A Phase 2, Randomized, Open-label Three-arm Clinical Study to Evaluate the Safety and Efficacy of Lenvatinib (E7080/MK-7902) in Combination With Pembrolizumab (MK-3475) Versus Standard of Care Chemotherapy and Lenvatinib Monotherapy in Participants With Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC) That Have Progressed After Platinum Therapy and Immunotherapy (PD-1/PD-L1 Inhibitors) (LEAP-009)
Phase: PHASE2
Conditions: Squamous Cell Carcinoma of Head and Neck
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
A Phase 2, randomized, open-label three-arm clinical study to 
evaluate the safety and efficacy of lenvatinib (E7080/MK-7902) in 
combination with pembrolizumab (MK-3475) versus standard of 
care chemotherapy and lenvatinib monotherapy in participants with 
recurrent/metastatic head and neck squamous cell carcinoma (R/M 
HNSCC) that have progressed after platinum therapy and 
immunotherapy (PD-1/PD-L1 inhibitors) (LEAP-009)
NCT04428151
25-NOV-2024

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TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 2, randomized, open-label three-arm clinical study to evaluate the 
safety and efficacy of lenvatinib (E7080/MK-7902) in combination with pembrolizumab 
(MK-3475) versus standard of care chemotherapy and lenvatinib monotherapy in participants 
with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) that have 
progressed after platinum therapy and immunotherapy (PD-1/PD-L1 inhibitors) (LEAP-009)
Protocol Number: 009-07 (E7080-G000-228)
Compound Number: MK-7902
Sponsor Name: Merck Sharp & Dohme LLC (hereafter called the Sponsor or MSD)
The study is co-funded by MSD and Eisai.
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
NCT
04428151
EU CT
2022-500820-31
EudraCT
2019-000569-19
JAPIC-CT
Not Applicable
WHO
Not Applicable
UTN
Not Applicable
IND
142277
Approval Date:   25 November 2024
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 7 
(Global)
25-NOV-2024
This amendment addresses a change in strategy
to stop the study based on the results of a 
periodic review of safety data using a data cutoff 
date of 31-MAY-2024 that was conducted by the 
eDMC. At the request of the eDMC, OS data 
were provided for review, though there was no 
preplanned statistical analysis for OS. At this 
safety analysis, the OS Kaplan-Meier curves did 
not favor pembrolizumab + lenvatinib versus 
SOC chemotherapy.
Amendment 6 
(Global)
08-JUL-2024
This change was made to address sponsor’s 
strategy to revise the primary endpoint from OR 
to OS, based on emerging external data for this 
patient population. 
Amendment 5 
(Global)
08-SEP-2022
To no longer require the most recent treatment 
prior to study entry to be anti-PD-1/PD-L1 
treatment.  
Amendment 4 
(Global)
30-MAR-2021
To update the dose modification table for 
pembrolizumab. To incorporate lenvatinib 
program level updates. To specify for 
participants of the UK, Romania, and Portugal 
that length of contraception for male participants 
receiving paclitaxel should be at least 6 months 
from the last dose to be consistent with the 
paclitaxel SmPC. To provide guidance regarding 
osteonecrosis of the jaw for participants treated 
with lenvatinib.
Amendment 03 
(UK-specific)
05-NOV-2020
To add updates from Global Protocol 
Amendment 1.
Amendment 02 
(UK-specific)
05-AUG-2020
To address regulatory authority requests, added 
precautionary measures for participants in the 
UK to be in accordance with the Summary of 
Product Characteristics of cetuximab, paclitaxel, 
docetaxel, and capecitabine. Also, for 
participants in the UK, required live vaccines to 
not be administered until 120 days after the last 
dose of pembrolizumab.
Note: This amendment is based on the original 
protocol per regulatory request.
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Document
Date of Issue
Overall Rationale
Amendment 1 
(Global)
24-JUL-2020
To clarify that medications known to prolong 
QT interval must be used cautiously; to clarify 
that independent retrospective analysis of 
radiographic response to pre-study treatment 
with anti-PD-1/PD-L1 therapy may occur; and to 
provide program-level updates, corrections, and 
clarifications.
Original Protocol
16-MAR-2020
Not applicable
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 07
Overall Rationale for the Amendment:
This amendment addresses a change in strategy to stop the study based on the results of a
periodic review of safety data using a data cutoff date of 31-MAY-2024 that was conducted 
by the eDMC. At the request of the eDMC, OS data were provided for review, though there 
was no preplanned statistical analysis for OS. At this safety analysis, the OS Kaplan-Meier 
curves did not favor pembrolizumab + lenvatinib versus SOC chemotherapy.
Summary of Changes Table
Section 
Number and 
Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 1.1, 
Synopsis
Hypotheses, Objectives, and Endpoints: A 
note has been added (in alignment with the 
study-specific investigator letter dated 05-
SEP-2024) with information regarding the 
results of a periodic review of safety data, 
the subsequent decision of the Sponsor to 
discontinue the combination of lenvatinib 
+ pembrolizumab (Arm 1) and lenvatinib 
monotherapy (Arm 3) from the study, and 
which analyses will or will not be 
conducted going forward. It also includes 
instructions for discontinuation of study 
interventions and a high-level summary of 
the modified protocol study procedures to 
be implemented as a result of the decision 
to terminate the study.
These changes were made to address a 
change in strategy to stop the study based 
on the results of a periodic review of safety 
data using a data cutoff date of 31-MAY-
2024 that was conducted by the eDMC. At 
the request of the eDMC, OS data were 
provided for review, though there was no 
preplanned statistical analysis for OS. At 
this safety analysis, the OS Kaplan-Meier 
curves did not favor pembrolizumab +
lenvatinib versus SOC chemotherapy.
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Section Number and Name
Description of Change
Brief Rationale
Additional Changes
Throughout
Minor administrative, formatting, 
grammatical, and/or typographical 
changes were made throughout the 
document.
To ensure clarity and accurate 
interpretation of the intent of the 
protocol.
Section 1.1, Synopsis
Overall Design: Updated estimated 
duration of study to 5 years from the time 
of consent of first participant or legally 
acceptable representative until last 
contact.
To align with current projections for 
the study completion date.
Initial Treatment: Added text clarifying 
that participants in the SOC chemotherapy 
arm or lenvatinib monotherapy arm may 
not crossover to receive lenvatinib +
pembrolizumab at the time of disease 
progression.
Refer to the rationale for primary 
reason for amendment.
Second Course: Removed information on 
Second Course and added a note that this 
section is no longer applicable. 
Refer to the rationale for primary 
reason for amendment.
End of Treatment: Added information on 
extension study.
To give study participants who are 
discontinued the option to enroll in an 
extension study with pembrolizumab 
in combination with lenvatinib or 
lenvatinib monotherapy.
Study Governance Committees: Added a 
note below the table clarifying that the 
Executive Oversight Committee and Data 
Monitoring Committee are no longer 
applicable.
Refer to the rationale for primary 
reason for amendment.
Section 1.2, Schema
Figure 1: Added text to footnotes 
clarifying that participants in the SOC 
chemotherapy arm or lenvatinib 
monotherapy arm may not crossover to 
receive lenvatinib + pembrolizumab at the 
time of disease progression.
Refer to the rationale for primary 
reason for amendment.
Figure 2: Deleted this figure for Second 
Course.
Refer to the rationale for primary 
reason for amendment.
Added information on extension study.
Refer to the Section 1.1 rationale 
regarding the extension study.
Section 1.3, Schedule of 
Activities
Added text to specify which activities will 
or will not be performed for the remaining 
duration of the study.
Refer to the rationale for primary 
reason for amendment.
Section 1.3.4, Second Course
Removed the Second Course SoA and 
added a note that this section is no longer 
applicable.
Refer to the rationale for primary 
reason for amendment.
Section 2.3, Benefit/Risk 
Assessment
Added a note explaining that the study 
will be discontinued based on a periodic 
review of safety data.
Refer to the rationale for primary 
reason for amendment.
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Section Number and Name
Description of Change
Brief Rationale
Section 3, Hypotheses, 
Objectives, and Endpoints
A note has been added (in alignment with 
the study-specific investigator letter dated 
05-SEP-2024) with information regarding 
the results of a periodic review of safety 
data, the subsequent decision of the 
Sponsor to discontinue the combination of 
lenvatinib + pembrolizumab (Arm 1) and 
lenvatinib monotherapy (Arm 3) from the 
study, and which analyses will or will not 
be conducted going forward. It also 
includes instructions for discontinuation 
of study interventions and a high-level 
summary of the modified protocol study 
procedures to be implemented as a result 
of the decision to terminate the study.
Refer to the rationale for primary 
reason for amendment.
Section 4.1, Overall Design
A note has been added (in alignment with 
the study-specific investigator letter dated 
05-SEP-2024) with information regarding 
the results of an interim safety analysis, 
the subsequent decision of the Sponsor to 
remove the combination of lenvatinib +
pembrolizumab (Arm 1) and lenvatinib 
monotherapy (Arm 3) from the study, and 
which analyses will or will not be 
conducted going forward. It also includes 
instructions for discontinuation of study 
interventions and a high-level summary of 
the modified protocol study procedures to 
be implemented as a result of the decision 
to terminate the study.
Refer to the rationale for primary 
reason for amendment.
Added a statement that enrollment was 
completed on 05-SEP-2024.
Refer to the rationale for primary 
reason for amendment.
Added text clarifying that participants in 
the SOC chemotherapy arm or lenvatinib 
monotherapy arm may not crossover to 
receive lenvatinib + pembrolizumab at the 
time of disease progression.
Refer to the rationale for primary 
reason for amendment.
Removed information on Second Course
and added a note that this section is no 
longer applicable.
Refer to the rationale for primary 
reason for amendment.
Section 4.3.4, Maximum Dose 
Exposure for This Study
Added information on discontinued study 
arms.
Refer to the rationale for primary 
reason for amendment.
Removed information on Second Course 
treatment.
Refer to the rationale for primary 
reason for amendment.
Section 4.4, Beginning and End-
of-Study Definition
Updated estimated duration of study to 5 
years from first participant entered 
through long-term follow-up.
Refer to rationale for Section 1.1 
related to estimated duration of study.
Section 6.1, Study Intervention(s)
Administered
Added a note with instructions for 
discontinuation of study interventions.
Refer to the rationale for primary 
reason for amendment.
In Table 2, updated the cetuximab 
intervention type from drug to 
biological/vaccine.
To further specify drug intervention 
type.
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Section Number and Name
Description of Change
Brief Rationale
Section 6.5, Concomitant Therapy
Removed information on Second Course.
Refer to the rationale for primary 
reason for amendment.
Section 6.6, Dose Modification 
(Escalation/Titration/Other)
Added a note with instructions for 
discontinuation of study interventions.
Refer to the rationale for primary 
reason for amendment.
Section 6.7, Intervention After the 
End of the Study
Added information on extension study. 
Refer to the Section 1.1 rationale 
regarding the extension study.
Section 7.1, Discontinuation of 
Study Intervention
Added language to note that the text in 
this section is original protocol text that 
was retained for reference.
Refer to the rationale for primary 
reason for amendment.
Added new information that central tumor 
response assessments will no longer be 
performed, and scans will no longer be 
sent to the iCRO.
Refer to the rationale for primary 
reason for amendment.
Added guidance for discontinuing study 
treatment due to RECIST 1.1 disease 
progression. 
Refer to the rationale for primary 
reason for amendment.
Added text clarifying that participants 
continuing lenvatinib + pembrolizumab on 
initial or crossover treatment may be 
permitted to continue treatment beyond 
disease progression following Sponsor 
consultation.
Refer to the rationale for primary 
reason for amendment.
Added text clarifying that participants in 
the SOC chemotherapy arm or lenvatinib 
monotherapy arm may not crossover to 
receive lenvatinib + pembrolizumab at the 
time of disease progression.
Refer to the rationale for primary 
reason for amendment.
Section 8.1.1.1, General Informed 
Consent
Removed reference to Second Course.
Refer to the rationale for primary 
reason for amendment.
Section 8.1.5.2, Concomitant 
Medications
Removed information on Second Course.
Refer to the rationale for primary 
reason for amendment.
Section 8.2.1, Tumor Imaging and 
Assessment of Disease
Added new information that tumor 
response assessments by BICR will no 
longer be performed and scans will no 
longer be sent to the iCRO.
Refer to the rationale for primary 
reason for amendment.
Section 8.2.1.4, End of Treatment 
and Follow-up Tumor Scans
Added new information that tumor 
response assessments by BICR will no 
longer be performed and scans will no 
longer be sent to the iCRO.
Refer to the rationale for primary 
reason for amendment.
Section 8.2.1.5, Crossover 
Treatment Tumor Scans
Added new information that imaging
scans will no longer be sent to the iCRO.
Refer to the rationale for primary 
reason for amendment.
Added text clarifying that participants in 
the SOC chemotherapy arm or lenvatinib 
monotherapy arm may not crossover to 
receive lenvatinib + pembrolizumab at the 
time of disease progression.
Refer to the rationale for primary 
reason for amendment.
Section 8.2.1.6, Second Course 
Scans
Deleted all text in this section as Second 
Course treatment will not be performed.
Refer to the rationale for primary 
reason for amendment.
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Section Number and Name
Description of Change
Brief Rationale
Section 8.2.1.7, RECIST 1.1 
Assessment of Disease
Added new information that tumor 
response assessments by BICR will no 
longer be performed and scans will no 
longer be sent to the iCRO.
Refer to the rationale for primary 
reason for amendment.
Section 8.2.2, Patient Reported 
Outcomes
Added text to indicate that ePRO 
assessments will be discontinued.
Refer to the rationale for primary 
reason for amendment.
Section 8.4.5, Pregnancy and 
Exposure During Breastfeeding
Added information on partner pregnancy 
reporting.
Partner pregnancy reporting is 
required as this study contains 
genotoxic IMP.
Section 8.6, Pharmacokinetics
Added a statement that sample collection 
for PK and/or ADA, RNA analysis, and 
plasma/serum biomarkers has been 
discontinued.
Refer to the rationale for primary 
reason for amendment.
Section 8.8, Biomarkers
Added text to indicate biomarker sample 
collections have been discontinued.
Refer to the rationale for primary 
reason for amendment.
Section 8.10.2.2, Addition of 
Pembrolizumab Following 
Progression on Lenvatinib 
Monotherapy
Added text clarifying that participants in 
the lenvatinib monotherapy arm may not 
crossover to receive lenvatinib + 
pembrolizumab at the time of disease 
progression.
Refer to the rationale for primary 
reason for amendment.
Section 8.10.3, Second Course
Deleted all text in this section as Second 
Course treatment will not be performed.
Refer to the rationale for primary 
reason for amendment.
Section 8.10.5.1, Safety Follow-
up Visit
Removed information on Second Course.
Refer to the rationale for primary 
reason for amendment.
Section 8.10.5.2, Efficacy 
Follow-up Visits
Added new information that Efficacy 
Follow-up Visits will be discontinued, and 
participants in efficacy follow-up and 
survival follow-up should be discontinued 
from the study.
Refer to the rationale for primary 
reason for amendment.
Added new information that tumor 
response assessments by BICR will no 
longer be performed and scans will no 
longer be sent to the iCRO.
Refer to the rationale for primary 
reason for amendment.
Removed information on Second Course.
Refer to the rationale for primary 
reason for amendment.
Section 8.10.5.3, Survival 
Follow-up Contacts
Added new information that Survival 
Follow-up Visits will be discontinued, and 
those participants remaining on study 
treatment at the time of Amendment 07 
should continue to be monitored in the 
study through the AE reporting period.
Refer to the rationale for primary 
reason for amendment.
Section 9, Statistical Analysis 
Plan
Added a note to clarify the scope of 
analyses to be performed subsequent to 
the decision to terminate the study.
Refer to the rationale for primary 
reason for amendment.
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Section Number and Name
Description of Change
Brief Rationale
Section 9.1, Statistical Analysis 
Plan Summary
Section 9.4.3, Patient Reported 
Outcome Endpoints
Removed text from this section as PRO 
endpoints will not be analyzed.
Refer to the rationale for primary 
reason for amendment.
Section 9.5.3, PRO Analysis 
Population
Removed this section as PRO endpoints 
will not be analyzed.
Refer to the rationale for primary 
reason for amendment.
Section 9.6.1, Statistical Methods 
for Efficacy Analyses
Removed information on analyses that 
will no longer be performed in the study.
Refer to the rationale for primary 
reason for amendment.
Removed reference to Second Course 
treatment.
Refer to the rationale for primary 
reason for amendment.
Section 9.6.1.1, Overall Survival
Removed information on analyses that 
will no longer be performed in the study.
Refer to the rationale for primary 
reason for amendment.
Section 9.6.1.2, Progression-Free 
Survival
Removed information on analyses that 
will no longer be performed in the study.
Refer to the rationale for primary 
reason for amendment.
Section 9.6.1.3, Objective 
Response Rate
Removed information on analyses that 
will no longer be performed in the study.
Refer to the rationale for primary 
reason for amendment.
Section 9.6.1.5, Analysis Strategy 
for Key Efficacy Variables
Removed information on analyses that 
will no longer be performed in the study.
Refer to the rationale for primary 
reason for amendment.
Section 9.6.2, Statistical Methods 
for Safety Analyses
Removed reference to Second Course 
treatment.
Refer to the rationale for primary 
reason for amendment.
Section 9.6.3, Statistical Methods 
for Patient Reported Outcome 
Analyses
Removed this section as PRO endpoints 
will not be analyzed.
Refer to the rationale for primary 
reason for amendment.
Former Section 9.6.4 renumbered to 
current Section 9.6.3.
Renumbering changes due to deletion 
of Section 9.6.3.
CCI
CCI
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Section Number and Name
Description of Change
Brief Rationale
CCI
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................20
1.1
Synopsis.................................................................................................................20
1.2
Schema ..................................................................................................................27
1.3
Schedule of Activities...........................................................................................28
1.3.1
Initial Treatment: Lenvatinib + Pembrolizumab (Arm 1) or Lenvatinib 
Monotherapy (Arm 3)..................................................................................29
1.3.2
Initial Treatment: SOC Chemotherapy (Arm 2)..........................................41
1.3.3
Crossover Treatment....................................................................................53
1.3.4
Second Course .............................................................................................62
2
INTRODUCTION..........................................................................................................63
2.1
Study Rationale....................................................................................................63
2.2
Background ..........................................................................................................65
2.2.1
Pharmaceutical and Therapeutic Background .............................................65
2.2.1.1
Pembrolizumab ..................................................................................65
2.2.1.2
Lenvatinib ..........................................................................................66
2.2.1.3
Pembrolizumab Plus Lenvatinib........................................................67
2.2.2
Preclinical and Clinical Studies ...................................................................67
2.2.2.1
Completed Studies with Pembrolizumab and Lenvatinib..................67
2.2.3
Ongoing Clinical Studies of Pembrolizumab and Lenvatinib .....................67
2.3
Benefit/Risk Assessment......................................................................................73
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................74
4
STUDY DESIGN............................................................................................................77
4.1
Overall Design......................................................................................................77
4.2
Scientific Rationale for Study Design.................................................................80
4.2.1
Rationale for Endpoints ...............................................................................81
4.2.1.1
Efficacy Endpoints.............................................................................81
4.2.1.2
Safety Endpoints................................................................................81
4.2.1.3
Exploratory Endpoints .......................................................................82
4.2.2
Rationale for Selected Standard-of-care Chemotherapies ...........................85
4.3
Justification for Dose...........................................................................................86
4.3.1
Pembrolizumab ............................................................................................86
4.3.2
Lenvatinib ....................................................................................................87
4.3.3
SOC Chemotherapy .....................................................................................87
4.3.4
Maximum Dose Exposure for This Study ...................................................87
4.4
Beginning and End-of-Study Definition ............................................................88
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4.4.1
Clinical Criteria for Early Study Termination .............................................88
5
STUDY POPULATION ................................................................................................89
5.1
Inclusion Criteria.................................................................................................89
5.2
Exclusion Criteria................................................................................................94
5.3
Lifestyle Considerations......................................................................................97
5.3.1
Meals and Dietary Restrictions....................................................................97
5.4
Screen Failures.....................................................................................................97
5.5
Participant Replacement Strategy......................................................................97
6
STUDY INTERVENTION............................................................................................98
6.1
Study Intervention(s) Administered...................................................................98
6.2
Preparation/Handling/Storage/Accountability ...............................................101
6.2.1
Dose Preparation........................................................................................101
6.2.2
Handling, Storage, and Accountability......................................................101
6.3
Measures to Minimize Bias: Randomization and Blinding............................102
6.3.1
Intervention Assignment............................................................................102
6.3.2
Stratification...............................................................................................102
6.3.3
Blinding......................................................................................................102
6.4
Study Intervention Compliance........................................................................102
6.5
Concomitant Therapy........................................................................................102
6.5.1
Prohibited Concomitant Medications ........................................................104
6.5.2
Drug Interactions .......................................................................................105
6.5.3
Rescue Medications and Supportive Care .................................................105
6.6
Dose Modification (Escalation/Titration/Other).............................................106
6.6.1
Lenvatinib Dose Modification and Toxicity Management........................106
6.6.1.1
Management of Hypertension..........................................................108
6.6.1.2
Management of Proteinuria..............................................................110
6.6.1.3
Management of Diarrhea .................................................................111
6.6.1.4
Management of Hepatotoxicity........................................................111
6.6.1.5
Management of Thromboembolic Events........................................111
6.6.1.6
Management of Posterior Reversible Encephalopathy 
Syndrome/Reversible Encephalopathy Syndrome/ Reversible 
Posterior Leukoencephalopathy Syndrome .....................................111
6.6.1.7
Management of Hypocalcemia ........................................................112
6.6.1.8
Management of Hemorrhage ...........................................................112
6.6.1.9
Management of Gastrointestinal Perforation or Fistula Formation .112
6.6.1.10
Management of QT Prolongation ....................................................112
6.6.1.11
Management of Osteonecrosis of the Jaw .......................................112
6.6.2
Dose Modifications for Overlapping Toxicities ........................................112
6.6.3
Pembrolizumab Dose Modifications..........................................................114
