ADAs) 
and PK are currently planned as specified in the SoA (Section 1.3). Study sites must have 
appropriately trained staff and adequate equipment for procuring and processing specimens. 
Instructions for the collection, handling, and shipping procedures of ADA and PK samples 
will be provided in the Laboratory Manual.
Blood samples for pembrolizumab PK and ADA collected may only be stored at this time. 
Further analysis may be performed if required and reported separately if conducted. If 
ongoing PK and/or ADA sampling is deemed to be unnecessary by the Sponsor, it may be 
reduced or discontinued.
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8.6.3
Blood Collection for Chemotherapy
Blood samples will be collected as specified in the SoA (Section 1.3). Study sites must have 
appropriately trained staff and adequate equipment for procuring and processing specimens. 
Instructions for the collection, handling, and shipping procedures of PK samples will be 
provided in the Laboratory Manual.
Blood samples for chemotherapy PK collected may only be stored at this time. Further 
analysis may be performed if required and reported separately if conducted.
If ongoing PK sampling is deemed to be unnecessary by the Sponsor, it may be reduced or 
discontinued.
8.7
Pharmacodynamics
Not applicable.
8.8
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/IEC does not approve) sample collection for these purposes, then such samples 
should not be collected at the corresponding sites.
8.9
Biomarkers
As of Amendment 08, 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.
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 serum biomarkers
•
Blood for plasma biomarkers
•
Blood for serum biomarkers
•
Blood for circulating tumor nucleic acids
•
Newly Obtained/Archival Tissue Sample for Biomarker Analysis
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Sample collection, storage, and shipment instructions for exploratory biomarker specimens 
will be provided in the operations/laboratory manual.
8.10
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics data associated with medical encounters, 
excluding protocol-mandated procedures, tests, and encounters, will be collected in the eCRF 
by the investigator and study site personnel for all participants.
The data collected may be used to conduct exploratory economic analyses.
All-cause hospitalizations and emergency room visits must be reported in the eCRF from the
time of randomization through 90 days after the last dose of study intervention, or 30 days 
after the last dose of study intervention if the participant initiates a new anticancer therapy, 
whichever is earlier.
8.11
Treatment Eligibility Assessment
The investigator must complete the eCRF and provide rationale to document the choice of (or 
potential treatment with) cisplatin prior to randomization.
8.12
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8. Unscheduled visits are permitted at any time during the course of the study.
8.12.1
Screening Period
Documented informed consent must be provided before performing any protocol-specific
procedure. Results of a test performed before the participant signs the ICF as part of routine
clinical management are acceptable in lieu of a Screening test if performed within the
specified time frame. Screening procedures are to be completed within 28 days before the
first dose of study intervention except for the following:
•
Full physical examination at Screening should be performed within 7 days prior to
Cycle 1 Day 1.
•
Evaluation of ECOG at Screening should be performed within 7 days prior to Cycle 1
Day 1 but before randomization.
•
For WOCBP, a urine or serum pregnancy test will be performed within 72 hours prior
to the first dose of study intervention. If a urine pregnancy test cannot be confirmed
as negative, a serum pregnancy test is required (performed by the local study site
laboratory).
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•
Laboratory tests at Screening should be performed within 10 days prior to Cycle 1
Day 1.
•
Urinalysis at Screening should be performed within 7 days prior to Cycle 1 Day 1.
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria.
Results from assessments during the initial Screening period are acceptable in lieu of a repeat
screening test if performed within the specified time frame and the corresponding
inclusion/exclusion criteria are met. Participants who are rescreened will retain their original
screening number.
8.12.2
Treatment Period
In Part 1 (safety run-in), participants who are eligible for study participation will be assigned 
to receive unblinded, open-label treatment with lenvatinib + pembrolizumab + platinum
doublet chemotherapy.
In Part 2 (Phase 3 study), participants who are eligible for study participation will be 
randomly assigned to receive lenvatinib + pembrolizumab + platinum doublet chemotherapy
(Arm 1) or matching placebo + pembrolizumab + platinum doublet chemotherapy (Arm 2).
Lenvatinib/matching placebo will be taken orally once daily, and pembrolizumab and 
platinum doublet chemotherapy will be given by IV infusion on Day 1 of each 21-day cycle, 
as outlined in Section 8.1.8.
In Cycles 1 and 2, study visits will occur on Days 1 and 15. Participants will be contacted by 
telephone on Cycle 1, Day 8. Beginning in Cycle 3, participants will be required to attend 
study visits on Day 1 only. Participants may be seen more frequently, if clinically indicated.
Tumor scans and response assessment will occur every 6 weeks from the day of 
randomization until Week 18, followed by every 9 weeks until Week 54, and every 12 weeks 
thereafter.
Study interventions will continue until reaching a discontinuation criterion (Section 7.1), 
examples of which include disease progression which is radiographically documented per 
RECIST 1.1, and only when clinically appropriate, confirmed by the site per iRECIST;
unacceptable toxicity; intercurrent illness that prevents further administration of treatment;
investigator’s decision to withdraw treatment; participant withdrawal of consent; pregnancy;
noncompliance with study intervention or procedure requirements; administrative reasons 
requiring cessation of treatment; or, for carboplatin, cisplatin, and pembrolizumab ONLY, 
treatment completion (4 cycles of carboplatin or cisplatin/35 cycles of pembrolizumab). 
There is no treatment duration limit for lenvatinib/matching placebo or pemetrexed.
Participants treated with pembrolizumab who complete 35 cycles of treatment with SD or 
better or participants who attain an investigator-determined CR and have received at least 
8 cycles of pembrolizumab may be eligible for Second Course Treatment as outlined in 
Section 7.1.1.
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8.12.3
Discontinued Participants Continuing to be Monitored in the Study
The Discontinuation Visit should occur at the time study intervention is discontinued for any 
reason. If the Discontinuation Visit occurs 30 days from the last dose of study intervention, at 
the time of the mandatory Safety Follow-up visit, the Discontinuation Visit procedures and 
any additional Safety Follow-up procedures should be performed.
Visit requirements are outlined in the SoA. Additional details regarding participant 
withdrawal and discontinuation are presented in Section 8.1.9.
8.12.4
Posttreatment Period
8.12.4.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before the initiation of a new anticancer therapy, whichever 
is earlier.
Participants who are eligible for retreatment with pembrolizumab may have up to 2 Safety 
Follow-up visits, 1 after the Initial Treatment Period and 1 after Second Course Treatment.
8.12.4.2
Efficacy Follow-up Visits
Participants who complete the protocol-required cycles of study intervention or who 
discontinue study intervention for a reason other than PD will move into Efficacy Follow-up 
and should be assessed as outlined in the SoA (Section 1.3) to monitor disease status. Every 
effort should be made to collect information regarding disease status until the start of new 
anticancer therapy, PD, death, or end of study, or if the participant begins retreatment with 
pembrolizumab, as detailed in Section 8.11.2. Information regarding poststudy anticancer 
treatment will be collected if new treatment is initiated. Participants who completed all 
efficacy assessments and/or will not have further efficacy assessments must enter Survival 
Follow-up.
Participants who are eligible to receive retreatment with pembrolizumab according to the 
criteria in Section 8.11.2 will move from Efficacy Follow-up to Second Course Treatment 
when they experience PD. Details are provided in the SoA (Section 1.3) for retreatment with 
pembrolizumab
8.12.4.3
Survival Follow-up Visits
Participant survival status will be assessed approximately every 12 weeks until death, 
withdrawal of consent, or the end of the study, whichever occurs first. Participants may be 
contacted for survival status at any time during the course of the study.
For participants who discontinue treatment intervention and who will not enter Efficacy 
Follow-up, the first Survival Follow-up assessment will be scheduled 12 weeks after the 
Discontinuation Visit and/or Safety Follow-up Visit (whichever is last).  
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For participants who completed assessments in Efficacy Follow-up, the first Survival Follow-
up assessment will be scheduled 12 weeks after the last efficacy assessment follow-up visit 
has been performed.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If changes 
are made to primary and/or key secondary hypotheses or the statistical methods related to 
those hypotheses after the study has begun, but prior to any unblinding/final database lock, 
then the protocol will be amended (consistent with ICH Guideline E9). Changes to 
exploratory or other nonconfirmatory analyses made after the protocol has been finalized, but 
prior to 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) may be developed to detail PK and biomarker analyses.