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6.6.3.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).....................................................................................114
6.6.3.2
Dose Modification and Toxicity Management of Infusion 
Reactions Related to Pembrolizumab..............................................120
6.6.4
Other Allowed Dose Interruptions.............................................................123
6.6.5
Dose Modification for Standard Treatment Chemotherapy.......................123
6.6.5.1
Dose Selection for Docetaxel (Preparation) ....................................123
6.6.5.2
Dose Modifications for Docetaxel...................................................123
6.6.5.3
Dose Selection for Paclitaxel (Preparation).....................................124
6.6.5.4
Dose Modifications for Paclitaxel ...................................................124
6.6.5.5
Dose Selection for Cetuximab (Preparation)...................................125
6.6.5.6
Dose Modifications for Cetuximab..................................................125
6.6.5.7
Dose Selection for Capecitabine (Preparation)................................126
6.6.5.8
Dose Modifications for Capecitabine ..............................................126
6.7
Intervention After the End of the Study..........................................................127
6.8
Clinical Supplies Disclosure..............................................................................127
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL..........................................................................................................128
7.1
Discontinuation of Study Intervention.............................................................128
7.2
Participant Withdrawal From the Study.........................................................130
7.3
Lost to Follow-up ...............................................................................................130
8
STUDY ASSESSMENTS AND PROCEDURES......................................................131
8.1
Administrative and General Procedures .........................................................131
8.1.1
Informed Consent.......................................................................................131
8.1.1.1
General Informed Consent...............................................................132
8.1.2
Inclusion/Exclusion Criteria ......................................................................132
8.1.3
Participant Identification Card...................................................................132
8.1.4
Medical History .........................................................................................133
8.1.5
Prior and Concomitant Medications Review.............................................133
8.1.5.1
Prior Medications.............................................................................133
8.1.5.2
Concomitant Medications................................................................133
8.1.5.3
Prior Anticancer Therapy for HNSCC.............................................133
8.1.6
Assignment of Screening Number.............................................................133
8.1.7
Assignment of Treatment/Randomization Number...................................134
8.1.8
Study Intervention Administration ............................................................134
8.1.8.1
Timing of Dose Administration.......................................................134
8.1.8.2
Compliance ......................................................................................136
8.1.9
Discontinuation and Withdrawal ...............................................................136
8.1.10
Participant Blinding/Unblinding................................................................136
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8.1.11
Calibration of Equipment...........................................................................136
8.1.12
Demographics ............................................................................................137
8.1.13
Tumor Tissue for Biomarker Status...........................................................137
8.2
Efficacy Assessments .........................................................................................137
8.2.1
Tumor Imaging and Assessment of Disease..............................................137
8.2.1.1
Pre-study Scans to Confirm Disease Progression............................138
8.2.1.2
Initial Tumor Scans..........................................................................139
8.2.1.3
Tumor Scans During the Study........................................................139
8.2.1.4
End of Treatment and Follow-up Tumor Scans...............................140
8.2.1.5
Crossover Treatment Tumor Scans..................................................140
8.2.1.6
Second Course Scans .......................................................................141
8.2.1.7
RECIST 1.1 Assessment of Disease................................................141
8.2.2
Patient Reported Outcomes........................................................................143
8.3
Safety Assessments.............................................................................................143
8.3.1
Physical Examinations...............................................................................143
8.3.2
Vital Signs..................................................................................................144
8.3.3
Electrocardiograms ....................................................................................145
8.3.4
Echocardiograms or Multigated Acquisition Scans...................................145
8.3.5
Clinical Safety Laboratory Assessments ...................................................145
8.3.5.1
CBC with Differential and Clinical Chemistry................................146
8.3.5.2
Urine Dipstick Testing/Urinalysis ...................................................146
8.3.5.3
Thyroid Function Testing ................................................................146
8.3.6
Pregnancy Testing......................................................................................146
8.3.7
Eastern Cooperative Oncology Group Performance Status.......................147
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events..................................................................................................................147
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................147
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....150
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.150
8.4.4
Regulatory Reporting Requirements for SAE ...........................................150
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................150
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................151
8.4.7
Events of Clinical Interest..........................................................................151
8.5
Treatment of Overdose......................................................................................152
8.6
Pharmacokinetics...............................................................................................152
8.6.1
Blood Collection for Serum Pembrolizumab.............................................153
8.6.2
Blood Collection for Plasma Lenvatinib....................................................153
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8.6.3
Blood Collection for RNA Analysis and Plasma and Serum Biomarker 
Analysis......................................................................................................153
8.7
Pharmacodynamics............................................................................................153
8.8
Biomarkers .........................................................................................................153
8.8.1
Planned Genetic Analysis Sample Collection............................................154
8.8.2
Human Papilloma Virus Testing................................................................154
8.9
Health Economics Medical Resource Utilization and Health Economics.....155
8.10
Visit Requirements.............................................................................................155
8.10.1
Screening....................................................................................................155
8.10.2
Initial Treatment Phase ..............................................................................155
8.10.2.1
Telephone Contact or Visit..............................................................155
8.10.2.2
Addition of Pembrolizumab Following Progression on Lenvatinib 
Monotherapy....................................................................................156
8.10.3
Second Course ...........................................................................................156
8.10.4
Discontinued Participants Continuing to be Monitored in the Study ........156
8.10.5
Posttreatment Visit.....................................................................................156
8.10.5.1
Safety Follow-up Visit.....................................................................156
8.10.5.2
Efficacy Follow-up Visits................................................................156
8.10.5.3
Survival Follow-up Contacts ...........................................................157
8.10.6
Vital Status.................................................................................................157
9
STATISTICAL ANALYSIS PLAN ...........................................................................158
9.1
Statistical Analysis Plan Summary...................................................................158
9.2
Responsibility for Analyses/In-house Blinding ...............................................159
9.3
Hypotheses/Estimation ......................................................................................159
9.4
Analysis Endpoints.............................................................................................159
9.4.1
Efficacy Endpoints.....................................................................................159
9.4.2
Safety Endpoints........................................................................................160
9.4.3
Patient Reported Outcome Endpoints........................................................160
9.5
Analysis Populations..........................................................................................160
9.5.1
Efficacy Analysis Population.....................................................................160
9.5.2
Safety Analysis Population........................................................................160
9.6
Statistical Methods.............................................................................................161
9.6.1
Statistical Methods for Efficacy Analyses.................................................161
9.6.1.1
Overall Survival...............................................................................161
9.6.1.2
Progression-Free Survival................................................................161
9.6.1.3
Objective Response Rate .................................................................162
9.6.1.4
Duration of Response.......................................................................162
9.6.1.5
Analysis Strategy for Key Efficacy Variables.................................163
9.6.2
Statistical Methods for Safety Analyses ....................................................164
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9.6.2.1
Overall Safety Assessment ..............................................................164
9.6.2.2
Assessment of Safety Topics of Special Interest .............................165
9.6.3
Demographic and Baseline Characteristics ...............................................166
9.7
Interim Analyses ................................................................................................167
9.8
Multiplicity .........................................................................................................167
9.9
Sample Size and Power Calculations ...............................................................167
9.10
Subgroup Analyses.............................................................................................167
9.11
Compliance (Medication Adherence)...............................................................168
9.12
Extent of Exposure.............................................................................................168
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................169
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......169
10.1.1
Code of Conduct for Interventional Clinical Trials ...................................169
10.1.2
Financial Disclosure...................................................................................172
10.1.3
Data Protection...........................................................................................173
10.1.3.1
Confidentiality of Data ....................................................................173
10.1.3.2
Confidentiality of Participant Records.............................................173
10.1.3.3
Confidentiality of IRB/IEC Information..........................................173
10.1.4
Committees Structure.................................................................................174
10.1.4.1
Scientific Advisory Committee (SAC)............................................174
10.1.4.2
Executive Oversight Committee......................................................174
10.1.4.3
External Data Monitoring Committee .............................................174
10.1.5
Publication Policy......................................................................................174
10.1.6
Compliance with Study Registration and Results Posting Requirements .175
10.1.7
Compliance with Law, Audit, and Debarment ..........................................175
10.1.8
Data Quality Assurance .............................................................................176
10.1.9
Source Documents .....................................................................................177
10.1.10
Study and Site Closure...............................................................................177
10.2
Appendix 2: Clinical Laboratory Tests............................................................178
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................180
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................180
10.3.2
Definition of AE ........................................................................................180
10.3.3
Definition of SAE ......................................................................................181
10.3.4
Additional Events Reported.......................................................................182
10.3.5
Recording AE and SAE .............................................................................182
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................186
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10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................188
10.5
Appendix 5: Contraceptive Guidance..............................................................189
10.5.1
Definitions..................................................................................................189
10.5.2
Contraceptive Requirements......................................................................190
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................191
10.7
Appendix 7: Country-specific Requirements..................................................192
10.7.1
Canada........................................................................................................192
10.7.2
UK..............................................................................................................192
10.7.3
France.........................................................................................................193
10.7.4
Romania.....................................................................................................193
10.7.5
Portugal......................................................................................................193
10.7.6
Norway.......................................................................................................193
10.8
Appendix 8: ECOG Performance Status.........................................................194
10.9
Appendix 9: Abbreviations ...............................................................................195
11
REFERENCES.............................................................................................................199
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values...............................................93
Table 2
Study Interventions.......................................................................................99
Table 3
Dose Modification Guidelines for Lenvatinib-Related Adverse Events.....107
Table 4
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated With Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ..........................................................115
Table 5
Pembrolizumab Infusion Reaction Dose modification and Treatment 
Guidelines ...................................................................................................121
Table 6
Cetuximab Dose Modifications for Adverse Reactions..............................125
Table 7
Recommended Dose Modifications for Capecitabine ................................126
Table 8
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events............................................................................148
.............................................162
.............................................163
Table 11
Summary of Analysis Strategy for Efficacy Endpoints ..............................163
Table 12
Analysis Strategy for Safety Parameters.....................................................166
Table 13
Protocol-required Safety Laboratory Assessments .....................................178
CCI
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LIST OF FIGURES
Figure 1
Initial Treatment............................................................................................27
Figure 2
Study Intervention Decision Making Process (PFS) ..................................142
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2, randomized, open-label three-arm clinical study to evaluate the 
safety and efficacy of lenvatinib (E7080/MK-7902) in combination with pembrolizumab 
(MK-3475) versus standard of care chemotherapy and lenvatinib monotherapy in participants 
with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) that have 
progressed after platinum therapy and immunotherapy (PD-1/PD-L1 inhibitors) (LEAP-009)
Short Title: A Phase 2 study of lenvatinib (E7080/MK-7902) with pembrolizumab (MK-
3475) versus SOC chemotherapy and lenvatinib monotherapy for R/M HNSCC after 
platinum therapy and immunotherapy
Acronym: LEAP-009 (E7080-G000-228)
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
Males and females with R/M HNSCC, who are at least 18 years old, and who have 
progressed after platinum-containing chemotherapy at any time (with or without cetuximab) 
and a PD 1/PD-L1 inhibitor will be enrolled in this study.
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 4.2.1.1.1 for further details.
NOTE: Based on a periodic review of safety data (data cutoff 31-MAY-2024) for LEAP-
009, OS Kaplan-Meier curves did not favor pembrolizumab + lenvatinib versus SOC 
chemotherapy, and it was considered that additional follow-up OS outcomes in favor of the 
combination are unlikely to support a clinically meaningful favorable benefit-risk ratio. The 
prespecified interim and final analyses of the study described in Section 9 will not be 
performed. Selected analyses of safety endpoints will be performed at the end of the study; 
there will be no further planned analyses for efficacy and ePRO endpoints. Updated analyses 
are described in Section 9.
In alignment with the study-specific investigator letter dated 05-SEP-2024, all participants 
should discontinue the combination of lenvatinib + pembrolizumab (Arm 1) or lenvatinib 
monotherapy (Arm 3), as applicable. On a case-by-case basis, investigators may contact the 
Sponsor for consideration of continuing lenvatinib plus pemrolizumab or lenvatinib 
monotherapy if they assess the participant is deriving clinical benefit. Treatment with SOC 
chemotherapy (Arm 2) can continue at the discretion of the investigator until a protocol 
specified discontinuation criterion is met. Participants who are continuing study treatment 
should follow the modified protocol study procedures as specified in this amendment.
All participants beyond the 30-day Safety Follow-up Visit in the initial treatment or 
Crossover treatment phases should be discontinued from the study; however, standard safety 
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reporting should continue, as applicable. As of Amendment 07, participants who are still on 
study treatment will no longer require ePRO assessments or tumor response assessments by 
BICR to be performed. Scans will no longer be required to be submitted to the iCRO; 
however, tumor imaging with investigator assessment should continue per protocol. 
Biomarker specimen collection is discontinued. The 30-day Safety Follow-up Visit is the last 
required visit. 
Primary Objective
Primary Endpoint
Objective: to compare lenvatinib + 
pembrolizumab combination therapy and 
SOC chemotherapy with respect to OS. 
Hypothesis (H1): lenvatinib + 
pembrolizumab is superior to SOC with 
respect to OS.
OS: The time from randomization to death 
due to any cause. 
Secondary Objectives
Secondary Endpoints
Objective: to compare lenvatinib + 
pembrolizumab combination therapy and 
SOC chemotherapy with respect to PFS per 
RECIST 1.1 by BICR 
Hypothesis (H2): lenvatinib + 
pembrolizumab is superior to SOC with 
respect to PFS per RECIST 1.1 by BICR.
PFS: The time from randomization to the 
first documented disease progression or 
death due to any cause, whichever occurs 
first.
Objective: to compare lenvatinib + 
pembrolizumab combination therapy and 
SOC chemotherapy with respect to ORR 
per RECIST 1.1 as assessed by BICR.
Hypothesis (H3): lenvatinib + 
pembrolizumab is superior to SOC with 
respect to ORR per RECIST 1.1 by BICR.
Objective Response (OR): complete 
response (CR) or partial response (PR).
Objective: to assess the efficacy of 
lenvatinib + pembrolizumab combination 
therapy and SOC chemotherapy with 
respect to DOR per RECIST 1.1, by BICR.
DOR: the first documented evidence of CR 
or PR until PD or death due to any cause, 
whichever occurs first.
Objective: to assess the safety and 
tolerability of study intervention with 
lenvatinib + pembrolizumab combination 
therapy, SOC chemotherapy, and lenvatinib 
monotherapy
-AEs
-Study drug discontinuations due to AEs
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Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment
Indication
Squamous cell carcinoma of head and neck, 
Head and neck cancer
Population
Participants with R/M HNSCC who have 
progressed after platinum-containing 
chemotherapy at any time (with or without 
cetuximab) and a PD-1/PD-L1 inhibitor
Study Type
Interventional
Intervention Model
Parallel
This is a multi site study.
Type of Control
Active Control Without Placebo
Study Blinding
Unblinded open-label
Blinding Roles
Outcomes Assessor
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 5 years from the time 
the first participant (or their legally 
acceptable representative) provides 
documented informed consent until the last 
participant’s last study-related contact.
Number of Participants:
Approximately 400 participants will be treated. Participants will be randomized to receive 
lenvatinib + pembrolizumab (Arm 1), SOC chemotherapy (Arm 2), or lenvatinib 
monotherapy (Arm 3). 
For lenvatinib + pembrolizumab and SOC chemotherapy, approximately 150 participants 
will be enrolled in each arm. 
For the lenvatinib monotherapy arm, an interim analysis based on BICR assessment of 
objective response rate (ORR) will be performed after 30 participants have been randomized. 
The results will be reviewed by the Sponsor. If futility rules are not met in this interim 
analysis, a total of 100 participants will be enrolled into the lenvatinib monotherapy arm.
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Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
Arm 1
Lenvatinib
10 mg
4 mg
20 mg
Oral
Once daily
Test Product
Arm 1
Pembrolizumab 25 mg/mL
200 mg
IV Infusion
Day 1 of each 
3-week cycle
Test Product
Arm 2
Docetaxel
20 mg/mL
75 mg/m2
IV Infusion
Day 1 of each 
3-week cycle
Comparator
Arm 2
Capecitabine
150 mg
500 mg
1250 mg/m2
Oral
BID (Twice a 
day) on Day 1 
to 14 of each 
3-week cycle
Comparator
Arm 2
Paclitaxel
6 mg/mL
80 mg/m2
IV Infusion
Day 1, 8, and 
15 of each 3-
week cycle
Comparator
Arm 2
Cetuximab
2 mg/mL
5 mg/mL
400 mg/m2
loading dose 
followed by 
250 mg/m2
IV Infusion
Day 1, 8, and 
15 of each 3-
week cycle
Comparator
Arm 3
Lenvatinib
10 mg
4 mg
24 mg
Oral
Once daily
Test Product
Other current or former name(s) or alias(es) for study intervention(s) are as follows: 
KEYTRUDA, MK-3475, SCH 900475; LENVIMA, MK-7902, and E7080.
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Total 
Number of 
Intervention 
Groups/Arms
3 arms
Duration of 
Participation
Each participant will participate in the study from the time of providing 
documented informed consent through the final protocol-specified contact.
The site’s study team must have reviewed and submitted pre-study images 
that are of diagnostic quality from at least 2 dates to determine that 
radiographic progression has occurred per RECIST 1.1 following initiation 
of prior PD-1/PD-L1 inhibitor treatment. These images include, at a 
minimum, the baseline image for prior anti-PD-1/PD-L1 or an image
showing nadir during prior anti-PD-1/PD-L1 treatment and an image 
showing progression on prior anti-PD-1/PD-L1 treatment (within 12 weeks 
of last dose of anti-PD-1/PD-L1 treatment). These pre-study images will be 
submitted to the iCRO to verify that the images are of diagnostic quality 
prior to randomization.
The baseline tumor image collected during the Screening period must be 
also submitted to the iCRO for verification of measurable disease per 
RECIST 1.1 for eligibility prior to randomization. 
Archival or newly obtained (within 90 days prior to start of study 
treatment) biopsy for biomarker analysis will be required prior to 
randomization.
Initial Treatment:
NOTE: As of Amendment 07, participants in the SOC chemotherapy arm 
or lenvatinib monotherapy arm may not crossover to receive lenvatinib + 
pembrolizumab at the time of disease progression.
After a Screening phase of up to 28 days, each participant meeting the 
study entry criteria will be randomized to receive either:

Lenvatinib + Pembrolizumab (Arm 1): Participants may continue 
receiving pembrolizumab for up to 35 cycles (approximately 2 years) 
or until a discontinuation criterion is met. Participants may continue 
receiving lenvatinib beyond the 35 cycles of pembrolizumab as per 
investigator-determined clinical benefit or until a discontinuation 
criterion is met.

SOC chemotherapy (Arm 2): Investigator’s choice of single-agent 
docetaxel, paclitaxel, cetuximab, or capecitabine. Participants may 
continue receiving SOC chemotherapy as per investigator-
determined clinical benefit or until a discontinuation criterion is met.
Note: Upon centrally verified radiographic PD by RECIST 1.1, 
pembrolizumab and lenvatinib treatment may be initiated at the 
discretion of the investigator after consultation with the Sponsor and 
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receiving informed consent. Participants may receive pembrolizumab 
alone during Crossover with Sponsor consultation.

Lenvatinib Monotherapy (Arm 3): Participants may continue 
receiving lenvatinib monotherapy as per investigator-determined 
clinical benefit until a discontinuation criterion is met.  
Note: Upon centrally verified PD by RECIST 1.1, pembrolizumab 
may be added to lenvatinib monotherapy, according to investigator 
decision with Sponsor consultation. The lenvatinib dose should be 
decreased to 20 mg daily or, if dose reduced to less than 20 mg, 
administered at the current reduced dose, when given in combination 
with pembrolizumab. Participants may receive pembrolizumab alone 
during Crossover with Sponsor consultation. Participants who 
discontinue lenvatinib prior to initiation of Crossover treatment will 
not restart lenvatinib.
Note: For participants who were randomized initially to lenvatinib 
monotherapy, lenvatinib treatment may be continued during 
Crossover screening at the discretion of the investigator after 
consultation with the Sponsor.
Second Course: 
NOTE: As of Amendment 07, there will be no Second Course. This 
section is no longer applicable. 
End of Treatment: 
After the end of treatment, each participant will be followed for the 
occurrence of AEs, spontaneously reported pregnancy and Survival 
Follow-up.
Participants who discontinue for reasons other than centrally verified 
radiographic PD will have post-treatment follow-up imaging for disease 
status until PD is documented radiographically per RECIST 1.1 and 
centrally verified, initiate a non-study cancer treatment, withdraw consent, 
or become lost to follow-up (ie, the participant is unable to be contacted by 
the investigator). 
All participants will be followed for overall survival (OS) until death, 
withdrawal of consent, lost to follow-up, or the end of the study. Upon 
withdrawal of consent, the investigator will ask the participant if they may 
be contacted periodically for survival status; the participant’s response will 
be documented in the study chart. 
The overall study ends when the last participant completes the last study-
related telephone call or visit, withdraws consent, or is lost to follow-up.
Upon study termination, participants are to be discontinued and may be 
enrolled in an extension study using pembrolizumab in combination with 
lenvatinib or lenvatinib monotherapy, if available.
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Study Governance Committees:
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Scientific Advisory Committee
Yes
Steering Committee
No
Study governance considerations are outlined in Appendix 1.
As of Amendment 07, the Executive Oversight Committee and Data Monitoring Committee 
are no longer applicable.
Study Accepts Healthy Participants: No
A list of abbreviations used in this document can be found in Appendix 9.
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1.2
Schema
The study design is depicted in Figure 1 (Initial Treatment). 
Figure 1
Initial Treatment
Abbreviations: ECOG PS = Eastern Cooperative Oncology Group Performance Status; HPV = human papilloma virus; IA = 
interim analysis; IV = intravenous; mAb = monoclonal antibody; PD = progressive disease; PD-1 = programmed cell death 
1; PD L1 = programmed cell death ligand-1; Q3W = every 3 weeks; R/M HNSCC = recurrent/metastatic head and neck 
squamous cell carcinoma; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1; SOC = standard of 
care; TPS = tumor proportion score. 
1.
SOC chemotherapy= Investigator’s choice of paclitaxel, docetaxel, cetuximab, or capecitabine. 
Note: Participants previously treated to one of the 4 SOC agents in this trial (i.e., docetaxel, paclitaxel, capecitabine, or
cetuximab) may not receive the same agent if randomized to the SOC chemotherapy arm.
2.
IA for the lenvatinib monotherapy arm will occur after 30 participants are enrolled into this arm and are followed for at 
least 12 weeks. Randomization will be paused for the lenvatinib monotherapy arm after the 30th participant is 
randomized to this arm.  If number of responses is <3, enrollment for this arm will be stopped. If futility is not met at 
the IA, randomization to the lenvatinib monotherapy arm will be resumed*. 
*Note: The futility analysis was completed, and futility not met.
3.
Participants who experience centrally verified PD in the lenvatinib monotherapy or SOC chemotherapy arms can 
crossover to receive lenvatinib + pembrolizumab at time of disease progression with Sponsor consultation. As of 
Amendment 07, participants in the SOC chemotherapy arm or lenvatinib monotherapy arm may not crossover to 
receive lenvatinib + pembrolizumab at the time of disease progression.
Upon study termination, participants are discontinued and may be enrolled in an extension 
study using pembrolizumab in combination with lenvatinib or lenvatinib monotherapy, if 
available. 
08QSNY

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25-NOV-2024
1.3
Schedule of Activities
As of Amendment 07, participants who are still on study treatment will no longer require ePRO assessments to be performed. 
PK/ADA and biomarker samples (blood for genetic analyses, plasma/serum biomarker, RNA analysis, and ctNA analysis) are 
discontinued.
All participants who are still on study treatment should continue tumor imaging and investigator assessments of imaging per protocol. 
Tumor response assessments by BICR will no longer be performed and scans will no longer be sent to the iCRO.
Efficacy follow-up visits will no longer be conducted. Therefore, participants in efficacy follow-up and survival follow-up should be 
discontinued from the study. 
As of Amendment 07, only the following procedures at the indicated time points are to be performed:
•
Imaging: while on study treatment, EOT, Safety FU
•
Physical examination; Vital signs: while on study treatment, EOT, Safety FU 
•
ECG, MUGA, or ECHO: while on study treatment, then Safety FU
•
ECOG: while on study treatment, EOT, Safety FU
•
Serum b-HCG or urine pregnancy (WOCBP only): while on study treatment, EOT, Safety FU
•
Hematology/Chemistry/Urinalysis: while on study treatment, EOT, Safety FU
•
Urinalysis/urine dipstick testing, as specified per protocol: while still on lenvatinib, EOT, and Safety FU
•
T3 or FT3, T4, TSH: while on study treatment, then Safety FU
The full SoA tables for Arm 1, Arm 2, Arm 3, and Crossover Treatment below are retained for reference.
08QSNY

PRODUCT: MK-7902
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25-NOV-2024
1.3.1
Initial Treatment: Lenvatinib + Pembrolizumab (Arm 1) or Lenvatinib Monotherapy (Arm 3)
NOTE: The same activities will apply both to participants in Arm 1 and Arm 3 unless specified in the SoA. 
Study Period
Screen-
ing
Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
C4
C5
C6 
to 
C35
≥C36
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival
FU
Visit/Cycle Number
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling Window 
(Days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
D/C
30d after 
last dose 
(+7d)
Q6W 
(Y1) 
or 
Q9W 
(after 
Y1) 
(±7d)
Q12W 
(±14d)
All procedures/assessments 
performed before 
administration of study 
intervention unless 
otherwise indicated.
Administrative Procedures
Informed Consent
X
Documented informed 
consent must be obtained 
prior to performing any 
protocol-specific procedures.
If the investigator plans to 
treat beyond centrally verified 
radiographic disease 
progression, additional 
consent is required.
Inclusion/Exclusion 
Criteria
X
AJCC v8 should be used for 
clinical evaluation and staging 
of participant’s tumor burden 
at initial diagnosis and at 
Screening.
Participant 
Identification Card
X
X*
* Update at C1D1 with 
randomization number.
Demographics and 
Medical History 
X
Includes smoking and tobacco 
use.
08QSNY