The PRO analysis plan will be included in the sSAP.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan (SAP) are summarized below. The 
comprehensive plan is provided in Section 9.2 through Section 9.12.
Study Design
Overview
A Phase 3 study of platinum doublet chemotherapy + pembrolizumab with or without 
lenvatinib as first-line treatment in patients with treatment-naïve, metastatic nonsquamous
NSCLC.
Treatment
Assignment
Part 1: Approximately 12 to 20 participants will be assigned to one of 2 treatment arms, at 
the discretion of the investigator, until at least 6 participants are treated per arm:
1.
Lenvatinib + pembrolizumab + carboplatin + pemetrexed
2.
Lenvatinib + pembrolizumab + cisplatin + pemetrexed
Part 2: Approximately 714 participants will be randomized in a 1:1 ratio to one of
2 treatment arms:
1.
Lenvatinib + platinum doublet chemotherapy + pembrolizumab
2.
Placebo + platinum doublet chemotherapy + pembrolizumab
Stratification factors for Part 2 are as follows:
•
PD-L1 TPS: <50% vs. ≥50%
•
Geography site: East Asian vs. non-East Asian
•
ECOG performance status: 0 vs. 1
Analysis
Populations
Part 1 and Part 2 participants will be analyzed separately.
Efficacy: Intention-to-Treat (ITT)
Safety: All-Participants-as-Treated (APaT)
Primary
Endpoints
Part 1: Safety and tolerability
Part 2:

Progression-free Survival (PFS) per RECIST 1.1 assessed by BICR

Overall Survival (OS)
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Secondary 
Endpoints
Part 2:

Objective response per RECIST 1.1 based on BICR

DOR per RECIST 1.1 based on BICR

Safety and tolerability

Change from baseline in Global health status/QoL, cough, chest pain, dyspnea, 
and physical functioning scores

TTD in global health status/QoL, cough, chest pain, dyspnea, and physical 
functioning

TTD in the composite endpoint of cough, chest pain, or dyspnea items 
Statistical
Methods for
Key Efficacy
Analyses
Part 2:
The dual primary hypotheses of PFS and OS will be evaluated by comparing lenvatinib to 
placebo in combination with platinum doublet chemotherapy and pembrolizumab using a 
stratified log-rank test. 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.
Statistical
Methods for
Key Safety
Analyses
Part 1: Descriptive summary statistics will be provided for safety endpoints by treatment 
as appropriate.
Part 2: The analysis of safety results will follow a tiered approach. There are no events of 
interest that warrant elevation to Tier 1 events in this study. All safety parameters are 
considered either Tier 2 or Tier 3. Tier 2 safety parameters will be assessed via point 
estimates with 95% confidence intervals (CIs) provided for between-treatment
comparisons. Tier 3 safety parameters will be assessed only via point estimates by 
treatment. Between-treatment differences will be analyzed using the Miettinen and 
Nurminen method.
Interim 
Analyses
Part 1: No formal interim analysis is planned. Participants will be closely followed for 
DLTs for 21 days after the first dose of study intervention.
Part 2 Efficacy:  Four analyses are planned for this study: 3 interim analyses and 1 final 
analysis. Results from the first 3 interim analyses will be reviewed by an external Data 
Monitoring Committee. Details are provided in Section 9.7.
Interim analysis 1 (IA1)
•
Timing: To be performed after ~ 420 participants are randomized with at 
least 9 months of follow-up (ie, ~ 19 months after study start)
•
Primary purpose: efficacy analysis for ORR
Interim analysis 2 (IA2)
•
Timing: To be performed after both ~ 420 PFS events have been observed and 
~8 months after last participant randomized
•
Primary purpose: efficacy analysis for PFS and OS 
Interim analysis 3 (IA3)
•
Timing: To be performed after both ~ 480 PFS events have been observed and 
~18 months after last participant randomized
•
Primary purpose: efficacy analysis for PFS and OS
Final Analysis (FA)
•
Timing: To be performed after both ~ 445 OS events have been observed and 
~29 months after last participant randomized
•
Primary purpose: efficacy analysis for OS 
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Note that for IA2, IA3 and FA, if the PFS (for IA2 and IA3) or OS (for FA) events 
accrue slower than expected, the Sponsor may conduct the analysis with additional 2 
months of follow-up, or the specified number of events is observed, whichever occurs 
first.
Part 2 Safety: An interim safety analysis will be performed and reviewed by the eDMC 
after at least 40 participants (~ 10 participants treated with carboplatin in each treatment 
arm and ~ 10 participants treated with cisplatin in each treatment arm) complete at least 
2 cycles of treatment. Afterwards, the eDMC will review safety data periodically in the 
study. Details will be specified in the DMC Charter. 
Multiplicity
Part 1: No multiplicity adjustment is planned.
Part 2: The overall Type I error over the primary and secondary hypotheses is strongly 
controlled at 2.5% (1-sided), with 0.1% initially allocated to ORR, 0.5% to PFS, and 1.9% 
to OS.
By using the graphical approach of Maurer and Bretz, if one hypothesis is rejected, the 
alpha will be shifted to other hypotheses.
Sample Size
and Power
Part 1: Approximately 12 to 20 participants will be enrolled.
Part 2: The planned sample size is approximately 714 participants with approximately 
357 participants in each treatment arm. 
There will be ~420 participants randomized with at least 9 months of follow-up at the 
ORR final analysis. The study has ~83% power for detecting a 20% point difference 
between treatment arms with an underlying 48% response rate in the control arm at an 
initially assigned 0.001 (1-sided) significance level.  
It is estimated that there will be ~ 480 events at the PFS final analysis (ie, IA3 of the 
study). With 480 PFS events, the study has ~90% power for detecting a HR of 0.7 at an 
initially assigned 0.005 (1-sided) significance level. 
It is estimated that there will be ~ 445 deaths at the OS final analysis. With 445 deaths, 
the study has ~90% power for detecting a HR of 0.725 at an initially assigned 0.019 (1-
sided) significance level.
China 
Extension 
Study
China participants randomized during the global study phase will be included in all global 
study analyses (efficacy and safety). China participants randomized during the China 
extension phase will be excluded from all global study analyses. China participants 
randomized during global and extension phases will both be included in the China-
specific analyses.
9.2
Responsibility for Analyses/In-house Blinding
Statistical analyses of the data obtained from this study will be the responsibility of the 
Sponsor’s Clinical Biostatistics department.
Part 1 of the study is being conducted as an open-label study, ie, participants, investigators, 
and Sponsor personnel will be aware of treatment assignments after each participant is 
enrolled and treatment is assigned. Safety data will be closely monitored for 21 days after the 
first dose of study intervention.
Part 2 of the study will be conducted as a double-blind study under in-house blinding 
procedures. The official, final database will not be unblinded until medical/scientific review 
has been performed, protocol deviations have been identified, and data have been declared 
final and complete.
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The Sponsor will generate the randomized allocation schedule for study intervention
assignment for this protocol and the randomization will be implemented in IVRS/IWRS.
Blinding issues related to the planned interim analyses are described in Section 9.7.
Extension Study in China
For all participants in China, including participants randomized in the global study and the 
extension study, participant level treatment randomization information will be blinded to the 
statistician(s)/programmer(s) responsible for the analysis of the Extension Study in China
until the extension study database lock is achieved. The extent to which individuals are 
unblinded to the results will be limited. Blinded and unblinded members will be clearly 
documented.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are provided in Section 3.
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for between-treatment arm differences 
are listed below.
9.4.1
Efficacy Endpoints
Primary Endpoints
Progression-free survival (PFS) using RECIST 1.1 assessed by BICR: PFS is defined as the 
time from randomization to the date of the first documentation of disease progression, as 
determined by BICR per RECIST 1.1, or death from any cause, whichever is earlier. See 
Section 9.6.1 for the definitions of censoring.
Overall Survival (OS): OS is defined as the time from randomization to the date of death 
from any cause.
Secondary Endpoints
Objective response using RECIST 1.1 assessed by BICR: Objective response is a confirmed 
complete response (CR) or partial response (PR), as determined by BICR per RECIST 1.1.
Duration of Response (DOR) using RECIST 1.1 assessed by BICR: DOR is defined as the 
time from the first documented evidence of CR or PR until disease progression or death due 
to any cause (whichever is earlier), for participants who demonstrate a confirmed CR or PR. 
Response will be determined by BICR per RECIST 1.1.
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9.4.2
Safety Endpoints
Dose-limiting toxicities for Part 1 are defined in Table 1. Other safety measurements for all 
participants are described in Section 8.3 and Section 8.4 and include AEs, SAEs, fatal AEs, 
laboratory test results, vital sign results, and ECG results. Furthermore, specific events will 
be collected and designated as ECIs as described in Section 8.4.7.
9.4.3
Patient-reported Endpoints
The following secondary PRO endpoints will be evaluated as described in Section 4.2.1.3
and analyzed as described in Section 9.6.3:
Change from baseline in
•
Global Health Status/QoL scale (QLQ-C30 items 29 and 30)
•
Single-item symptom scales: cough (QLQ-LC13 item 31), chest pain (QLQ-LC13 
item 40), and dyspnea (QLQ-C30 item 8)
•
Physical functioning scale (QLQ-C30 items 1-5)
Time to true deterioration (TTD) in 
•
Global Health Status/QoL scale (QLQ-C30 items 29-30)
•
Single-item symptom scales: cough (QLQ-LC13 item 31), chest pain (QLQ-LC13 
item 40), and dyspnea (QLQ-C30 item 8)
•
Physical functioning scale (QLQ-C30 items 1-5)
•
Composite symptom endpoint: cough (QLQ-LC13 Item 31), chest pain (QLQ-LC13 
Item 40), and dyspnea (QLQ-C30 Item 8)
The TTD in global health status/QoL, cough, chest pain, dyspnea, and physical functioning is 
defined as the time from baseline to the first onset of a 10 or more points deterioration from 
baseline with confirmation by the subsequent visit of a 10 or more points deterioration from 
baseline. The TTD in the composite endpoint of cough, chest pain, or dyspnea is defined as 
the time to first onset of 10 or more points deterioration from baseline in any one of 3 scale 
items with confirmation by the subsequent visit of 10 points or more deterioration from 
baseline in the same scale as the first onset. The EQ-5D-5L will be evaluated as an 
exploratory endpoint. These analyses and other supportive PRO analyses will be described in 
the sSAP.
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9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The ITT population will serve as the population for primary efficacy analyses. All 
randomized participants will be included in this population. Participants will be analyzed in 
the treatment arm to which they were randomized.
Part 1 participants will be excluded from all Part 2 efficacy analyses and therefore will not 
contribute to the analyses to assess the primary/secondary objectives of Part 2.
Details on the approach to handling missing data are provided in Section 9.6.
Extension Study in China
After enrollment of the global study is closed, the study will continue to randomize
participants in China until the sample size for participants in China reaches approximately 
200. The participants in China who are randomized in the extension study will not be
included in the primary efficacy analysis population for the global study. The China ITT 
population, including all participants in China randomized in the global study and the 
extension study, will be analyzed separately.
9.5.2
Safety Analysis Populations
The APaT population will be used for the analysis of safety data in this study. The APaT 
population will consist of all enrolled (Part 1) and all randomized (Part 2) participants who 
received at least 1 dose of study intervention. Participants will be included in the treatment 
arm corresponding to the study intervention they actually received for the analysis of safety 
data using the APaT population. For most participants this will be the treatment arm to which 
they were randomized. Participants who take 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 treatment for all other cycles will be analyzed according to 
the correct (ie, randomized) treatment arm and a narrative will be provided for any events 
that occurred during the cycle for which the participant was incorrectly dosed.
At least 1 laboratory, vital sign, or ECG 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.
Participants in Part 1 and Part 2 will be analyzed separately.
Extension Study in China
The participants in China randomized and treated in the extension study after completion of 
the global enrollment will not be included in the primary safety analysis population for the 
global study. The China APaT population, including all participants in China randomized in 
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the global study and the extension study who received at least 1 dose of study treatment, will 
be analyzed separately.
9.5.3
PRO Analysis Population
The PRO Full Analysis Set (FAS) population will be used for the analysis of PRO data in 
this study. The PRO FAS population will consist of all randomized participants who have at 
least 1 PRO assessment available and have received at least 1 dose of study intervention.
PRO analyses will be performed in Part 2 participants only.
9.5.4
Pharmacokinetic Analysis Population
The Population PK Analysis Set will be used for the analysis of PK data in this study. The 
Population PK Analysis Set will include all participants who received at least 1 dose of study 
intervention with documented dosing history in the lenvatinib plus pembrolizumab and 
chemotherapy treatment arm and have measurable plasma levels of lenvatinib and/or serum 
levels of pembrolizumab.
PK analyses will be performed using PK data from participants in Part 1 and Part 2 combined.
9.6
Statistical Methods
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the sSAP.
Efficacy analyses will be performed in Part 2 participants only. Efficacy results that are 
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.
All statistical inferential tests, unless otherwise specified, will be stratified for the 
stratification factors used in randomization (See Section 6.3.2). In the event that there are 
small strata, for the purpose of analysis, strata will be combined to ensure sufficient number 
of participants, responses and events in each stratum. Details regarding the pooling strategy 
will be prespecified in the sSAP, and decisions regarding the pooling will be based on a 
blinded review of response and event counts by stratum.
The efficacy analyses for ORR, DOR and PFS will include responses and documented 
progression events that occur prior to Second Course Treatment.
9.6.1.1
Progression-free Survival
The nonparametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment arm. Treatment differences in PFS will be assessed by the stratified log-rank test 
(based on the stratification factors outlined in Section 6.3.2). A stratified Cox proportional 
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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 randomization (Section 6.3.2) 
will be applied to both the stratified log-rank test and the stratified Cox model.
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. The true date of PD will be approximated by the earlier of the date of the first 
assessment at which PD is objectively documented per RECIST 1.1 by BICR and the date of 
death. Death is always considered a PD event.
For the primary analysis, any participant who experiences an event (PD or death) 
immediately after 2 or more missed disease assessments will be censored at the last disease 
assessment prior to the missed visits. In addition, any participant who initiates new 
anticancer therapy prior to documented PD will be censored at the last disease assessment 
prior to the initiation of new anticancer therapy. Participants who do not start new anticancer 
therapy and who do not experience an event will be censored at the last disease assessment.
If a participant meets multiple criteria for censoring, the censoring criterion that occurs 
earliest will be applied. Sensitivity analyses will be performed for comparison of PFS based 
on investigator's assessment.
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 by BICR, 
two sensitivity analyses with a different set of censoring rules will be performed. The first 
sensitivity analysis follows intention-to-treat principles. That is, disease progressions/deaths 
are counted as events regardless of missed study visits or initiation of new anticancer 
therapy. The second sensitivity analysis considers discontinuation of treatment or initiation of 
a new anticancer therapy subsequent to discontinuation of study-specified treatments, 
whichever is later, to be a disease progression event for participants without documented 
disease progression 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 12.
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Table 12
Censoring Rules for Primary and Sensitivity Analyses of Progression-free
Survival
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
No PD and no death; and 
new anticancer therapy is 
not initiated
Censored at last disease 
assessment
Censored at last 
disease assessment
Progressed at treatment
discontinuation due to 
reasons other than 
complete response; 
otherwise censored at last 
disease assessment if still 
on study treatment or 
completed study treatment
No PD and no death; new 
anticancer therapy is 
initiated
Censored at last disease 
assessment before new 
anticancer therapy
Censored at last 
disease assessment
Progressed at date of new 
anticancer therapy
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
Death or progression 
immediately after 
≥2 consecutive missed 
disease assessments, or after 
new anticancer therapy
Censored at last disease 
assessment prior to 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
Abbreviation: PD = progressive disease
9.6.1.2
Overall Survival
The nonparametric Kaplan-Meier method will be used to estimate the survival curves. 
Treatment differences in survival will be assessed by the stratified log-rank test (based on the 
stratification factors outlined in Section 6.3.2). A stratified Cox proportional hazard model 
with Efron's method of tie handling will be used to assess the magnitude of the treatment 
difference (ie, the HR) between the treatment arms. The HR and its 95% CI from the 
stratified Cox model with a single treatment covariate will be reported. The stratification 
factors used for randomization (Section 6.3.2) will be applied to both the stratified log-rank 
test and the stratified Cox model. Participants without documented death at the time of 
analysis will be censored at the date of last known contact. Analysis using the RMST method 
may be used for OS to account for the possible nonproportional hazards effect.