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25-NOV-2024
Study Period
Screen-
ing
Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
C4
C5
C6 
to 
C35
≥C36
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival
FU
Visit/Cycle Number
Cycle Day
1
8
15
1
15
1
1
1
1
1
Prior/Concomitant 
Medication Review
Medications received within 
30 days before the first dose 
of study intervention through 
30 days after the last dose of 
study intervention or 90 days 
if used to treat an SAE or 
30 days after last dose if 
participant starts a new 
antineoplastic therapy, 
whichever is sooner. 
Prior Anticancer 
Therapies for 
Treatment of 
HNSCC
X
Randomization
X
It is strongly preferred that 
participants receive first dose 
of study intervention on day 
of randomization. Study 
intervention should begin 
within 3 days of 
randomization.
Subsequent 
Anticancer 
Treatment
X
X
X
X
All anticancer therapy will be 
recorded until the time of 
death or termination of 
survival FU. If a clinic visit is 
not feasible, follow-up 
information may be obtained 
by telephone, email or from 
other sources.
08QSNY

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25-NOV-2024
Study Period
Screen-
ing
Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
C4
C5
C6 
to 
C35
≥C36
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival
FU
Visit/Cycle Number
Cycle Day
1
8
15
1
15
1
1
1
1
1
Survival Status
X
Survival Follow-up continues 
after centrally verified PD, 
after discontinuation of study 
intervention, and after the start 
of new anticancer treatment.
In addition, upon Sponsor 
request, participants may be 
contacted for survival status at 
any time during the course of 
the study.
Study Intervention Administration
Lenvatinib 
Dispensing
X
X
X
X
X
X
X
Collect and record the number 
of lenvatinib capsules 
returned.
Lenvatinib 
Administration 
X*
X
X*
X*
X
X
X
X
X
X
* Lenvatinib will be given in 
the clinic on C1D1, C1D15, 
and C2D1
Participants randomized to 
lenvatinib + pembrolizumab 
should be given lenvatinib 
within 0 to 4 hours after 
completion of pembrolizumab 
infusion on C1D1 and C2D1.
On C1D15 the dose of 
lenvatinib will be given in the 
clinic within 2 hours prior to 
the lenvatinib postdose PK 
blood sample. 
Participants will self –
administer lenvatinib on all 
other days.
08QSNY

PRODUCT: MK-7902
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25-NOV-2024
Study Period
Screen-
ing
Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
C4
C5
C6 
to 
C35
≥C36
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival
FU
Visit/Cycle Number
Cycle Day
1
8
15
1
15
1
1
1
1
1
Pembrolizumab 
Administration
X
X
X
X
X
X
For participants randomized to 
lenvatinib + pembrolizumab 
study intervention only.
After C1D1, pembrolizumab 
may be administered up to 3 
days before or after the 
scheduled Day 1 of each 
subsequent cycle due to 
administrative reasons.
Efficacy Procedures/Assessments
Submission of Pre-
study Imaging
X
Diagnostic quality pre-study 
images from ≥2 dates must 
have been reviewed at site to 
determine radiographic 
progression per RECIST 1.1 
following initiation of pre-
study anti-PD-1/PD-L1 agent. 
The iCRO must have received 
these scans and have verified 
that they are of diagnostic 
quality prior to randomization.
Tumor Imaging 
(head and neck, chest 
and abdomen) and 
Response 
Assessment
Note:  Imaging of the 
brain and pelvis are 
optional (if clinically 
indicated).
X
X
X
X*
X
X
Imaging should be performed 
at Screening, Week 6 
(42-49 days) from the date of 
randomization.
* After Week 6 imaging every 
6 weeks (±7 days) for 1 year 
(48 weeks). After 1 year (48 
weeks), imaging will occur 
every 9 weeks (±7 days). 
Schedule should be followed 
regardless of treatment delays. 
Follow-up imaging will use 
the same imaging schedule 
used while on study 
intervention calculated from 
the date of randomization. 
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25-NOV-2024
Study Period
Screen-
ing
Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
C4
C5
C6 
to 
C35
≥C36
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival
FU
Visit/Cycle Number
Cycle Day
1
8
15
1
15
1
1
1
1
1
Safety Procedures/Assessments
AE/SAE Review
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.
* Report Pregnancy 120 days 
following pembrolizumab or 
30 days following cessation of 
lenvatinib, whichever occurs 
last.
Full Physical 
Examination 
X
X
Full physical examination to 
be performed within 10 days 
prior to start of study 
intervention.
Height
X
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
Telephone Contact
X
A phone visit will be 
scheduled to report blood 
pressure and record AEs. 
Blood pressure will be 
taken, for example, at home 
or at a local pharmacy, and 
will be reviewed with the 
investigator or designee.
Vital Signs 
(resting BP, heart 
rate, respiratory rate, 
and temp) and weight
X
X
X*
X
X*
X
X
X
X
X
X
X
* The D15 visits are 
mandatory for C1 and C2. 
During C3 and subsequent 
cycles, participants may return 
for the D15 visit if BP 
monitoring is required. 
08QSNY

PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.: 009-07 (E7080-G000-228)
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25-NOV-2024
Study Period
Screen-
ing
Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
C4
C5
C6 
to 
C35
≥C36
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival
FU
Visit/Cycle Number
Cycle Day
1
8
15
1
15
1
1
1
1
1
12-lead ECG with 
QTcF Determination
X
X
X
X*
X*
X
X
ECG at Screening, C1D1, 
C2D1, 
* D1 of every 4th cycle (12 
weeks) 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 participants (as 
defined in lenvatinib product 
label), conduct ECG 
monitoring every cycle. 
Additional time points may be 
performed as clinically 
necessary.
If lenvatinib is discontinued, 
ECGs are only required at the 
EOT and Safety FU visits.
MUGA or ECHO 
Scan
X
X
Additional LVEF assessments 
may be performed as 
clinically indicated.
ECOG Performance 
Status
X
X*
X
X
X
X
X
X
X
X
At Screening, obtain within 7 
days before initiation of study 
intervention and then on D1 of 
each cycle prior to dosing.
ECOG will need to be 
repeated if the assessment was 
performed outside of the 
protocol window.
* If screening ECOG 
performance status is obtained 
within 3 days prior to C1D1, 
no need to repeat at C1D1. 
08QSNY

PRODUCT: MK-7902
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25-NOV-2024
Study Period
Screen-
ing
Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
C4
C5
C6 
to 
C35
≥C36
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival
FU
Visit/Cycle Number
Cycle Day
1
8
15
1
15
1
1
1
1
1
Laboratory Procedures/Assessments (Local Laboratory)
Serum β-HCG or 
Urine Pregnancy 
(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.
HIV, Hepatitis B, 
and Hepatitis C  
X
Required at baseline only if 
mandated by local health 
authority.
Serum FSH 
(WONCBP only)
X
In the absence of 12 months 
of amenorrhea, confirmation 
with 2 FSH measurements in 
postmenopausal range is 
required.
CBC with 
Differential
X*
X
X
X
X
X
X
X
X
X
* Perform within 7 days 
before first dose. 
After C1D1, collect samples 
within 3 days before dosing.
Clinical Chemistry
X*
X
X
X
X
X
X
X
X
X
08QSNY

PRODUCT: MK-7902
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MK-7902-009-07 FINAL PROTOCOL
25-NOV-2024
Study Period
Screen-
ing
Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
C4
C5
C6 
to 
C35
≥C36
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival
FU
Visit/Cycle Number
Cycle Day
1
8
15
1
15
1
1
1
1
1
Urine Dipstick 
Testing (or 
Urinalysis)
X*
X
X
X
X
X
X
X
X
X
* Perform within 7 days 
before first dose. 
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. If lenvatinib 
is discontinued, urine dipstick 
testing is no longer required. 
After Screening, urine 
dipstick-testing for protein 
will be performed within 3 
days before Day 1 of every 
cycle while participants are 
taking lenvatinib.
Urinalysis
X
X
X
X
Perform within 7 days before 
first dose. During study 
intervention obtain urinalysis 
at every 6th cycle (eg, 6, 12, 
18, etc.), within 3 days of 
dosing.
INR or PT and aPTT 
or PTT
X*
* Perform screening labs 
within 7 days prior to the first 
dose. 
Additional testing is to be 
performed as clinically 
indicated for participants 
taking anticoagulants.
08QSNY

PRODUCT: MK-7902
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25-NOV-2024
Study Period
Screen-
ing
Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
C4
C5
C6 
to 
C35
≥C36
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival
FU
Visit/Cycle Number
Cycle Day
1
8
15
1
15
1
1
1
1
1
T3 or FT3, T4, TSH
X*
X
X
X
X
X
* Perform screening labs 
within 7 days prior to the first 
dose, then within 3 days 
before dosing on subsequent 
cycles. Perform at C2 and 
every 2 cycles thereafter (C4, 
C6, C8, etc.).
Participants may be dosed in 
subsequent cycles after C1D1 
while thyroid function test are 
pending.
Free T3/T4 is acceptable if 
total T3/T4 cannot be 
determined.
The central laboratory may be 
used only if the local 
laboratory cannot perform 
these tests.
Pharmacokinetics/Pharmacodynamics/ Biomarkers (Central Laboratory)
Serum for 
Pembrolizumab PK 
X
X
X*
PK samples will be collected 
from Arm 1 (lenvatinib + 
pembrolizumab). Collect 
predose on C1D1, C2D1, and 
*C8D1.
Serum Anti-
pembrolizumab 
Antibodies (ADA)
X
X
X*
ADA samples will be 
collected from Arm 1 
(lenvatinib + pembrolizumab). 
Collect predose on C1D1, 
C2D1, and *C8D1.
08QSNY

PRODUCT: MK-7902
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25-NOV-2024
Study Period
Screen-
ing
Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
C4
C5
C6 
to 
C35
≥C36
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival
FU
Visit/Cycle Number
Cycle Day
1
8
15
1
15
1
1
1
1
1
Plasma for 
Lenvatinib PK
X
X
X
Lenvatinib PK samples will 
be collected from both Arms 1 
and 3 (lenvatinib + 
pembrolizumab and lenvatinib
monotherapy) C1D1: postdose 
at any time from 0.5 to 4h, 
collection from 6 to 10h 
postdose is optional. 
C1D15: collect predose within 
2h of lenvatinib dosing and 
postdose at any time from 2 to 
12h postdose.
C2D1: collect predose within 
2h of lenvatinib dosing and 
postdose at any time from 0.5 
to 4h, collection from 6 to 10h 
postdose is optional.
Note: Postdose samples will 
not be collected if lenvatinib 
dosing is on hold due to dose 
modifications, etc.
Tissue Collection for 
Participants with 
Oropharynx Cancer 
(Tested Centrally or 
Locally for HPV 
status) 
X
Archival or newly obtained 
(within 90 days prior to start 
of study treatment) tumor 
specimen for HPV status only 
if prior results are not 
available.
Tissue Collection for 
Biomarker Analysis 
(Tested Centrally)
X
Archival or newly obtained 
(within 90 days prior to start 
of study treatment) tumor 
specimen. 
Should be submitted to the 
central laboratory before 
randomization.
08QSNY

PRODUCT: MK-7902
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25-NOV-2024
Study Period
Screen-
ing
Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
C4
C5
C6 
to 
C35
≥C36
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival
FU
Visit/Cycle Number
Cycle Day
1
8
15
1
15
1
1
1
1
1
Blood for Genetic 
Analyses
X
Collect predose.  See Section 
8.8 for additional information.
Blood for Plasma 
Biomarkers 
X
X
X
X
X
X
X
Collect at predose on D1 of 
C1, C2, C3, C5, C7, C9, C11, 
C13, C15, C17, then on D1 of 
every 3 cycles until EOT, 
including at the EOT visit.
Blood for Serum 
Biomarkers 
X
X
X
X
X
X
Collect predose. Collect on 
C1D1, C1D15, C2D1, C3D1, 
C5D1, and at EOT.
Blood for RNA 
Analysis
X
X
X
X
X
Collect predose on C1D1, 
C2D1, C3D1, C5D1, and at 
EOT.
Blood for Circulating 
Tumor Nucleic Acids
X
X
X
X
X
X
X
Collect at predose on D1 of 
C1, C2, C3, C5, C7, C9, C11, 
C13, C15, C17, then on D1 of 
every 3 cycles until EOT, 
including at the EOT visit.
08QSNY

PRODUCT: MK-7902
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MK-7902-009-07 FINAL PROTOCOL
25-NOV-2024
Study Period
Screen-
ing
Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
C4
C5
C6 
to 
C35
≥C36
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival
FU
Visit/Cycle Number
Cycle Day
1
8
15
1
15
1
1
1
1
1
Patient reported Outcomes (PRO)*
EQ-5D-5L
X
X
X
X
X
X*
X
X
It is a best practice and 
strongly recommended that 
ePROs are administered 
before any other visit 
procedures and in the order 
listed in the SoA, starting with 
EuroQoL EQ-5D-5L. 
Collection begins at C1 and 
continues until C35 or 
treatment discontinuation, 
whichever occurs first. 
* Obtain on Day 1 of every 
cycle from C1 through C9, 
then Day 1 of every other 
cycle through C17 (C9, C11, 
C13, C15, C17), then collect 
every 3 cycles through C35 
(C20, C23, C26, C29, C32, 
C35).  Obtain at EOT and 
Safety FU.
Refer to Section 8.2.2. 
EORTC QLQ-C30
X
X
X
X
X
X*
X
X
EORTC QLQ-
H&N35
X
X
X
X
X
X*
X
X
Abbreviations: ADA = anti-drug antibodies (pembrolizumab); AE = adverse event; AJCC = American Joint Committee on Cancer; aPTT = activated partial thromboplastin time; 
BP = blood pressure; β-HCG; = β human chorionic gonadotropin; C = cycle; CBC = complete blood count; CXDY= Cycle X Day Y; d = days; D = day; D/C = discontinuation; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; ECHO = echocardiogram; EORTC = European Organization for Research and Treatment of Cancer; 
EOT = end of treatment; ePRO = electronic patient reported outcome; EQ-5D-5L = European Quality of Life Five-Dimensional Five-Level Scale Questionnaire; FSH = follicle-
stimulating hormone; FT3 = free triiodothyronine; FU = follow-up; h = hours; HIV = human immunodeficiency virus; HNSCC = head and neck squamous cell carcinoma; HPV = 
human papilloma virus; iCRO = imaging clinical research organization; INR = international normalized ratio; LVEF = left ventricular ejection fraction; MUGA = multigated 
acquisition; PD = progressive disease; PD-1 = programmed cell death 1; PD-L1 = programmed cell death ligand 1; PK = pharmacokinetics; PRO = patient reported outcome; PT = 
prothrombin time; PTT = partial prothrombin time, Q6W = every 6 weeks; Q9W = every 9 weeks; Q12W = every 12 weeks; QLQ-C30 = Quality of Life Questionnaire-Core 30 
items; QTcF = QT interval corrected with Fridericia’s formula; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1; RNA= ribonucleic acid; SAE = 
serious adverse event; SoA = schedule of activities; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WOCBP = women of childbearing potential; 
WONCBP = women of non-childbearing potential; Y = year.
08QSNY

PRODUCT: MK-7902
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25-NOV-2024
1.3.2
Initial Treatment: SOC Chemotherapy (Arm 2)
Note: Participants receiving Capecitabine or Docetaxel will not have visits/procedures on Day 8 or Day 15.
Study Period
Screen-
ing
SOC Chemotherapy Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
≥C4
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival 
FU
Visit/Cycle 
Number
Cycle Day
1
8
15
1
8
15
1
8
15
1
8
15
Scheduling 
Window (Days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
D/C
30d 
after 
last dose 
(+7d)
Q6W 
(Y1) 
or 
Q9W 
(Y2+) 
(±7d)
Q12W 
(±14d)
All 
procedures/assessments 
performed before 
administration of study 
intervention unless 
otherwise indicated.
Administrative Procedures
Informed 
Consent
X
Documented informed 
consent must be obtained 
prior to performing any 
protocol-specific 
procedures.
If the investigator plans to 
treat beyond centrally 
verified radiographic 
disease progression, 
additional consent is 
required.
Inclusion/Exclus
ion Criteria
X
AJCC v8 should be used 
for clinical evaluation and 
staging of participant’s 
tumor burden at initial 
diagnosis and at 
Screening.
Participant 
Identification 
Card
X
X*
* Update at C1D1 with 
randomization number.
08QSNY

PRODUCT: MK-7902
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MK-7902-009-07 FINAL PROTOCOL
25-NOV-2024
Study Period
Screen-
ing
SOC Chemotherapy Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
≥C4
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival 
FU
Visit/Cycle 
Number
Cycle Day
1
8
15
1
8
15
1
8
15
1
8
15
Demographics 
and Medical 
History 
X
Prior/
Concomitant 
Medication 
Review
Medications received 
within 30 days before the 
first dose of study 
intervention through 
30 days after the last dose 
of study intervention or 
90 days if used to treat an 
SAE or 30 days after last 
dose if participant starts a 
new antineoplastic 
therapy, whichever is 
sooner. 
Prior Anticancer 
Therapies for 
Treatment of 
HNSCC
X
Randomization
X
It is strongly preferred 
that participants receive 
first dose of study 
intervention on day of 
randomization. Study 
intervention should begin 
within 3 days of 
randomization.
08QSNY

PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.: 009-07 (E7080-G000-228)
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25-NOV-2024
Study Period
Screen-
ing
SOC Chemotherapy Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
≥C4
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival 
FU
Visit/Cycle 
Number
Cycle Day
1
8
15
1
8
15
1
8
15
1
8
15
Subsequent 
Anticancer 
Treatment
X
X
X
X
All anticancer therapy 
will be recorded until the 
time of death or 
termination of survival 
FU. If a clinic visit is not 
feasible, follow-up 
information may be 
obtained by telephone, 
email or from other 
sources.
Survival Status
X
Survival follow-up 
continues after centrally 
verified PD, after 
discontinuation of study 
intervention and after the 
start of new anticancer 
treatment.
In addition, upon Sponsor 
request, participants may 
be contacted for survival 
status at any time during 
the course of the study.
08QSNY

PRODUCT: MK-7902
44
PROTOCOL/AMENDMENT NO.: 009-07 (E7080-G000-228)
MK-7902-009-07 FINAL PROTOCOL
25-NOV-2024
Study Period
Screen-
ing
SOC Chemotherapy Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
≥C4
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival 
FU
Visit/Cycle 
Number
Cycle Day
1
8
15
1
8
15
1
8
15
1
8
15
Study Intervention Administration
SOC 
Chemotherapy
Docetaxel
X
X
X
X
Docetaxel 75 mg/m2: Day 
1 of each 21-day cycle.
Participants receiving 
docetaxel will not have 
visits/procedures on Day 
8 or Day 15. 
Paclitaxel
X
X
X
X
X
X
X
X
X
X
X
X
Paclitaxel 80 mg/m2: Days 
1, 8, and 15 of each 21-
day cycle.
Cetuximab
X
X
X
X
X
X
X
X
X
X
X
X
Cetuximab 400 mg/m2
loading dose followed by 
250 mg/m2: Days 1, 8, 
and 15 of each 21-day 
cycle.
Capecitabine
X
X
X
X
Capecitabine 1250 mg/m2
BID on Days 1 to 14 of 
each 21-day cycle, 
followed by a rest period 
of 1 week.
Participants will self –
administer capecitabine. 
Participants receiving 
capecitabine will not have 
visits/procedures on Day 
8 or Day 15. 
08QSNY

PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.: 009-07 (E7080-G000-228)
MK-7902-009-07 FINAL PROTOCOL
25-NOV-2024
Study Period
Screen-
ing
SOC Chemotherapy Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
≥C4
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival 
FU
Visit/Cycle 
Number
Cycle Day
1
8
15
1
8
15
1
8
15
1
8
15
Efficacy Procedures/Assessments
Submission of 
Pre-study 
Imaging
X
Diagnostic quality pre-
study images from ≥2 
dates must have been 
reviewed at site to 
determine radiographic 
progression per 
RECIST 1.1 following 
initiation of pre-study 
anti-PD-1/PD-L1 agent. 
The iCRO must have 
received these scans and 
have verified that they are 
of diagnostic quality prior 
to randomization.
08QSNY

PRODUCT: MK-7902
46
PROTOCOL/AMENDMENT NO.: 009-07 (E7080-G000-228)
MK-7902-009-07 FINAL PROTOCOL
25-NOV-2024
Study Period
Screen-
ing
SOC Chemotherapy Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
≥C4
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival 
FU
Visit/Cycle 
Number
Cycle Day
1
8
15
1
8
15
1
8
15
1
8
15
Tumor Imaging 
(head and neck, 
chest and 
abdomen) and 
Response 
Assessment
Note:  Imaging 
of the brain and 
pelvis are 
optional (if 
clinically 
indicated).
X
X
X*
X
X
Imaging should be 
performed at Screening, 
Week 6 (42-49 days) from 
the date of randomization.
* After Week 6 imaging 
every 6 weeks (±7 days). 
After 1 year (48 weeks), 
imaging will occur every 
9 weeks (±7 days). 
Schedule should be 
followed regardless of 
treatment delays. Follow-
up imaging will use the 
same imaging schedule 
used while on study 
intervention calculated 
from the date of 
randomization.
Safety Procedures/Assessments
AE/SAE review
X
X
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.
Full Physical 
Examination 
X
X
Full physical examination 
to be performed within 
10 days prior to start of 
study intervention.
Height
X
08QSNY

PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.: 009-07 (E7080-G000-228)
MK-7902-009-07 FINAL PROTOCOL
25-NOV-2024
Study Period
Screen-
ing
SOC Chemotherapy Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
≥C4
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival 
FU
Visit/Cycle 
Number
Cycle Day
1
8
15
1
8
15
1
8
15
1
8
15
Directed 
Physical 
Examination
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs 
(resting BP, 
heart rate, 
respiratory rate, 
and temp) and 
weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
with QTcF 
Determination
X
MUGA or 
ECHO Scan
X
Additional LVEF 
assessments may be 
performed as clinically 
indicated.
ECOG 
Performance 
Status
X
X*
X
X
X
X
X
At Screening, obtain 
within 7 days before 
initiation of study 
intervention and then on 
D1 of each cycle prior to 
dosing.
ECOG will need to be 
repeated if the assessment 
was performed outside of 
the protocol window.
* If screening ECOG 
performance status is 
obtained within 3 days 
prior to C1D1, no need to 
repeat at C1D1.
08QSNY

PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.: 009-07 (E7080-G000-228)
MK-7902-009-07 FINAL PROTOCOL
25-NOV-2024
Study Period
Screen-
ing
SOC Chemotherapy Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
≥C4
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival 
FU
Visit/Cycle 
Number
Cycle Day
1
8
15
1
8
15
1
8
15
1
8
15
Laboratory Procedures/Assessments (Local Laboratory)
Serum β-HCG 
or Urine 
Pregnancy 
(WOCBP only)
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.
If a urine pregnancy test 
cannot be confirmed as 
negative, a serum 
pregnancy test is required.
HIV, Hepatitis 
B, and Hepatitis 
C  
X
Required at baseline only 
if mandated by local 
health authority.
Serum FSH 
(WONCBP 
only)
X
In the absence of 
12 months of amenorrhea, 
confirmation with 2 FSH 
measurements in 
postmenopausal range is 
required.
CBC with 
Differential
X*
X
X
X
X
X
X
X
X
X
X
X
X
X
* Perform within 7 days 
before first dose. 
After C1D1, collect 
samples within 3 days 
before dosing.
Clinical 
Chemistry
X*
X
X
X
X
X
X
X
X
X
X
X
X
X
08QSNY

PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.: 009-07 (E7080-G000-228)
MK-7902-009-07 FINAL PROTOCOL
25-NOV-2024
Study Period
Screen-
ing
SOC Chemotherapy Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
≥C4
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival 
FU
Visit/Cycle 
Number
Cycle Day
1
8
15
1
8
15
1
8
15
1
8
15
Urine Dipstick 
Testing
X
Perform within 7 days 
before first dose.
Urinalysis
X
X
X
X
Perform within 7 days 
before first dose. During 
study intervention obtain 
urinalysis at every 6th
cycle (eg, 6, 12, 18, etc.), 
within 3 days of dosing.
INR or PT and 
aPTT or PTT
X*
* Perform within 7 days 
prior to first dose in C1. 
Additional testing to be 
conducted as clinically 
indicated for participants 
taking anticoagulants.
T3 or FT3, T4, 
TSH
X*
X
X
X
* Perform screening labs 
within 7 days prior to the 
first dose, then within 3 
days before dosing on 
subsequent cycles. 
Perform at C2 and every 2 
cycles thereafter (C4, C6, 
C8, etc.). 
Participants may be dosed 
in subsequent cycles after 
C1D1 while thyroid 
function test are pending.
Free T3 is acceptable if 
T3 cannot be determined.
The central laboratory 
may be used only if the 
local laboratory cannot 
perform these tests.
08QSNY

PRODUCT: MK-7902
50
PROTOCOL/AMENDMENT NO.: 009-07 (E7080-G000-228)
MK-7902-009-07 FINAL PROTOCOL
25-NOV-2024
Study Period
Screen-
ing
SOC Chemotherapy Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
≥C4
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival 
FU
Visit/Cycle 
Number
Cycle Day
1
8
15
1
8
15
1
8
15
1
8
15
Pharmacokinetics/Pharmacodynamics/ Biomarkers (Central Laboratory)
Tissue 
Collection for 
Participants 
with 
Oropharynx 
Cancer (Tested 
Centrally or 
Locally for HPV 
status) 
X
Archival or newly 
obtained (within 90 days 
prior to start of study 
treatment) tumor 
specimen for HPV status 
only if prior results are 
not available.
Tissue 
Collection for 
Biomarker 
Analysis 
(Tested 
Centrally)
X
Archival or newly 
obtained (within 90 days 
prior to start of study 
treatment) tumor 
specimen. 
Tissue should be 
submitted to the central 
laboratory before 
randomization.
Blood for 
Genetic 
Analyses
X
Collect predose.  See 
Section 8.8 for additional 
information.
Blood for 
Plasma 
Biomarkers 
X
X
X
X
X
Collect at predose on D1 
of C1, C2, C3, C5, C7, 
C9, C11, C13, C15, C17, 
then on D1 of every 3 
cycles until EOT, 
including at the EOT 
visit.
08QSNY

PRODUCT: MK-7902
51
PROTOCOL/AMENDMENT NO.: 009-07 (E7080-G000-228)
MK-7902-009-07 FINAL PROTOCOL
25-NOV-2024
Study Period
Screen-
ing
SOC Chemotherapy Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
≥C4
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival 
FU
Visit/Cycle 
Number
Cycle Day
1
8
15
1
8
15
1
8
15
1
8
15
Blood for Serum 
Biomarkers 
X
X
X
X
X*
X
Collect predose. Collect 
on C1D1, C1D15, C2D1, 
C3D1, *C5D1, and at 
EOT.
Blood for RNA 
Analysis
X
X
X
X*
X
Collect predose on C1D1, 
C2D1, C3D1, *C5D1, and 
at EOT.
Blood for 
Circulating 
Tumor Nucleic 
Acids
X
X
X
X
X
Collect at predose on D1 
of C1, C2, C3, C5, C7, 
C9, C11, C13, C15, C17, 
then on D1 of every 3 
cycles until EOT, 
including at the EOT 
visit.
08QSNY

PRODUCT: MK-7902
52
PROTOCOL/AMENDMENT NO.: 009-07 (E7080-G000-228)
MK-7902-009-07 FINAL PROTOCOL
25-NOV-2024
Study Period
Screen-
ing
SOC Chemotherapy Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
≥C4
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival 
FU
Visit/Cycle 
Number
Cycle Day
1
8
15
1
8
15
1
8
15
1
8
15
Patient reported Outcomes (PRO)*
EQ-5D-5L
X
X
X
X*
X
X
It is a best practice and 
strongly recommended 
that ePROs are 
administered before any 
other visit procedures and 
in the order listed in the 
SoA, starting with 
EuroQoL EQ-5D-5L. 
Collection begins at C1 
and continues until C35 or 
treatment discontinuation, 
whichever occurs first. 
* Obtain on Day 1 of 
every cycle from C1 
through C9, then Day 1 of 
every other cycle through 
C17 (C9, C11, C13, C15, 
C17), then collect every 3 
cycles through C35 (C20, 
C23, C26, C29, C32, 
C35).  Obtain at EOT and 
Safety FU.
Refer to Section 8.2.2.
EORTC QLQ-
C30
X
X
X
X*
X
X
EORTC QLQ-
H&N35
X
X
X
X*
X
X*
Abbreviations: AE = adverse event; AJCC = American Joint Committee on Cancer; aPTT = activated partial thromboplastin time; BID = twice daily; BP = blood pressure; β-HCG; 
= β human chorionic gonadotropin; C = cycle; CBC = complete blood count; CXDY= Cycle X Day Y; d = days; D = day; D/C = discontinuation; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; ECHO = echocardiogram; EORTC = European Organization for Research and Treatment of Cancer; EOT = end of treatment; 
ePRO = electronic patient reported outcome;; EQ-5D-5L = European Quality of Life Five-Dimensional Five-Level Scale Questionnaire; FSH = follicle-stimulating hormone; FT3 
= free triiodothyronine; FU = follow-up HIV = human immunodeficiency virus; HNSCC = head and neck squamous cell carcinoma; HPV = human papilloma virus; iCRO = 
imaging clinical research organization; INR = international normalized ratio; LVEF = left ventricular ejection fraction; MUGA = multigated acquisition; PD = progressive disease; 
PD-1 = programmed cell death 1; PD-L1 = programmed cell death ligand 1;PRO = patient reported outcome; PT = prothrombin time; PTT = partial prothrombin time; Q6W = 
every 6 weeks; Q9W = every 9 weeks; Q12W = every 12 weeks; QLQ-C30 = Quality of Life Questionnaire-Core 30 items; QTcF = QT interval corrected with Fridericia’s 
formula; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1; RNA= ribonucleic acid; SAE = serious adverse event; SoA = schedule of activities; SOC 
= standard of care; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WOCBP = women of childbearing potential; WONCBP = women of non-
childbearing potential; Y = year.
08QSNY

PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.: 009-07 (E7080-G000-228)
MK-7902-009-07 FINAL PROTOCOL
25-NOV-2024
1.3.3
Crossover Treatment
NOTE: If all required assessments are performed within specified windows of Crossover C1D1, Screening visit for Crossover 
is not required.
Study Period
Crossover 
Screen-
ing
Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
C4
C5
C6 to 
C35
≥C3
6
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival 
FU
Visit/Cycle Number
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling Window 
(Days)
-28 to -1
+3
±
3
±3
±3
+3
±
3
±3
±3
±3
±3
At 
D/C
30d 
after 
last 
dose 
(+7d)
Q6W 
(Y1) 
or 
Q9W 
(Y2+) 
(±7d)
Q12
W 
(±14d
)
All procedures/assessments 
performed before 
administration of study 
intervention unless otherwise 
indicated.
Administrative Procedures
Prior/Concomitant 
Medication Review
Medications received within 
30 days before the first dose of 
study intervention through 
30 days after the last dose of 
study intervention or 90 days if 
used to treat an SAE or 30 days 
after last dose if participant 
starts a new antineoplastic 
therapy, whichever is sooner. 
Subsequent 
Anticancer 
Treatment
X
X
X
X
All anticancer therapy will be 
recorded until the time of death 
or termination of survival FU. If 
a clinic visit is not feasible, 
follow-up information may be 
obtained by telephone, email or 
from other sources.
08QSNY

PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.: 009-07 (E7080-G000-228)
MK-7902-009-07 FINAL PROTOCOL
25-NOV-2024
Study Period
Crossover 
Screen-
ing
Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
C4
C5
C6 to 
C35
≥C3
6
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival 
FU
Visit/Cycle Number
Cycle Day
1
8
15
1
15
1
1
1
1
1
Survival Status
X
Survival follow-up continues 
after centrally verified PD, after 
discontinuation of study 
intervention and after the start of 
new anticancer treatment.
In addition, upon Sponsor 
request, participants may be 
contacted for survival status at 
any time during the course of 
the study.
Study Intervention Administration
Lenvatinib 
Dispensing
X
X
X
X
X
X
X
Collect and record number of 
lenvatinib capsules returned.
Lenvatinib 
Administration 
X*
X
X
*
X*
X
X
X
X
X
X
* Lenvatinib will be given in the 
clinic on C1D1, C1D15, and 
C2D1
Participants receiving lenvatinib
+ pembrolizumab should be 
given lenvatinib within 0 to 
4 hours after completion of 
pembrolizumab infusion on 
C1D1 and C2D1.
On C1D15 the dose of 
lenvatinib will be given in the 
clinic within 2 hours prior to the 
lenvatinib postdose PK blood 
sample. 
Participants will self –
administer lenvatinib on all 
other days.
Pembrolizumab 
Administration
X
X
X
X
X
X
Crossover C1D15 and C2D15 
visits are not required for 
patients initiating crossover 
treatment with pembrolizumab 
alone.
08QSNY

PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.: 009-07 (E7080-G000-228)
MK-7902-009-07 FINAL PROTOCOL
25-NOV-2024
Study Period
Crossover 
Screen-
ing
Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
C4
C5
C6 to 
C35
≥C3
6
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival 
FU
Visit/Cycle Number
Cycle Day
1
8
15
1
15
1
1
1
1
1
Efficacy Procedures/Assessments
Tumor Imaging 
(head and neck, chest 
and abdomen) and 
Response 
Assessment
Note:  Imaging of the 
brain and pelvis are 
optional (if clinically 
indicated).
X
X
X
X*
X
X
Imaging should be performed at 
Screening (a new baseline 
within 28 days of C1D1 will be 
needed [this can be the centrally 
verified PD scan if it’s within 
the 28-day window]), Week 6 
(42-49 days) from the date of 
C1D1
* After Week 6 imaging every 
6 weeks (±7 days) for 1 year (48 
weeks). After 1 year (48 weeks), 
imaging will occur every 
9 weeks (±7 days). 
Schedule should be followed 
regardless of treatment delays. 
Follow-up imaging will use the 
same imaging schedule used 
while on study intervention 
calculated from the date of
Crossover C1D1. 
Safety Procedures/Assessments
AE/SAE Review
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.
* Report Pregnancy 120 days 
following pembrolizumab or 30 
days following cessation of 
lenvatinib, whichever occurs 
last.
Full Physical 
Examination 
X
X
Full physical examination to be 
performed within 10 days prior 
to start of study intervention.
Height
X
08QSNY

PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.: 009-07 (E7080-G000-228)
MK-7902-009-07 FINAL PROTOCOL
25-NOV-2024
Study Period
Crossover 
Screen-
ing
Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
C4
C5
C6 to 
C35
≥C3
6
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival 
FU
Visit/Cycle Number
Cycle Day
1
8
15
1
15
1
1
1
1
1
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
Telephone Contact
X
A phone visit will be 
scheduled to report blood 
pressure and record AEs. 
Blood pressure will be taken, 
for example, at home or at a 
local pharmacy, and will be 
reviewed with the investigator 
or designee.
Vital Signs 
(resting BP, heart 
rate, respiratory rate, 
and temp) and weight
X
X
X
*
X
X
*
X
X
X
X
X
X
X
* The D15 visits are 
mandatory for C1 and C2. 
During C3 and subsequent 
cycles, participants may return 
for the D15 visit if BP 
monitoring is required. 
12-lead ECG with 
QTcF Determination
X
X
X
X*
X*
X
X
ECG at Screening, C1D1, 
C2D1.
* D1 of every 4th cycle (12 
weeks) 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 participants (as 
defined in lenvatinib product 
label), conduct ECG monitoring 
every cycle. 
Additional time points may be 
performed as clinically 
necessary.
If lenvatinib is discontinued, 
ECGs are only required at the 
EOT and Safety FU visits.
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Study Period
Crossover 
Screen-
ing
Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
C4
C5
C6 to 
C35
≥C3
6
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival 
FU
Visit/Cycle Number
Cycle Day
1
8
15
1
15
1
1
1
1
1
ECOG Performance 
Status
X
X*
X
X
X
X
X
X
X
X
At screening, obtain within 7 
days before initiation of study 
intervention and then on D1 of 
each cycle prior to dosing.
ECOG will need to be repeated 
if the assessment was performed 
outside of the protocol window.
* If screening ECOG 
performance status is obtained 
within 3 days prior to Crossover 
C1D1, no need to repeat at C1.
Laboratory Procedures/Assessments (Local Laboratory)
Serum β-HCG or 
Urine Pregnancy 
(WOCBP only)
X
X
X
X
X
X
X
X
X
WOCBP require negative test 
prior to Crossover C1D1. 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.
Serum FSH 
(WONCBP only)
X
In the absence of 12 months of 
amenorrhea, confirmation with 
2 FSH measurements in 
postmenopausal range is 
required.
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Study Period
Crossover 
Screen-
ing
Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
C4
C5
C6 to 
C35
≥C3
6
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival 
FU
Visit/Cycle Number
Cycle Day
1
8
15
1
15
1
1
1
1
1
CBC with 
Differential
X*
X
X
X
X
X
X
X
X
X
* Perform within 7 days before 
first dose. 
After C1D1, collect samples 
within 3 days before dosing.
Clinical Chemistry
X*
X
X
X
X
X
X
X
X
X
Urine Dipstick 
Testing (or 
Urinalysis)
X*
X
X
X
X
X
X
X
X
X
X
* Perform within 7 days before 
first dose. After C1, collect 
samples within 3 days before D1 
of each cycle.
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 If lenvatinib is 
discontinued, urine dipstick 
testing is no longer required. 
After Screening, urine dipstick-
testing for protein will be 
performed within 3 days before 
Day 1 of every cycle while 
participants are taking 
lenvatinib.
Urinalysis
X*
X
X
X
Perform within 7 days before 
first dose. During study 
intervention, obtain urinalysis at 
every 6th cycle (eg, 6, 12, 18, 
etc.), within 3 days of dosing.
* Assessment should be done 
within 7 days of C1D1.
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Study Period
Crossover 
Screen-
ing
Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
C4
C5
C6 to 
C35
≥C3
6
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival 
FU
Visit/Cycle Number
Cycle Day
1
8
15
1
15
1
1
1
1
1
INR or PT and aPTT 
or PTT
X*
* Perform within 7 days prior to 
the first dose. 
Additional testing is to be 
performed as clinically indicated 
for participants taking 
anticoagulants.
T3 or FT3, T4, TSH
X*
X
X
X
X
X
* Perform screening labs within 
7 days prior to the first dose, 
then at C2 and every 2 cycles 
thereafter (C4, C6, C8, etc.).
Participants may be dosed in 
subsequent cycles after C1D1 
while thyroid function test are 
pending.
Free T3/T4 is acceptable if total 
T3/T4 cannot be determined.
The central laboratory may be 
used only if the local laboratory 
cannot perform these tests.
Pharmacokinetics/Pharmacodynamics/ Biomarkers (Central Laboratory)
Serum for 
Pembrolizumab PK 
X
X
X*
Collect predose on C1D1, 
C2D1, and *C8D1.
Serum Anti-
pembrolizumab 
Antibodies (ADA)
X
X
X*
Collect predose on C1D1, 
C2D1, and *C8D1.
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Study Period
Crossover 
Screen-
ing
Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
C4
C5
C6 to 
C35
≥C3
6
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival 
FU
Visit/Cycle Number
Cycle Day
1
8
15
1
15
1
1
1
1
1
Plasma for 
Lenvatinib PK
X
X
X
C1D1: postdose at any time 
from 0.5 to 4h; collection from 6 
to 10h postdose is optional. 
C1D15: collect predose within 
2h of lenvatinib dosing and 
postdose at any time from 2 to 
12h postdose.
C2D1: collect predose within 2h 
of lenvatinib dosing and 
postdose at any time from 0.5 to 
4h; collection from 6 to 10h 
postdose is optional.
Postdose samples will not be 
collected if lenvatinib dosing is 
on hold due to dose 
modifications, etc.
Blood for Plasma 
Biomarkers 
X
X
X
X
X
X
X
Collect at predose on D1 of C1, 
C2, C3, C5, C7, C9, C11, C13, 
C15, C17, then on D1 of every 3 
cycles until EOT, including at 
the EOT visit.
Blood for Serum 
Biomarkers 
X
X
X
X
X
X
Collect predose. Collect on 
C1D1, C1D15, C2D1, C3D1, 
C5D1, and at EOT.
Blood for RNA 
Analysis
X
X
X
X
X
Collect predose on C1D1, 
C2D1, C3D1, C5D1, and at 
EOT.
Blood for Circulating 
Tumor Nucleic Acids
X
X
X
X
X
X
X
Collect at predose on D1 of C1, 
C2, C3, C5, C7, C9, C11, C13, 
C15, C17, then on D1 of every 3 
cycles until EOT, including at 
the EOT visit.
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Study Period
Crossover 
Screen-
ing
Intervention (21-Day Cycles)
Post-Intervention Visit
Notes
C1
C2
C3
C4
C5
C6 to 
C35
≥C3
6
EOT
Safety 
FU
Effi-
cacy 
FU
Sur-
vival 
FU
Visit/Cycle Number
Cycle Day
1
8
15
1
15
1
1
1
1
1
Patient reported Outcomes (PRO)*
EQ-5D-5L
X
X
X
X
X
X*
X
X
It is a best practice and strongly 
recommended that ePROs are 
administered before any other 
visit procedures and in the order 
listed in the SoA, starting with 
EuroQoL EQ-5D-5L. 
Collection begins at C1 and 
continues until C35 or treatment 
discontinuation, whichever 
occurs first. 
* Obtain on Day 1 of every 
cycle from C1 through C9, then 
Day 1 of every other cycle 
through C17 (C9, C11, C13, 
C15, C17), then collect every 3 
cycles through C35 (C20, C23, 
C26, C29, C32, C35).  Obtain at 
EOT and Safety FU.
Refer to Section 8.2.2. 
EORTC QLQ-C30
X
X
X
X
X
X*
X
X
EORTC QLQ-
H&N35
X
X
X
X
X
X*
X
X*
Abbreviations: ADA = anti-drug antibodies (pembrolizumab); AE = adverse event; aPTT = activated partial thromboplastin time; BP = blood pressure; β-HCG; = β human 
chorionic gonadotropin; C = cycle; CBC = complete blood count; CXDY= Cycle X Day Y; d = days; D = day; D/C = discontinuation; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; EORTC = European Organization for Research and Treatment of Cancer; EOT = end of treatment; ePRO = electronic patient reported outcome; 
EQ-5D-5L = European Quality of Life Five-Dimensional Five-Level Scale Questionnaire; FSH = follicle-stimulating hormone; FT3 = free triiodothyronine; FU = follow-up; h = 
hours; INR = international normalized ratio; PD = progressive disease; PK = pharmacokinetics; PRO = patient reported outcome; PT = prothrombin time; PTT = partial 
prothrombin time; Q6W = every 6 weeks; Q9W = every 9 weeks; Q12W = every 12 weeks; QLQ-C30 = Quality of Life Questionnaire-Core 30 items; QTcF = QT interval 
corrected with Fridericia’s formula; RNA= ribonucleic acid; SAE = serious adverse event; SoA = schedule of activities; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-
stimulating hormone; WOCBP = women of childbearing potential; WONCBP = women of non-childbearing potential; Y = year.
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1.3.4
Second Course
NOTE: As of Amendment 07, there will be no Second Course. This section is no longer applicable. 
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2
INTRODUCTION
Lenvatinib with or without pembrolizumab and SOC chemotherapy study interventions are 
being evaluated for previously treated participants with R/M HNSCC who progressed after 
platinum-containing chemotherapy at any time (with or without cetuximab) and a PD-1/PD-
L1 inhibitor, in this randomized, open-label, Phase 2 study.
2.1
Study Rationale
Head and neck cancer describe an anatomically heterogeneous group of cancers that arise 
most often from the oral cavity, the oropharynx, hypopharynx, and the larynx [Dorsey, K. 
2013]. More than 90% of head and neck cancers are squamous cell carcinomas, originating 
from the epithelium of the mucosal lining of the upper aerodigestive tract [Gupta, B., et al 
2016]. As the sixth most common cancer worldwide, head and neck cancer is diagnosed in 
approximately 630,000 new patients annually, accounting for 350,000 deaths every year.  
[Vigneswaran, N. 2014]. Head and neck cancers have high mortality rates in developing 
countries (age-standardized mortality rates of 7.9 and 2.2 per 100,000 in males and females, 
respectively) [Gupta, B., et al 2016].
More than 90% of patients with HNSCC initially present with disease confined to the head 
and neck mucosa and/or to the regional cervical lymph nodes [Machiels, J. P. 2011]. Surgery 
and radiation therapy are markedly effective for patients with Stage I and II disease. 
However, despite intensive multimodal treatment, approximately 50-60% of patients with 
locally advanced Stage III or Stage IV HNSCC recur initially with locoregional disease. 
However, a significant proportion of these patients ultimately have incurable disease 
recurrence requiring palliative systemic treatment. The prognosis for patients with R/M 
HNSCC is dismal and OS is less than 1 year [Argiris, A., et al 2017].
Patients with R/M HNSCC present a therapeutic challenge. First-line treatment generally 
includes the combination of either cetuximab or docetaxel with a platinum-based 
chemotherapy with or without 5-FU. Patients who are asymptomatic usually are treated with 
monotherapy to balance the side-effects associated with combination regimens. Options for 
first-line single-agent treatment include platinum, 5-FU, paclitaxel, docetaxel, methotrexate, 
cetuximab, gemcitabine, or capecitabine [National Comprehensive Cancer Network 2018]. 
No Phase 3 randomized trial showed an improvement in OS for any regimen until the 
EXTREME trial [Vermorken, J. B., et al 2008]. This trial demonstrated that the addition of 
cetuximab to the combination of platinum plus 5-FU improved median OS to 10.1 months 
from 7.4 months when compared to platinum plus 5-FU alone. 
Data from the final analysis of KEYNOTE-048, an ongoing Phase 3, open-label trial to 
compare the efficacy and safety of pembrolizumab as monotherapy or in combination with 
chemotherapy (platinum plus 5-FU) in first-line treatment versus the standard EXTREME 
chemotherapy regimen (cetuximab in combination with platinum plus 5-FU) is provided in 
Section 2.2.3. In the population of all participants regardless of PD-L1 expression status, 
there was a clinically meaningful difference in OS when comparing pembrolizumab plus 
chemotherapy with standard treatment. The pembrolizumab plus chemotherapy group had a 
longer duration of response than the EXTREME regimen and the safety profile was 
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comparable. There was a clinically meaningful difference in OS when comparing 
pembrolizumab monotherapy group compared to standard treatment for participants whose 
tumors expressed PD-L1 (CPS ≥1). The pembrolizumab monotherapy group had more 
responders who achieved a CR and a more durable duration of response (DOR). The safety 
profile for pembrolizumab monotherapy was favorable. Based on this data, pembrolizumab is 
now approved in the US, Japan, Western Europe and other countries as monotherapy and in 
combination with chemotherapy for 1L HNSCC treatment.
After failure of first-line therapy in the R/M setting, objective responses to second-line 
cytotoxic chemotherapy are uncommon, particularly when contemporary response criteria are 
applied. Single-agent therapy and combination regimens using either conventional cytotoxic 
chemotherapy and/or molecularly targeted agents, combined with best supportive care is 
palliative for patients with R/M HNSCC, and their prognosis is generally poor despite these 
therapies [National Comprehensive Cancer Network 2018]. The most widely used agents 
include platinum compounds (cisplatin, carboplatin), taxanes (docetaxel, paclitaxel), 5- FU, 
and single-agent cetuximab. Other single agents have produced higher response rates but 
these have generally been associated with increased toxicity, and without an impact on OS 
[Vermorken, J. B. 2010] [Price, K. A. 2012] [Colevas, A. D. 2006] [Sacco, A. G. 2015] 
[Dorsey, K. 2013]. Furthermore, there is no approved therapy or supporting data from 
existing clinical trials for the treatment of patients who progress after failure of prior 
immunotherapy (PD-1/PD-L1 inhibitors, such as nivolumab and pembrolizumab).
In preclinical models, lenvatinib decreased the TAM population, which is known as an 
immune-regulator in the tumor microenvironment. The decrease in TAM population was 
accompanied by increases in activated cytotoxic T-cell populations through stimulation of 
interferon-gamma signaling, resulting in increased immune activation [Kato, Y., et al 2019]. 
The immune-modulating effect of lenvatinib may result in a potent combination effect with 
PD-1/L1 signal inhibitors. The effect of combining lenvatinib with an anti-human PD-1 
humanized mAb was investigated in 4 murine tumor isograft models, which showed 
significant tumor growth inhibition compared to control. In the RAG murine tumor isograft 
tumor model, survival in the group treated with the combination was significantly longer than 
that of the respective monotherapy groups. In the CT26 murine tumor isograft model, 
treatment with the combination significantly increased the population of activated cytotoxic 
T cells compared to that of the respective monotherapy groups [Kato, Y., et al 2019]. All 
treatments were well-tolerated and severe body weight loss was not observed.
The ongoing lenvatinib + pembrolizumab combination Study 111/KEYNOTE-146 (Section 
2.2.3) in participants with HNSCC has shown promising clinical activity and a manageable 
tolerability and safety profile [Taylor, M. H., et al 2018]. These results demonstrated an 
initial ORR of 40.9% that strongly suggest greater efficacy with the combination of 
lenvatinib + pembrolizumab than with either single agent, a possibly additive effect. Follow-
up data for the KEYNOTE-146 HNSCC cohort demonstrated an overall ORR of 46% (10/22; 
95% CI: 24.4, 67.8). The median DOR was 8.2 months (95% CI: 2.2, 12.6), and the median 
progression-free survival (PFS) was 4.7 months (95% CI: 4.0, 9.8). In total, treatment was 
ongoing for 14% (3/22) of patients with HNSCC at the time of data cutoff [Taylor, M. H., et 
al 2020].
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Given the approvals of pembrolizumab and nivolumab for patients with R/M HNSCC who 
have progressed on prior platinum therapy as well as approval for pembrolizumab for 
patients with 1st line R/M HNSCC, there is a growing medical need for safe and efficacious 
subsequent treatment options for patients who experience disease progression on or after 
immunotherapy treatment. 
Data suggest that the combination or sequencing of immune checkpoint inhibitors may be 
used to restore activity in participants who have progressed on a particular inhibitor. This 
strategy may also offer a more powerful tool to induce immune activity in tumors that 
respond poorly (ie, those that may have a greater level of immune suppression) [Pennock, G. 
K. 2015]. Additionally, combining therapies with differing mechanisms of action has the 
potential to further enhance their clinical benefits compared with using single-agent 
immunotherapy. 
The intended population of this Phase 2 study represents patients with a high unmet medical 
need considering all of these patients have incurable R/M HNSCC disease. In these patients 
who have failed prior platinum-containing therapy and have acquired resistance to 
immunotherapy, the combination of pembrolizumab with lenvatinib could lead to a greater 
depth of response and an increase in OS. The current study is designed to further evaluate the 
safety and efficacy of combination therapy with pembrolizumab + lenvatinib as 2L+ 
treatment for R/M HNSCC patients.
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.
Lenvatinib inhibits the kinase activities of vascular endothelial growth factor (VEGF) 
receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib inhibits 
other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and 
cancer progression in addition to their normal cellular functions, including fibroblast growth 
factor (FGF) receptors FGFR1, 2, 3, and 4; platelet-derived growth factor receptor alpha 
(PDGFRα), KIT, and RET. Lenvatinib also exhibited antiproliferative activity in cell lines 
dependent on activated FGFR signaling with a concurrent inhibition of FGF-receptor 
substrate 2α phosphorylation. Refer to the respective IBs/approved labeling for detailed 
background information on pembrolizumab and lenvatinib.
2.2.1
Pharmaceutical and Therapeutic Background
2.2.1.1
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 
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responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 that has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
[Greenwald, R. J., et al 2005] [Okazaki, T., et al 2001].
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an 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 R/M HNSCC.
2.2.1.2
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.
Lenvatinib inhibited cell free kinase activities for VEGFR1-3 and FGFR1-3 with Ki values 
around 1 nmol/L, and 8-22 nmol/L, respectively. In cell-based assays, lenvatinib inhibited 
VEGF-derived and FGF-derived tube formation of HUVEC with IC50 values of 2.1 and 
7.3 nmol/L, respectively. Analysis of the signal transduction molecules revealed that 
lenvatinib inhibited both the MAPK pathway and the mTOR-S6K-S6 pathway in HUVECs 
triggered by activated VEGFR and FGFR. Furthermore, lenvatinib (10, 30 mg/kg) 
significantly inhibited both VEGF- and FGF-driven angiogenesis in a murine in vivo model 
[Yamamoto, Y., et al 2014]. In vivo, lenvatinib exhibited antitumor activity against various 
human tumor xenografts in athymic mice including 5 types of thyroid carcinomas 
(differentiated [papillary and follicular], anaplastic, squamous, and medullary thyroid 
carcinomas), RCC, HCC, melanoma, gastric cancer, NSCLC, ovarian cancer, Ewing’s 
sarcoma, and osteosarcoma. In addition, the antitumor activity of lenvatinib in combination 
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with other anticancer agents in several xenograft models was greater than that of lenvatinib 
or the other agents alone.
In summary, lenvatinib inhibited VEGF-driven VEGFR2 phosphorylation and suppressed 
proliferation and tube formation in HUVEC models. Antitumor activity of lenvatinib in vivo 
has been shown in numerous xenograft animals. These results suggest that lenvatinib may be 
a novel anticancer therapy through inhibition of angiogenesis and may be useful as either 
monotherapy or in combination with other anticancer drugs. 
2.2.1.3
Pembrolizumab Plus Lenvatinib
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of CD8+ T cells and the ratio 
of CD8+ effector T cells/FoxP3+ regulatory T cells (T-regs) correlates with improved 
prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and 
pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. 
Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable 
objective tumor responses in cancers such as melanoma [Dudley, M. E., et al 2005] [Hunder, 
N. N., et al 2008].
In preclinical models, lenvatinib decreased the TAM population, which is known as an 
immune-regulator in the tumor microenvironment. The decrease in TAM population was 
accompanied by increases in activated cytotoxic T-cell populations through stimulation of 
interferon-gamma signaling, resulting in increased immune activation [Kimura, T., et al 
2018]. The immune-modulating effect of lenvatinib may result in a potent combination effect 
with PD-1/L1 signal inhibitors. The effect of combining lenvatinib with an anti-human PD-1 
humanized mAb was investigated in 4 murine tumor isograft models, which showed 
significant tumor growth inhibition compared to control. In the RAG murine tumor isograft 
tumor model, survival in the group treated with the combination was significantly longer than 
that of the respective monotherapy groups.  In the CT26 murine tumor isograft model, 
treatment with the combination significantly increased the population of activated cytotoxic 
T cells compared to that of the respective monotherapy groups [Kato, Y., et al 2019]. All 
treatments were well tolerated, and severe body weight loss was not observed.
2.2.2
Preclinical and Clinical Studies
2.2.2.1
Completed Studies with Pembrolizumab and Lenvatinib
Refer to the respective IBs/approved labeling for detailed background information on 
pembrolizumab and lenvatinib.
2.2.3
Ongoing Clinical Studies of Pembrolizumab and Lenvatinib
There is an expansive ongoing research program of clinical studies evaluating 
pembrolizumab in patients with a number of hematological and solid malignancies, including 
HNSCC. The clinical program for HNSCC consists of the completed and ongoing studies for 
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R/M disease (KN012, KN055, KN040, and KN048), as well as planned studies, LEAP-009 
and LEAP-010.
Lenvatinib is undergoing studies in participants with different types of solid tumors, 
including HNSCC, in combination with other therapies including PD-1 targeted therapies. 
Pembrolizumab + lenvatinib study 111/KEYNOTE-146 is summarized under ongoing 