Further details of sensitivity analyses will be described in the sSAP as needed.
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9.6.1.3
Objective Response Rate and Duration of Response
The stratified Miettinen and Nurminen method will be used for comparison of ORR between
treatment arms. The difference in ORR 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 randomization (Section 6.3.2) will be used in the analysis.
The point estimate of ORR will be provided by treatment group, together with 95% CI using 
exact binomial method proposed by Clopper and Pearson (1934) [Clopper, C. J. and Pearson, 
E. S. 1934]. 
If sample size permits, DOR will be summarized descriptively using Kaplan-Meier medians 
and quartiles. Only the subset of participants who show a confirmed CR or PR will be 
included in this analysis.
For each DOR analysis, a corresponding summary of the reasons responding participants are 
censored will also be provided. Responding participants who are alive, have not progressed, 
have not initiated new anticancer therapy, and have not been determined to be lost to 
follow-up, and have had a disease assessment within ~5 months of the data cutoff date are
considered ongoing responders at the time of analysis. If a participant meets multiple criteria 
for censoring, the censoring criterion that occurs earliest will be applied. Censoring rules for 
DOR are summarized in Table 13.
Table 13
Censoring Rules for Duration of Response
Situation
Date of Progression or 
Censoring
Outcome
No progression or death, no new 
anticancer therapy initiated
Last adequate disease assessment
Censor
(Nonevent)
No progression or death, new 
anticancer therapy initiated
Last adequate disease assessment 
before new anticancer therapy 
initiated
Censor
(Nonevent)
Death or progression immediately
after ≥2 consecutive missed disease 
assessments or after new anticancer 
therapy, if any
Earlier date of last adequate 
disease assessment prior to 
≥2 missed adequate disease 
assessments and new anticancer 
therapy, if any
Censor
(Nonevent)
Death or progression after ≤1 missed 
disease assessment and before new 
anticancer therapy, if any
PD or death
End of response
(Event)
Abbreviation: PD = progressive disease
Note: A missed disease assessment includes any assessment that is not obtained or is considered inadequate for 
evaluation of response.
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9.6.1.4
Analysis Strategy for Key Efficacy Endpoints
Table 14 summarizes the primary analysis strategy for key efficacy endpoints.
Table 14
Analysis Methods for Key Efficacy Endpoints
Endpoint/Variable
Statistical Method
Analysis
Population
Missing Data 
Approach
Primary Analyses:
PFS (RECIST 1.1 by 
BICR)
Testing: Stratified log-rank test
Estimation: Stratified Cox model 
with Efron's tie handling method 
ITT
Censored according 
to rules in Table 12
OS
Testing: Stratified log-rank test 
Estimation: Stratified Cox model 
with Efron's tie handling method 
ITT
Censored at the date 
participants last 
known to be alive
Secondary Analyses:
ORR (RECIST 1.1 by 
BICR)
Testing and Estimation: 
Stratified Miettinen and 
Nurminen method
ITT
Participants with 
missing data are 
considered 
nonresponders
DOR (RECIST 1.1 by 
BICR)
Descriptive statistics for range 
and Kaplan-Meier estimate of 
median
All 
responders in 
ITT
Censored according 
to the rules in 
Table 13
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
Part 1: Participants will be closely followed for DLTs for 21 days after the first dose of 
study intervention. Descriptive summary statistics (eg, counts, percentages) will be provided 
for DLTs by treatment as appropriate.
Part 2: Safety and tolerability will be assessed by clinical review of all relevant parameters 
including AEs, laboratory test results, vital sign results, and ECG results.
The analysis of safety results will follow a tiered approach (Table 15). The tiers differ with 
respect to the analyses that will be performed. Adverse events (specific terms as well as 
system organ class terms) and events that meet predefined limits of change (PDLCs) in 
laboratory, vital sign, and 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.
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Tier 1 Events
Safety parameters or AEs of special interest 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 with 95% CIs provided for differences in 
the proportion of participants with events 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 any 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 one 
of the treatment arms) and SAEs (≥5% of participants in one of the treatment arms) 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 vital sign parameters, summary 
statistics for baseline, on-treatment, and change from baseline values will be provided by 
treatment arm in table format. For laboratory parameters, the number and percentage of 
participants with increases from baseline in laboratory test toxicity grades based on the 
highest postbaseline toxicity grade, and shift of toxicity grade from baseline to the worst 
postbaseline toxicity grade, will be summarized by treatment arm.
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Table 15
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE (≥10% of participants in one of the treatment 
arms)
X
X
Any Grades 3 to 5 AE (≥5% of participants in one of 
the treatment arms)
X
X
Any serious AE (≥5% of participants in one of the 
treatment arms)
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
9.6.3
Statistical Methods for PRO Analyses
PRO analyses will be performed in Part 2 participants only. 
Mean change from baseline
The time point for the mean change from baseline will be determined based on blinded data 
review prior to the database lock for any PRO analysis and documented in the sSAP.
To assess the treatment effects on the PRO score change from baseline in the PRO endpoints 
defined in Section 9.4.3, a cLDA model proposed by Liang and Zeger [Liang, K.-Y. and 
Zeger, S. L. 2000] will be applied, with the PRO score as the response variable, and 
treatment, time, the treatment by time interaction, and stratification factors used for 
randomization (See Section 6.3.2) as covariates. The treatment difference in terms of LS 
mean change from baseline will be estimated from this model together with 95% CI. Model-
based LS mean with 95% CI will be provided by treatment group for PRO scores at baseline 
and postbaseline time point.
Time to True Deterioration (TTD)
For the TTD endpoints defined in Section 9.4.3, the Kaplan-Meier method will be used to 
estimate the TTD curve for each treatment group. The estimate of median TTD and its 
95% CI will be obtained from the Kaplan-Meier estimates. The treatment difference in TTD 
will be assessed by the stratified log-rank test. A stratified Cox proportional hazard model 
with Efron’s method of tie handling and with a single treatment covariate will be used to 
assess the magnitude of the treatment difference (ie, HR). The HR and its 95% CI will be 
reported. The same stratification factors used for the stratified PFS and OS analyses will be 
used as the stratification factors in both the stratified log-rank test and the stratified Cox 
model.  
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9.6.4
Summaries of Baseline Characteristics and Demographics
Part 1 and Part 2: The comparability of the treatment arms for each relevant demographic 
and baseline characteristic will be assessed by the use of tables and/or graphs. No statistical 
hypothesis tests will be performed on these characteristics. The number and percentage of 
participants randomized and the primary reason for screening failure and discontinuation will 
be displayed. Demographic variables (such as age), baseline characteristics, primary and 
secondary diagnoses, and prior and concomitant therapies will be summarized by treatment 
either by descriptive statistics or categorical tables.
9.7
Interim Analyses
9.7.1
Interim Analysis for Part 1
In this open-label safety run-in phase, participants will be closely followed for DLTs for 
21 days after the first dose of study intervention.
9.7.2
Interim Analysis for Part 2
Blinding to treatment assignment will be maintained at all investigational sites. The results of
interim analyses will not be shared with the investigators prior to the completion of the study. 
Participant-level unblinding will be restricted to an external unblinded statistician and 
scientific programmer performing the interim analysis, who will have no other 
responsibilities associated with the study.
An external DMC will serve as the primary reviewer of the results of the interim analyses of 
the study and will make recommendations for discontinuation of the study or protocol 
modifications to the Executive Oversight Committee. If the DMC recommends modifications 
to the design of the protocol or discontinuation of the study, this executive committee (and 
potentially other limited Sponsor personnel) may be unblinded to results at the treatment
level in order to act on these recommendations. The extent to which individuals are 
unblinded with respect to results of interim analyses will be documented by the unblinded 
statistician. Additional logistical details will be provided in the DMC Charter. Key aspects of 
the interim analyses are described in Section 9.7.2.2.
Treatment-level results from the interim analyses will be provided to the DMC by the 
unblinded statistician. The unblinded statistician will not be involved in any discussions 
regarding modifications to the protocol, statistical methods, identification of protocol 
deviations, or data validation efforts after the interim analyses.
9.7.2.1
Efficacy Interim Analyses
There are 3 planned IAs in addition to the FA for this study. For ORR efficacy IA1, the first 
~420 randomized participants will be included. For subsequent IAs and the final efficacy 
analysis, all randomized participants will be included. Results of the IAs will be reviewed by 
the external DMC. Details of the boundaries for establishing statistical significance with 
regard to efficacy are discussed further in Section 9.8.
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The analyses planned, endpoints evaluated, and drivers of timing are summarized in
Table 16. OS will only be examined at IA1 if the external DMC suggests it is necessary to 
evaluate risk benefit for any safety considerations. There is no intent to declare a positive 
finding for OS at IA1. The HR lower bound will be calculated using asymmetric nonbinding 
testing with Pocock spending function under the alternative hypothesis. The probability of 
crossing the lower bound HR of 1.2814 is approximately 0.1% if the underlying HR is 0.725.
Table 16
Summary of Interim and Final Analyses Strategy
Analysis
Key 
Endpoint(s)
Timing
Estimated Time after First 
Participant Randomized
Primary Purpose of 
Analysis
IA1
ORR
~ 420 participants 
randomized with
~ 9 months of 
follow-up
~ 19 months
Final ORR analysis
IA2
PFS; OS
Both ~ 420 PFS 
events have 
occurred and ~ 8 
months after last 
participant 
randomized
~ 26 months
Interim PFS analysis
Interim OS analysis 
IA3
PFS; OS
Both ~ 480 PFS 
events have 
occurred and ~18 
months after last 
participant 
randomized
~ 36 months
Final PFS analysis
Interim OS analysis
FA
OS
Both ~ 445 deaths
have occurred and ~ 
29 months after last 
participant 
randomized
~ 47 months
Final OS analysis
Note that for IA2, IA3 and the FA, if the events accrue slower than expected, the Sponsor may conduct the analysis with 
additional 2 months of follow-up, or the specified number of events is observed, whichever occurs first.
Abbreviations: FA = final analysis; IA = interim analysis; ORR = objective response rate; OS = overall survival; PFS = 
progression-free survival.
9.7.2.2
Safety Interim Analyses
In Part 2, an external DMC will review accumulating safety data periodically. The first safety 
data review will occur after at least 40 participants (~ 10 participants treated with carboplatin 
in each treatment arm and ~ 10 participants treated with cisplatin in each treatment arm) 
complete at least 2 cycles of treatment to assess the safety and tolerability of lenvatinib when 
administered in combination with platinum doublet chemotherapy and pembrolizumab.
Further details of the timing of safety monitoring will be specified in the DMC Charter.
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9.8
Multiplicity
9.8.1
Multiplicity for Part 1
No multiplicity adjustment is planned.
9.8.2
Multiplicity for Part 2
The study uses the graphical method of Maurer and Bretz [Maurer, W. and Bretz, F. 2013] to 
control multiplicity for multiple hypotheses as well as IAs. According to this approach, study 
hypotheses may be tested more than once, and when a particular null hypothesis is rejected, 
the alpha allocated to that hypothesis can be reallocated to other hypothesis tests. Figure 3
shows the initial one-sided alpha 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.
Abbreviations: α = alpha; IA = interim analysis; ORR = objective response rate; OS = overall survival; 
PFS = progression-free survival
Note: If both PFS and OS null hypotheses are rejected, the reallocation strategy allows re-testing of ORR at alpha = 0.025 
based on the ORR p-value at IA1.
Figure 3
Type I Error Reallocation Strategy Following Closed Testing Principle
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9.8.2.1
Objective Response Rate
The study will test ORR only once at IA1, at an initial alpha level of 0.001 (Figure 3). Note 
that if superiority for both the PFS and OS hypotheses is declared at a future planned 
analysis, α = 0.024 will be rolled over to the hypothesis for ORR, then the test statistics 
previously computed at IA1 for the ORR hypothesis will be used for inferential testing with 
an updated alpha level of 0.025.
Based on the first 420 randomized participants with at least 9 months of follow-up, power at 
the initially assigned alpha level and the maximum possible alpha level as well as the 
approximate treatment difference required to reach the bound (ΔORR) are shown in
Table 17, assuming underlying 48% and 68% response rates in the control and experimental 
groups, respectively.
Table 17
Possible Alpha-levels and Approximate ORR Difference Required to 
Demonstrate Efficacy for ORR at IA1
Alpha
~Δ Objective Response Rate (ORR)
Power (Δ ORR = 0.2)
0.001
~ 0.15
83%
0.025
~ 0.10
98%
Abbreviations: IA = interim analysis; ORR = objective response rate
9.8.2.2
Progression-free Survival
The study will test PFS at IA2 and IA3 only. Following the multiplicity strategy as outlined 
in Figure 3, the PFS hypothesis may be tested at α=0.005 (initially allocated alpha), at 
α=0.006 (if the ORR null hypothesis is rejected but not the OS hypothesis), at α=0.023981 (if 
the OS null hypothesis is rejected but not the ORR hypothesis), or at α=0.025 (if both the OS 
and ORR null hypotheses are rejected). For the superiority hypothesis, a Lan-DeMets alpha-
spending function approximating O'Brien-Fleming bounds is used to construct group 
sequential boundaries to control the Type I error rate. Table 18 shows the boundary 
properties for each of these alpha levels for the PFS analysis. Note that the final row 
indicates the total power to reject the null hypothesis for PFS at each alpha level. Also, note 
that if the OS null hypothesis is rejected at IA3 or FA of the study, the previously computed 
PFS test statistics may be used for inferential testing with its updated bounds, considering the 
alpha reallocation from the OS hypothesis.
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Table 18
Efficacy Boundaries and Properties for Progression-free Survival Analyses
Analysis
Value
α = 0.005
α = 0.006
α =0.023981
α = 0.025
IA 2: 88%1
N: 714
Events: ~ 420
Month: 26
Z
2.7831 
2.7155 
2.1492
2.1304 
p (1-sided)2
0.0027 
0.0033 
0.0158
0.0166 
HR at bound3
0.762 
0.767 
0.8106
0.8121 
P (Cross) if 
HR = 14
0.0027 
0.0033 
0.0158
0.0166 
P (Cross) if 
HR = 0.75
0.8094 
0.827 
0.9337
0.9361 
IA 3
N: 714
Events: ~ 480
Month: 36
Z
2.6344 
2.5732 
2.063
2.0462 
p (1-sided)2
0.0042 
0.005 
0.0196
0.0204 
HR at bound3
0.7861 
0.7905 
0.8282
0.8295 
P (Cross) if 
HR = 14
0.005 
0.006 
0.024 
0.025 
P (Cross) if 
HR = 0.75
0.9045
0.9146
0.9705
0.9717
Abbreviations: α = alpha; FA = final analysis; HR = hazard ratio; IA = interim analysis; N = number
1.
Percentage of total planned events at the interim analysis.
2.
p (1-sided) is the nominal alpha for group sequential testing.
3.
HR at bound is the approximate HR required to reach an efficacy bound.
4.
P (Cross if HR = 1) is the probability of crossing a bound under the null hypothesis.
5.
P (Cross if HR = 0.7) is the probability of crossing a bound under the alternative hypothesis.
Note: Number of events and timing of analyses are estimated.
9.8.2.3
Overall Survival
The study will test OS at IA2, IA3 and FA. Following the multiplicity strategy as outlined in 
Figure 3, the OS hypothesis may be tested at α=0.019 (initially allocated alpha), or 
α=0.023995 (if the PFS null hypothesis is rejected but not the ORR hypothesis), or α=0.025 
(if both the PFS and ORR null hypotheses are rejected). Table 19 shows the bounds and 
boundary properties for OS hypothesis testing derived using a Lan-DeMets spending 
function approximating O’Brien-Fleming bounds. 
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Table 19
Efficacy Boundaries and Properties for Overall Survival Analyses
Analysis
Value
α = 0.019
α = 0.023995
α = 0.025
IA 2: 59%1
N: 714
Events: ~ 264
Month: 26
Z
2.8338 
2.7114
2.6895 
p (1-sided)2
0.0023 
0.0033
0.0036 
HR at bound3
0.7051 
0.7159
0.7178 
P (Cross) if HR = 14
0.0023 
0.0033
0.0036 
P (Cross) if HR = 0.7255
0.4113 
0.4594
0.4679 
IA 3: 82%1
N: 714
Events: ~ 364
Month: 36
Z
2.3744 
2.2723
2.254 
p (1-sided)2
0.0088 
0.0115
0.0121 
HR at bound3
0.7795 
0.788
0.7895 
P (Cross) if HR = 14
0.0095 
0.0126
0.0132 
P (Cross) if HR = 0.7255
0.7601 
0.7911
0.7963 
FA
N: 714
Events: ~ 445
Month: 47
Z
2.1436 
2.0524
2.0360 
p (1-sided)2
0.0160
0.0201
0.0209 
HR at bound3
0.8160 
0.8231
0.8244 
P (Cross) if HR = 14
0.0190 
0.0240
0.0250 
P (Cross) if HR = 0.7255
0.9000
0.9155
0.9180
Abbreviations: α = alpha; FA = final analysis; HR = hazard ratio; IA = interim analysis; N = number
1.
Percentage of total planned events at the interim analysis.
2.
p (1-sided) is the nominal alpha for group sequential testing.
3. HR at bound is the approximate HR required to reach an efficacy bound.
4. P (Cross if HR = 1) is the probability of crossing a bound under the null hypothesis.
5. P (Cross if HR = 0.725) is the probability of crossing a bound under the alternative hypothesis.
Note: Number of events and timing of analyses are estimated.
The bounds provided in Table 18 and Table 19 above are based on the assumption that the 
expected number of PFS events at IA2 and IA3 (FA for PFS) are 420 and 480, respectively, 
and number of OS events at IA2, IA3 and FA are 264, 364, and 445, respectively. At the time 
of an analysis, the observed number of events may differ substantially from the expected. To 
avoid overspending at an IA and leave reasonable alpha for the FA, the minimum alpha-
spending strategy will be adopted. At an IA, the information fraction used in Lan-DeMets 
spending function to determine the alpha-spending at the IA will be based on the minimum 
of the expected information fraction and the actual information fraction at each analysis. 
Specifically,  

In the scenario that the events accrue slower than expected and the observed number of 
events is less than the expected number of events at a given analysis, the information 
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fraction will be calculated as the observed number of events at the IA over the target 
number of events at FA. 

In the scenario that the events accrue faster than expected and the observed number of 
events exceeds the expected number of events at a given analysis, then the information 
fraction will be calculated as the expected number of events at the IA over the target 
number of events at FA.
The FA will use the remaining Type I error that has not been spent at the earlier analyses. 
The event counts for all analyses will be used to compute correlations.
Of note, while the information fraction used for alpha-spending calculation will be the 
minimum of the actual information fraction and the expected information fraction, the 
correlations required for deriving the bounds will still be computed using the actual 
information fraction based on the observed number of events at each analysis over the target 
number of events at FA.
The minimum spending approach assumes timing is not based on any observed Z-value and 
thus the Z test statistics used for testing conditioned on timing are multivariate normal. Given 
the probabilities derived with the proposed spending method, the correlations based on actual 
event counts are used to compute bounds that control the Type I error at the specified alpha 
level for a given hypothesis conditioned on the IA timing. Since this is true regardless of 
what is conditioned on, the overall Type I error for a given hypothesis unconditionally is 
controlled at the specified level. By using more conservative spending early in the study, 
power can be retained to detect situations where the treatment effect may be delayed.
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Efficacy Analyses
Part 1
Approximately 12 participants will be enrolled in Part 1. The total sample size is based on 
clinical considerations and not statistical considerations.
Part 2
The study will randomize ~714 participants in a 1:1 ratio into each arm. PFS and OS are 
primary endpoints for the study, with ORR and DOR as the secondary endpoints.
With ~ 420 participants with at least 9 months of follow-up, the study has ~ 83% power to 
detect a 20% point difference in ORR between an underlying 48% ORR in the control arm 
and a 68% ORR in the experimental arm at an initially assigned 0.001 (one-sided) 
significance level. 
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For the PFS endpoint, based on a target number of ~ 480 events at the final PFS analysis and 
1 IA at approximately 88% of the target number of events, the study has approximately 90% 
power to detect a HR of 0.7 at an initially assigned 0.005 (one-sided) significance level.
For the OS endpoint, based on a target number of ~ 445 events and 2 IAs at approximately 
59% and 82% of the target number of events, the study has approximately 90% power to 
detect a HR of 0.725 at an initially assigned 0.019 (-one-sided) significance level.
Based on KEYNOTE-189 data, the above sample size and power calculations for PFS and 
OS assume the following:
•
PFS follows a piecewise exponential distribution, with the first piece median as 
8.8 months and monthly hazard rate as 0.08 up to 15 months, and second piece median as 
17 months and monthly hazard rate as 0.04 for the control group 
•
OS follows an exponential distribution, with a median of 22 months for the control group
•
Enrollment period is approximately 18 months
•
Annual drop-out rate is 15% and 2% for PFS and OS, respectively
•
Follow-up period is approximately 18 and 29 months for PFS and OS, respectively, after 
the last participant is randomized
The sample size and power calculations were performed in R (package “gsDesign”).
Extension Study in China
To evaluate the consistency of efficacy and safety in the population in China compared with 
the global population, after completion of global study enrollment, participants in China will 
continue to be randomized in a 1:1 ratio into the lenvatinib + pembrolizumab + platinum 
doublet chemotherapy arm and the matching placebo + pembrolizumab + platinum doublet 
chemotherapy arm until the planned sample size of approximately 200 participants in China 
is reached. Participants in China randomized after completion of enrollment in the global 
study will not be included in the analysis of the global study.
9.10
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
between-treatment effect for PFS, OS, and ORR (with a nominal 95% CI) will be estimated 
and plotted by treatment arm within each category of the following classification variables:
•
Stratification factors
•
PD-L1 TPS (<50% vs. ≥50%)
•
Geographic site (East Asian vs. non-East Asian)
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•
ECOG performance status at Screening (0 vs. 1)
•
PD-L1 TPS (<1%, 1% to 49%, ≥50%)
•
PD-L1 TPS (<1%, ≥1%)
•
Age category (<65 years, ≥65 years)
•
Sex (female, male)
•
Race (white, nonwhite)
•
Brain metastasis (presence vs. absence at Screening)
•
Liver metastasis (presence vs. absence at Screening)
•
Smoking status (never vs. former/current smoker)
•
Investigator’s choice of chemotherapy
The consistency of the treatment effect will be assessed using descriptive statistics for each 
category of the subgroup variables listed above. If the number of participants in a category of 
a subgroup variable is <10% of the ITT population, the subgroup analysis will not be 
performed for this category of the subgroup variable, and this subgroup variable will not be 
displayed in the forest plot. Unless further specified in the sSAP, the subgroup analyses for 
PFS and OS will be conducted using an unstratified Cox model, and the subgroup analyses 
for ORR will be conducted using the unstratified Miettinen and Nurminen method.
9.11
Compliance (Medication Adherence)
Drug accountability data for study intervention will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
9.12
Extent of Exposure
The extent of exposure for a participant is defined as the number of cycles in which the 
participant received study intervention. Summary statistics will be provided on extent of 
exposure for the APaT population.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and 
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities 
and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, 
sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to 
successfully conduct the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts 
to raise awareness of clinical trial opportunities in various communities. MSD will seek to engage 
underrepresented groups and those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to those who will ultimately 
use the products under investigation.
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3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
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D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
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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 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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10.1.4
Committees Structure
10.1.4.1
Steering Committee
This study will be conducted in consultation with a Steering Committee. The Steering 
Committee is composed of:

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 Executive Oversight Committee (EOC) is comprised of members of Sponsor Senior 
Management. The EOC will receive and decide upon any recommendations made by the
DMC or Steering Committee regarding the study.
10.1.4.3
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7, Interim 
Analysis) and recommend to the EOC whether the study should continue in accordance with 
the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team OR external 
collaborating organization protocol team; meeting facilitation; the study governance 
structure; and requirements for and proper documentation of DMC reports, minutes, and 
recommendations will be described in the DMC charter that is reviewed and approved by all 
the DMC members.
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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 International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of GCP); and all applicable federal, state and local laws, rules and 
regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Studies.
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The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
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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 stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 20 will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study if determined necessary 
by the investigator or required by local regulations.

Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at monthly intervals during intervention.
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the end of relevant systemic exposure and correspond with the time 
frame for female participant contraception in Section 5.1.
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the subject's participation in the study.
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Table 20
Protocol-required Safety Laboratory Assessments
Hematology
Comprehensive 
Chemistry Panel
Urinalysis
Other
Hematocrit
Hemoglobin
Platelet count
RBC
WBC count with 
differential (absolute 
or percentage):
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Albumin
Alkaline phosphatase
ALT
AST
Carbon dioxide (CO2 or 
Bicarbonate)a
Calcium
Chloride
Creatinine
Glucose
Magnesium
Phosphorus
Potassium
Sodium
Total bilirubin
Direct bilirubin, if total 
bilirubin is elevated 
above the upper limit of 
normal
Total protein
BUN or Ureab
Amylase
Lipase
Blood
Glucose
Protein
Specific gravity
Microscopic 
examination, if 
abnormal results are 
noted
Follicle-stimulating hormone 
(FSH)c
Highly sensitive serum or 
urine human chorionic 
gonadotropin (hCG) 
pregnancy testd
Hepatitis B and C testinge,f
HIV testingf
PT/INR and aPTT/PTT
Total T3, FT4, and TSHg,h
Plasma sample for lenvatinib 
PK
Serum for pembrolizumab 
PK
Antipembrolizumab 
antibodies
Blood sample for carboplatin 
PK
Blood sample for cisplatin 
PK
Blood sample for pemetrexed 
PK
Blood for genetic analysis
Blood for serum biomarkers
Blood for RNA analysis
Blood for circulating tumor 
nucleic acids
Blood for plasma biomarkers
Abbreviations: ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; DNA = deoxyribonucleic acid; FT3 = free triiodothyronine; FT4 = free 
thyroxine; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; INR = international normalized ratio; PK = pharmacokinetics; PT = prothrombin time; PTT = 
partial thromboplastin time; RNA = ribonucleic acid; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating 
hormone; WBC = white blood cell; WOCBP = women of childbearing potential
a
Carbon dioxide or bicarbonate, only if available as standard of care in the region
b
BUN or urea (one or the other should be collected per institutional standard).
c
If necessary, to check menopausal status.
d
Perform on WOCBP only 24 hours before first dose. Pregnancy tests must be repeated before every cycle.
e
HBsAg or HBV-DNA. HCV-RNA (qualitative) or HCV antibody.
f
Not required unless mandated by local health authorities.
g
After Cycle 1, participants may be dosed while thyroid function test results are pending.
h
Free T3/T4 is acceptable when total T3/T4 cannot be determined.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
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Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
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•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
•
Is a new cancer (that is not a condition of the study)
•
Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
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•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs,
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI Common Terminology for Adverse Events 
(CTCAE), version 4.0. Any AE that changes CTCAE grade over the course of a given 
episode will have each change of grade recorded on the AE CRFs/worksheets.
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL).
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
• Grade 4: Life-threatening consequences; urgent intervention indicated.
• Grade 5: Death related to AE.
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed
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document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment 
(pill count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE 
compatible with a drug-induced effect (applies to studies with investigational 
medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors.
-
Dechallenge: Was the Sponsor’s product discontinued or 
dose/exposure/frequency reduced?
-
If yes, did the AE resolve or improve?
-
If yes, this is a positive dechallenge.
-
If no, this is a negative dechallenge.
-
(Note: This criterion is not applicable if: (1) the AE resulted in death or 
permanent disability; (2) the AE resolved/improved despite continuation of the 
Sponsor’s product; (3) the study is a single-dose drug study; or (4) Sponsor’s 
product(s) is/are only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this 
study?
-
If yes, did the AE recur or worsen?
-
If yes, this is a positive rechallenge.
-
If no, this is a negative rechallenge.
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(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
-
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor's product relationship:
-
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
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•
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.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.
•
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
•
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
•
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
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•
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 e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
This section is not applicable.
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
Premenarchal
Premenopausal female with 1 of the following:
Documented hysterectomy
Documented bilateral salpingectomy
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than 
the above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
Postmenopausal female
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause.
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or 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
Female participants of childbearing potential are eligible to participate if they agree to 
consistently and correctly use of a highly effective method of contraception as described in 
Table 21 during the protocol defined- time frame in Section 5.1.
Table 21
Highly Effective Contraception Methods
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
Progestogen-only subdermal contraceptive implantb
Intrauterine hormone-releasing system (IUS)c
Intrauterine device (IUD)
Bilateral tubal occlusion
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used. A spermatogenesis 
cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview.
Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
a. Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b. If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive implants are limited to those which inhibit ovulation.
c. IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
-
Periodic abstinence (calendar, symptothermal, 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).
In addition, during treatment and up to 180 days after the last dose of treatment with 
chemotherapeutic agents, female participants must also agree not to donate eggs (ova, 
oocytes) to others or freeze/store eggs for their own use for the purpose of reproduction.
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Pregnancy Testing
All women who are being considered for participation in the study, and who are not 
surgically sterilized or postmenopausal, must be tested for pregnancy within 24 hours of the 
first dose of study intervention. If a urine test is positive or not evaluable, a serum test will be 
required. Participants must be excluded/discontinued from the study in the event of a positive 
test result. Repeated pregnancy test (such as monthly testing) may be conducted if required 
by local regulation. WOCBP should only be included after a negative highly sensitive urine 
or serum pregnancy test.
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: Description of the iRECIST Process for Assessment of Disease 
Progression
iRECIST is based on RECIST 1.1 but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor 
response and progression, and to guide decisions about changes in management.
Assessment at Screening and 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 radiological PD by RECIST 1.1 as determined by the 
investigator, the investigator will decide whether to continue a participant on study 
intervention until repeat scans are obtained (using iRECIST for participant management [see 
Table 10 and Figure 2]). 
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:
•
Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir
o Note: the iRECIST publication uses the terminology “sum of measurements,” but 
“sum of diameters” will be used in this protocol, consistent with the original 
RECIST 1.1 terminology.
•
Unequivocal progression of nontarget lesion(s) identified at baseline
•
Development of new lesion(s)
iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, 
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression.
At this visit, target and 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 by RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target. 
The sum of diameters of these lesions will be calculated and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively 
as New Lesions – Nontarget.
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Assessment at the Confirmatory Scans
On the confirmatory scans, 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 (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:
•
Any of the factors that were the basis for the iUPD at the previous visit show 
worsening
o
For target lesions, worsening is a further increase in the sum of diameters of 
≥5 mm, compared to any prior iUPD time point
o
For 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
o
For new lesions, worsening is any of these:
◦
An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD 
time point 
◦
Visible growth of new nontarget lesions 
◦
The appearance of additional new lesions
•
Any new factor appears that would have triggered PD by RECIST 1.1
Persistent iUPD
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 scans for confirmation are to be scheduled 4 to 8 weeks from the scans on which 
iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation scan proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
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Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:
•
None of the progression-confirming factors identified above occurs, AND
•
The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset”. This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Scan
If repeat scans do not confirm PD and the participant continues to be clinically stable, study 
intervention is to continue. The regular scan schedule is to be followed. If PD is confirmed, 
participants may be discontinued from study intervention.
NOTE: If a participant has confirmed radiographic progression (iCPD) and clinically 
meaningful benefit, study intervention may be considered following consultation with the 
Sponsor. In this case, if study intervention is continued, tumor scans are to be performed 
following the intervals outlined in the SoA (Section 1.3).
Detection of Progression at Visits After Pseudo-progression Resolves
After resolution of pseudo-progression (ie, after iSD/iPR/iCR), another instance of 
progression (another 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 pseudo-progression. 
The nadir is always the smallest sum of diameters seen during the entire study, 
either before or after an instance of pseudo-progression.
•
Nontarget lesions
-
If nontarget lesions have never shown unequivocal progression, their doing so for 
the first time results in iUPD.
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-
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 the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.
The decision process on the subsequent iUPD is identical to the iUPD confirmation process 
for the initial PD, with one exception, which can occur if new lesions had occurred at a prior 
instance of iUPD, had not resolved, then worsened (increase in size or number) leading to the 
second iUPD. If new lesion worsening has not resolved at the confirmatory scan, 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 new or worsening causes of progression 
indicates iCPD.
Additional details about iRECIST are provided in the iRECIST publication [Seymour, L., et 
al 2017].
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Germany-specific Requirements
1. Exclusion Criterion 8: HIV testing is mandatory.
2. Exclusion Criterion 9: Hepatitis B and C testing is mandatory.
3. Exclusion Criterion 13: TB testing is mandatory.
4. 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.
5. Additional pregnancy tests at monthly intervals up to 120 days after the last dose of 
Pembrolizumab and/or Lenvatinib/Placebo and up to 180 days after the last dose of 
chemotherapeutic agents should also be performed if the participant initiates new 
anticancer therapy in that timeframe.
10.7.2
UK-specific Requirements
1. Section 6.5.2, Prohibited Concomitant Medications: Live vaccines must not be 
administered for 90 days after the last dose of study intervention.
2. In extenuating circumstances only, when a central supply of pembrolizumab is not 
readily available, pembrolizumab may be sourced locally after consultation with and
approval by the Sponsor.
10.7.3
Japan-specific Requirements
1. For the assistance to early diagnosis of pneumonitis/ILD in study participants, the 
following items such as pulse oximetry monitoring (SpO2), CRP, KL-6, and SP-D will be 
measured in this study. These items should be measured in the following timing.
o
SpO2: at the timing of vital sign assessment.
o
CRP, KL-6 and SP-D: at Screening*, predose of Day 1 of every cycle, end of 
treatment and Safety Follow-up Visit (30 days after last dose).
1. * Should be measured at the timing of clinical laboratory tests (such as 
hematology/ chemistry).
2. In the case that pneumonitis/ILD occurs regardless of causality with study medication, an 
independent ILD evaluation committee will conduct adjudication of cases of the 
pneumonitis/ILD. For this purpose, relevant data such as chest imaging (from the 
baseline to the recovery of pneumonitis/ILD) will be submitted to MSD K.K.
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10.7.4
Argentina-specific Requirements
1. Exclusion Criterion 8: HIV testing is mandatory
2. Exclusion Criterion 9: Hepatitis B and C testing is mandatory
10.7.5
France-specific Requirements
Treatment with pembrolizumab should be permanently discontinued in cases of confirmed 
Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN).
10.7.6
Canada-specific Requirements
1. Please refer to the current lenvatinib product monograph for management of AEs 
associated with lenvatinib administration.
2. Section 6.6.1.9 - Management of Gastrointestinal Perforation or Fistula Formation:
Lenvatinib should be discontinued in any participant who develops gastrointestinal 
perforation of any grade or ≥ Grade 3 fistula.
3. Section 6.6.2.1 - Dose Modification and Toxicity Management for Immune-related AEs 
Associated with Pembrolizumab:
Pembrolizumab should be permanently discontinued in case of confirmed TEN or SJS.
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
ADA
Antidrug antibody
ADL
Activities of daily living  
AE
Adverse event 
AJCC
American Joint Committee on Cancer
ALK
Anaplastic lymphoma kinase
ALT
Alanine transaminase
APaT
All Participants as Treated
ASCO
American Society of Clinical Oncology
AST
Aspartate transaminase
AUC
Area under the plasma drug concentration time curve
BICR
Blinded independent central review
BP
Blood pressure
CI
Confidence interval
cLDA
Constrained longitudinal data analysis
CNS
Central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
CR
Complete response
CRF
Case Report Form 
CRP
C-reactive protein
CSF
Colony-stimulating factor
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
CTFG
Clinical Trial Facilitation Group 
CTLA-4
Cytotoxic T-lymphocyte-associated protein 4
CVA
Cerebrovascular accident
CYP
Cytochrome P450
DILI
Drug-induced liver injury
DLT
Dose-limiting toxicity
DMC
Data Monitoring Committee 
DNA
Deoxyribonucleic acid 
DOR
Duration of response
DTC
Differentiated thyroid cancer
ECG
Electrocardiogram 
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
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Abbreviation
Expanded Term
EGFR
Epidermal growth factor receptor
EDC
Electronic data collection 
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EORTC
European Organisation for Research and Treatment of Cancer
EQ
EuroQoL
FA
Final analysis
FAS
Full Analysis Set
FDA
US Food and Drug Administration
FFPE
Formalin fixed, paraffin-embedded
FGF
Fibroblast growth factor
FGFR
Fibroblast growth factor receptor
FSH
Follicle stimulating hormone 
GCP
Good Clinical Practice 
HBsAg
Hepatitis B surface antigen
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HR
Hazard ratio
HRQoL
Health related quality of life
HRT
Hormone replacement therapy
IA
Interim analysis
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use
iCPD
iRECIST-confirmed radiographic progression
iCR
iRECIST complete response
iCRO
imaging Contract Research Organization
IEC
Independent Ethics Committee
IgG4
Immunoglobulin G4
IHC
Immunohistochemistry
ILD
interstitial lung disease
IND
Investigational New Drug 
iPR
iRECIST partial response
irAE
Immune-related AEs
IRB
Institutional Review Board 
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Abbreviation
Expanded Term
iRECIST 1.1
Response Evaluation Criteria in Solid Tumors version 1.1 for immune-
based therapeutics
iSD
iRECIST stable disease
ITT
Intent-to-treat
IUD
Intrauterine device
iUPD
iRECIST-unconfirmed progressive disease
IUS
Intrauterine hormone-releasing system
IV
Intravenous
1L
Front-line (or first-line)
KL-6
Krebs von den Lungen-6 antigen
LMWH
Low molecular-weight heparin
LVEF
Left ventricular ejection fraction
mAb
Monoclonal antibody
MASCC
Multinational Association of Supportive Care in Cancer
MHRA
Medicines and Healthcare products Regulatory Agency
MRI
magnetic resonance imaging
mRNA
messenger RNA
MTD
Maximum tolerated dose 
MUGA
Multigated acquisition scan
NCI
National Cancer Institute
NSCLC 
Non-small cell lung cancer
NYHA
New York Heart Association
ONJ
Osteonecrosis of the jaw
ORR
Objective response rate
OS
Overall survival
PD
Progressive disease
PD 1
Programmed cell death 1
PD-L1
Programmed cell death ligand 1
PD-L2
Programmed cell death ligand 2
PDGFRα
Platelet-derived growth factor receptor-alpha
PFS
Progression-free survival
Pgp
P glycoprotein
PK
Pharmacokinetic
PR
Partial response
PRES
Posterior reversible encephalopathy syndrome
PRO
Patient-reported outcome
PS
Performance status
qd
Once daily
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Abbreviation
Expanded Term
QoL
Quality of life
QLQ
Quality of Life Questionnaire
QLQ-LC13
Quality of Life Questionnaire and Lung Cancer Module 13
QLQ-C30
Quality of Life Questionnaire Core 30
Q3W
Every 3 weeks
RCC
Renal cell carcinoma
RECIST 1.1
Response Evaluation Criteria in Solid Tumors version 1.1
RNA
Ribonucleic acid
RP2D
Recommended Phase 2 dose
ROS1
ROS proto-oncogene 1
RPLS
Reversible posterior leukoencephalopathy syndrome
RTKi
Receptor tyrosine kinase inhibitor
SAE
Serious adverse event 
SD
Stable disease
SJS
Stevens-Johnson syndrome
SoA
Schedule of Activities
SOC
Standard of care
SP-D
Surfactant protein D
SpO2
blood oxygen saturation
sSAP
Supplemental statistical analysis plan
TAM
Tumor-associated macrophage
TEN
Toxic epidermal necrolysis
TPS
Tumor proportion score
TTD
Time to true deterioration
UPCR
Spot urine protein-to-creatinine ratio
VAS
Visual analog scale
VEGF
Vascular endothelial growth factor 
VEGFR
Vascular endothelial growth factor receptor
WOCBP
Woman/women of childbearing potential 
WONCBP
Woman/women of nonchildbearing potential 
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10.9
Appendix 9: MASCC 2016 Guidelines
Rolia F, Molassiotis A, Herrstedt J, et al. 2016 MASCC and ESMO guideline update for the 
prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea 
and vomiting in advanced cancer patients. Ann Oncol (2016) 27 (suppl_5): v119-v133, 2016.
http://www.mascc.org/antiemetic-guidelines
Investigators may use local equivalent or more current guidelines, if available.
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11
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