clinical studies of pembrolizumab in HNSCC. Refer to the respective IBs/approved labeling 
for full lists of ongoing studies and detailed background information on pembrolizumab and 
lenvatinib. 
Ongoing Clinical Studies of Pembrolizumab in HNSCC
KEYNOTE-012 (KN012) 
KN012 is a Phase 1b, multi-cohort study evaluating the single-agent activity of 
pembrolizumab in various solid tumors, including 2 cohorts of participants (Cohorts B and 
B2) with R/M HNSCC. Cohort B consisted of 60 participants with PD-L1 positive HNSCC 
who received pembrolizumab 10 mg/kg Q2W. Cohort B2 consisted of 132 participants 
regardless of PD-L1 status, who received pembrolizumab 200 mg Q3W. Responses were 
seen in both HPV positive and HPV-negative participants. This was the first immunotherapy 
demonstrating clinically meaningful antitumor activity in a heavily pretreated incurable 
HNSCC population with R/M disease. Enrollment is closed, but participants are ongoing in 
the study.
The efficacy and safety results after long-term follow-up based on pooled data from 
Cohorts B and B2 were presented at ASCO 2016 [Mehra, R., et al 2016]. In the R/M HNSCC 
population (n=192), the ORR was 21.9% (95% CI; 12.5%, 34.0%) in HPV positive 
participants and 15.9% (95% CI: 10.0%, 23.4%) in HPV-negative participants. In a separate 
publication, when PD-L1 expression analyses were restricted to only tumor cells (TPS), there 
was no statistically significant increase ORR with PD-L1 positive (≥1%) versus negative 
(<1%) tumors. Conversely, when PD-L1 expression was assessed both on tumor cells and 
immune cells by evaluating the CPS, PD-L1 expression significantly correlated with ORR, 
PFS, and OS [Chow, L. Q., et al 2016]. The ORR with pembrolizumab is greater than that of 
existing standard single-agent cytotoxic chemotherapies such as cetuximab, which in the 
setting of second-line R/M disease has an ORR of approximately 11% based on a meta-
analysis estimating a pooled ORR for cetuximab based on 3 Phase II trials in the R/M 
HNSCC setting. Median OS was 8.5 months (95% CI: 6.5, 10.5), compared to the historical 
OS rate of 6 months for participants who progress following first-line treatment. The 6-
month PFS rate was 24.9% [Lala, M., et al 2018].
Importantly, the responses seen with pembrolizumab were durable. Among participants with 
R/M HNSCC, the DOR ranged from 1.8+ to 21.8+ months, and the median was not reached. 
Among participants who responded (n=34), 85% of responses lasted ≥6 months and 71% of 
responses lasted ≥12 months, and 65% of responses were ongoing at the data cutoff with 3 
lasting at least 2 years [Soulieres, D., et al 2017]. These results demonstrate the consistent 
durability of responses seen with pembrolizumab treatment and compare favorably to SOC 
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chemotherapy or epidermal growth factor receptor inhibitors, which have reported median 
DOR of 4 to 6 months. 
These results of KN012 demonstrate consistent and clinically meaningful activity of 
pembrolizumab in heavily pretreated participants with HNSCC and demonstrate a robust and 
unprecedented antitumor activity observed compared to available current SOC chemotherapy 
agents. The prolonged DOR seen in the majority of participants that respond to 
pembrolizumab is substantially distinct from what is expected with chemotherapy in 
previously treated patients with HNSCC.  
KEYNOTE-055 (KN055)
KN055 is a Phase 2, nonrandomized, single cohort study of pembrolizumab (200 mg Q3W) 
monotherapy in a heavily pretreated population of patients with R/M HNSCC who have 
progressed on prior platinum and cetuximab therapy. Results from 171 participants treated 
with pembrolizumab were presented by Bauml et al [Bauml, J., et al 2017]. When confirmed 
responses were evaluated, the ORR was 16% (CR, n=1; PR, n=27; 95% CI: 11%, 23%) with 
a median DOR of 8 months (range, 2+ to 12+ months); the stable disease rate was 19% 
(n=33; 95% CI: 14%, 26%). Response rates were slightly higher in participants that were PD-
L1 positive; 18% of participants with CPS ≥1% PD-L1 expression responded to 
pembrolizumab compared with 12% of participants with CPS <1% expression. Nonetheless, 
PD-L1–negative participants responded to pembrolizumab at a rate that is clinically 
meaningful; 6- and 12-month PFS and OS rates were relatively similar between PD-L1–
negative and PD-L1–positive participants. The results presented by Bauml et al [Bauml, J., et 
al 2017], confirm findings from KN012 in the R/M HNSCC population; pembrolizumab 
monotherapy (200 mg Q3W) demonstrates consistent and clinically meaningful activity in 
heavily pretreated participants with HNSCC.
KEYNOTE-040 (KN040) 
KN040 is an ongoing Phase 3, randomized, active-controlled, open-label study of 
pembrolizumab versus the choice of 3 different SOC therapies in participants with R/M 
HNSCC. Four hundred and ninety-five participants with R/M HNSCC were randomized 1:1 
to receive pembrolizumab 200 mg Q3W or the investigator’s choice of one of the following 
therapies chosen prior to randomization: single-agent methotrexate, single-agent docetaxel, 
or single-agent cetuximab. Randomization was stratified by ECOG performance status (0 vs. 
1), HPV status (Oropharynx – p16 positive vs. Oropharynx – p16 negative or 
larynx/hypopharynx/oral cavity HNSCC), and PD-L1 status (strong positive or not; strong 
positive was defined as TPS ≥50% PD-L1 testing by IHC). The primary objective of the 
study was to evaluate OS in participants with R/M HNSCC treated with pembrolizumab 
compared to SOC treatment. Enrollment is closed, but participants are ongoing in the study.
The efficacy and safety data from the final analysis were reported, and at the time of the final 
analysis, 181 (73%) of 247 patients in the pembrolizumab group and 207 (83%) of 248 
patients in the SOC group had died. The median OS in the intention-to-treat (ITT) population 
was 8.4 months (95% CI 6.4-9.4) with pembrolizumab and 6.9 months (5.9-8.0) with SOC 
(hazard ratio 0.8, 0.65-0.98; nominal p=0.0161). In the ITT population, the median DOR was 
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18.4 months in the pembrolizumab group compared with only 5 months for SOC [Cohen, E. 
E. W., et al 2019].
For participants with a PD-L1 CPS1 tumor score, the HR for OS was 0.74 (95% CI 0.58-
0.93; nominal p=0.0049), with a median survival of 8.7 months (95% CI 6.9-11.4) for 
pembrolizumab vs. 7.1 months (5.7-8.3) with SOC. In participants whose tumor had PD-L1 
TPS ≥50% expression, the HR for death was 0.53 (95% CI 0.35-0.81; nominal p=0.0014), 
and median OS was 11.6 months (95% CI 8.3-19.5) compared to 6.6 months (4.8-9.2) for 
pembrolizumab and SOC, respectively. 
Fewer patients treated with pembrolizumab than with SOC had treatment-related AEs (63% 
vs. 84%), as well as higher toxicity adverse events (Grade ≥3 treatment-related AEs 13% vs. 
36%).
KEYNOTE-048 (KN048)
KN048 is an ongoing Phase 3, randomized, active-controlled, open-label study of 
pembrolizumab, or pembrolizumab plus platinum plus 5-fluorouracil chemotherapies versus 
platinum plus 5-fluorouracil plus cetuximab (EXTREME regimen) in participants with first-
line R/M HNSCC. A total of 882 participants with first-line R/M HNSCC were randomized 
worldwide 1:1:1 between the 3 arms of the study to examine the efficacy and safety of 
pembrolizumab (n=301 participants), or pembrolizumab plus chemotherapy (n=281 
participants) versus SOC with cetuximab and chemotherapy (n=300 participants). 
Randomization was stratified by PD-L1 tumor expression (strongly positive TPS ≥50% vs. 
not strongly positive), HPV status for oropharyngeal cancer (positive vs. negative), and 
ECOG performance status (0 vs. 1). The primary endpoints of the study are PFS per RECIST 
1.1 as assessed by BICR, and OS. Enrollment is closed, but participants are ongoing in the 
study.
Data from the second interim analysis were presented at the 2018 European Society of 
Medical Oncology (ESMO) 2018 for KEYNOTE-048[Burtness, B., et al 2018]. For OS, 
pembrolizumab monotherapy was superior to the EXTREME regimen in participants with a 
combined positive score (CPS ≥ 20), HR 0.61 (95% CI 0.45-0.83, p=0.0007), and yielded a 
median OS that was longer with pembrolizumab (14.9 months) than the EXTREME regimen 
(10.7 months). Statistical significance was also achieved for pembrolizumab monotherapy in 
participants whose tumors had PD-L1 expression of CPS ≥1 with HR 0.78 (95% CI 0.64-
0.96, p=0.0086) and a median OS of 12 months versus 10.3 months in participants receiving 
the EXTREME regimen.
Confirmed ORR for pembrolizumab versus EXTREME was 23% vs. 36% for CPS ≥20 with 
a more durable DOR of 20.9 vs. 4.2 months, and 19% vs. 35% for CPS ≥1 with a median 
DOR of 20.9 versus 4.5 months for CPS ≥1.
Pembrolizumab monotherapy had a more favorable toxicity profile compared to the 
EXTREME regimen with few related AEs (58.3% vs. 96.9%), fewer related Grade 3-5 AEs 
(16.7% vs. 69%), and fewer related AEs that led to treatment discontinuation (4.7% vs. 
19.9%).
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At final analysis, for participants whose tumors had PD-L1 expression, OS results further 
confirmed the statistically and clinically meaningful results observed at the second interim 
analysis, with an HR of 0.74 [95% CI: 0.61, 0.90] for CPS ≥1 and HR of 0.58 [95% CI: 0.44, 
0.78] for CPS ≥20. In the population of all participants, there was a clinically meaningful 
difference in OS when comparing pembrolizumab monotherapy with standard treatment.  
The pembrolizumab monotherapy group had more responders who achieved a CR and a 
more durable DOR (22.6 vs. 4.5 months). The safety results at final analysis were similar to 
those observed at the second interim analysis.
At the second interim analysis, pembrolizumab + chemotherapy significantly improved OS in 
the total population (HR 0.77 [95% CI 0.63-0.93]; p=0.0034, median 13 vs. 10 months). 
Additionally, the safety profiles for pembrolizumab + chemotherapy and the EXTREME 
regimen were comparable (95.3% vs. 96.9% related AEs for pembrolizumab vs. EXTREME; 
71.0% vs. 69.0% related Grade 3-5 AEs for pembrolizumab vs. EXTREME; and 22.8% vs. 
19.9% related AEs that led to treatment discontinuation). At final analysis, pembrolizumab + 
chemotherapy OS results (HR 0.72 [95% CI: 0.60, 0.87]) further confirmed the statistically 
significant and clinically meaningful OS observed at the second interim analysis. In the 
population of participants who tumors express PD-L1, OS was statistically significant and 
clinically meaningful in PD-L1 CPS ≥1 (HR 0.65 [95% CI: 0.53, 0.80], p=0.00002) and in 
CPS ≥20 (HR 0.60 [95% CI: 0.45, 0.82], p=0.00044). Furthermore, in participants whose 
tumors had PD-L1 expression, ORR and median time to response were similar, but the 
pembrolizumab + chemotherapy group had more durable DOR of 6.7 vs. 4.3 months for CPS 
≥1 and 7.1 vs. 4.2 months for CPS ≥20. The safety results at final analysis were similar to 
those observed at the second interim analysis.
Study 111/KEYNOTE-146
Study 111/KEYNOTE-146 is a multicenter, open-label, Phase 1b/2 clinical study being 
conducted to evaluate the efficacy and safety of lenvatinib in combination with 
pembrolizumab in selected solid tumors (ie, HNSCC, NSCLC, RCC, endometrial cancer, 
urothelial carcinoma, and melanoma) [IB Edition 16 2019]. The Phase 1b portion of this 
study has been completed and Phase 2 is ongoing. During the Phase 1b portion of the study, 
the MTD was determined to be 20 mg lenvatinib daily in combination with 200 mg of 
pembrolizumab IV Q3W. The safety and efficacy of the combination at the lenvatinib RP2D 
is being assessed in the Phase 2 portion of the study.
As of 01-DEC-2017, 22 study participants with measurable, confirmed metastatic HNSCC 
and ECOG performance status of 0 or 1 were enrolled in this cohort and received lenvatinib 
(20 mg/day orally) + pembrolizumab (200 mg IV Q3W). Participants were not preselected 
based on PD-L1 status. Tumor assessments were performed by study investigators using 
iRECIST. Of the participants, 9.1% had received no prior anticancer therapy, 63.6% had 
received 1 prior line of anticancer therapy, and 13.6% had received 2 prior lines of anticancer 
therapies and 13.6% had received ≥3 prior lines of anticancer therapies, respectively. At data 
cutoff, ORR was 40.9% (95% CI: 20.7, 63.6); ORR (at Week 24) was 36.4% (95% CI: 17.2, 
59.3), including 1 (4.5%) CR, 8 (36.4%) PR, 11 (50%) SD, 0 (0%) PD, and 2 (9.1%) 
unknown; median PFS of 8.2 months (95% CI: 4.3, NE); and PFS rate at 12 months was 41.9 
% (95% CI: 17.6, 64.7) [Taylor, M. H., et al 2018]. 
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Grade 3 or 4 TRAEs occurred in 72.7% of participants [Grade 3 TRAEs 15 (68.2%) and 
Grade 4 TRAEs 1 (4.5%)]. The most common TRAEs were fatigue (50.0%; Grade 3: 4.5%), 
hypertension (40.9%, Grade 3: 18.2%), and diarrhea (36.4%, Grade 3: 4.5%). Five 
participants experienced serious TRAEs including hypertension, acute kidney injury, 
dehydration, hemoptysis and pulmonary edema. There were 5 fatal AEs reported; none were 
deemed treatment-related [Taylor, M. H., et al 2018].
Follow-up data for the KEYNOTE-146 HNSCC cohort demonstrated an overall ORR of 46% 
(10/22; 95% CI: 24.4, 67.8). The median DOR was 8.2 months (95% CI: 2.2, 12.6), and the 
median PFS was 4.7 months (95% CI: 4.0, 9.8). In total, treatment was ongoing for 14% 
(3/22) of patients with HNSCC at the time of data cutoff [Taylor, M. H., et al 2020].
Overall, the study demonstrated promising clinical activity and manageable toxicities, 
supporting further evaluation of the lenvatinib + pembrolizumab in participants with HNSCC 
[Taylor, M. H., et al 2018a]. Interim analysis results for NSCLC, urothelial carcinoma, and 
melanoma study arms produced similar response rates and acceptable safety and tolerability 
[Brose, M., et al 2018] [Vogelzang, N., et al 2018] [Taylor, M., et al 2018]. From these 
studies, the combination of pembrolizumab and lenvatinib showed promising clinical activity 
and a manageable safety profile that is consistent with the safety profile of each agent when 
administered as monotherapy.
Based on Study 111/KEYNOTE-146, lenvatinib 20 mg QD in combination with 
pembrolizumab 200 mg IV Q3W was the dose selected for this Phase 2 study.
LEAP-010
LEAP-010 is an ongoing Phase 3, randomized, double-blind, placebo-controlled study 
comparing pembrolizumab monotherapy versus pembrolizumab in combination with 
lenvatinib for patients with 1st line R/M HNSCC. Primary outcome measures include ORR 
per RECIST 1.1, PFS per RECIST 1.1, and OS. The study enrolled a total of 511 patients. To 
date, both IA1 and IA2 have been completed. ORR at IA1 was significantly higher for the 
lenvatinib + pembrolizumab arm at 46.1% compared with 25.4% for the pembrolizumab plus 
placebo arm (difference 20.2%, 95% CI 10.5-29.6, P=0.0000251). Median PFS at IA1 was 
statistically higher at 6.2 months for the lenvatinib + pembrolizumab arm versus 2.8 months 
for the pembrolizumab plus placebo arm (HR 0.64, 95% CI 0.50-0.81; P=0.0001040) 
[Licitra, L., et al 2024]. Median OS at IA2 was found not to be statistically different between 
treatment arms. Median OS was 15.0 months for the lenvatinib + pembrolizumab arm versus 
17.9 months for the pembrolizumab plus placebo arm (HR 1.15, 95% CI: 0.91-1.45; 
P=0.882). The study did not proceed with additional protocol specified efficacy analyses, 
because the probability of reaching statistical significance for OS was low [Merck & Co., 
Inc. 2023]. Therefore, LEAP-010 did not meet its primary endpoint of OS, despite 
demonstrating a statistically significant ORR and PFS with lenvatinib plus pembrolizumab 
compared with those of pembrolizumab plus placebo. In addition, the safety profile was 
consistent with previously reported data; more TRAEs were found in participants receiving 
lenvatinib + pembrolizumab.
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2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
With the approval of immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway as a 
second-line therapy for HNSCC, there is an unmet medical need for safe and efficacious 
therapy in participants whose disease has progressed with this treatment. SOC chemotherapy 
will be utilized in the control arm. The existing data suggest that inhibiting angiogenesis in 
combination with PD-1 blockade is a promising therapeutic strategy, and the benefit/risk 
assessment for participants in this study is considered to be favorable, making the 
combination of lenvatinib + pembrolizumab a promising second-line or greater therapeutic 
option in participants with R/M HNSCC, regardless of PD-L1 expression. 
Refer to the informed consent documents and the respective IBs/approved labeling for 
additional details regarding specific benefits and risks for participants participating in this 
clinical study, and detailed background information on pembrolizumab and lenvatinib.
NOTE: Based on the results of a periodic review of safety data (data cutoff 31-MAY-2024) 
for LEAP-009, the study will be discontinued. At the request of the eDMC, OS data were 
provided for review, though there was no preplanned statistical analysis for OS. At this safety 
analysis, the OS Kaplan-Meier curves did not favor the combination of lenvatinib + 
pembrolizumab versus SOC chemotherapy. Furthermore, it was considered that additional 
follow-up OS outcomes in favor of the combination are unlikely to support a clinically 
meaningful favorable benefit-risk ratio. The prespecified interim and final analyses of the 
study described in Section 9 will not be performed. Selected analyses of safety endpoints will 
be performed at the end of the study; there will be no further analyses of efficacy or ePRO 
endpoints.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
Males and females with R/M HNSCC, who are at least 18 years old, and who have 
progressed after platinum-containing chemotherapy at any time (with or without cetuximab) 
and a PD 1/PD-L1 inhibitor will be enrolled in this study.
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 4.2.1.1.1 for further details.
NOTE: Based on a periodic review of safety data (data cutoff 31-MAY-2024) for LEAP-
009, OS Kaplan-Meier curves did not favor pembrolizumab + lenvatinib versus SOC 
chemotherapy, and it was considered that additional follow-up OS outcomes in favor of the 
combination are unlikely to support a clinically meaningful favorable benefit-risk ratio. The 
prespecified interim and final analyses of the study described in Section 9 will not be 
performed. Selected analyses of safety endpoints will be performed at the end of the study; 
there will be no further planned analyses for efficacy and ePRO endpoints. Updated analyses 
are described in Section 9.
In alignment with the study-specific investigator letter dated 05-SEP-2024, all participants 
should discontinue the combination of lenvatinib + pembrolizumab (Arm 1) or lenvatinib 
monotherapy (Arm 3), as applicable. On a case-by-case basis, investigators may contact the 
Sponsor for consideration of continuing lenvatinib plus pemrolizumab or lenvatinib 
monotherapy if they assess the participant is deriving clinical benefit. Treatment with SOC 
chemotherapy (Arm 2) can continue at the discretion of the investigator until a protocol 
specified discontinuation criterion is met. Participants who are continuing study treatment 
should follow the modified protocol study procedures as specified in this amendment.
All participants beyond the 30-day Safety Follow-up Visit in the initial treatment or 
Crossover treatment phases should be discontinued from the study; however, standard safety 
reporting should continue, as applicable. As of Amendment 07, participants who are still on 
study treatment will no longer require ePRO assessments or tumor response assessments by 
BICR to be performed. Scans will no longer be required to be submitted to the iCRO; 
however, tumor imaging with investigator assessment should continue per protocol. 
Biomarker specimen collection is discontinued. The 30-day Safety Follow-up Visit is the last 
required visit. 
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Primary Objective
Primary Endpoint
Objective: to compare lenvatinib + 
pembrolizumab combination therapy and 
SOC chemotherapy with respect to OS. 
Hypothesis (H1): lenvatinib + 
pembrolizumab is superior to SOC with 
respect to OS.
OS: The time from randomization to death 
due to any cause. 
Secondary Objectives
Secondary Endpoints
Objective: to compare lenvatinib + 
pembrolizumab combination therapy and 
SOC chemotherapy with respect to PFS per 
RECIST 1.1 by BICR 
Hypothesis (H2): lenvatinib + 
pembrolizumab is superior to SOC with 
respect to PFS per RECIST 1.1 by BICR.
PFS: The time from randomization to the 
first documented disease progression or 
death due to any cause, whichever occurs 
first.
Objective: to compare lenvatinib + 
pembrolizumab combination therapy and 
SOC chemotherapy with respect to ORR 
per RECIST 1.1 as assessed by BICR.
Hypothesis (H3): lenvatinib + 
pembrolizumab is superior to SOC with 
respect to ORR per RECIST 1.1 by BICR.
Objective Response (OR): complete 
response (CR) or partial response (PR).
Objective: to assess the efficacy of 
lenvatinib + pembrolizumab combination 
therapy and SOC chemotherapy with 
respect to DOR per RECIST 1.1, by BICR.
DOR: the first documented evidence of CR 
or PR until PD or death due to any cause, 
whichever occurs first.
Objective: to assess the safety and 
tolerability of study intervention with 
lenvatinib + pembrolizumab combination 
therapy, SOC chemotherapy, and lenvatinib 
monotherapy
-AEs
-Study drug discontinuations due to AEs
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Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
Objective: to assess the efficacy of 
lenvatinib monotherapy with respect to 
ORR, PFS, DOR per RECIST 1.1 by BICR, 
and OS.
-OR
-PFS
-DOR
-OS
Objective: to evaluate changes from 
baseline in HRQoL with lenvatinib + 
pembrolizumab combination therapy, SOC 
chemotherapy and lenvatinib monotherapy 
using the EORTC QLQ-C30 and EORTC 
QLQ-H&N35.
Scores from the EORTC QLQ-C30 and 
H&N35. Global health status/quality of life 
and physical functioning scores of the 
EORTC QLQ-C30 will be evaluated as 
overall measures of HRQoL.
Objective: to evaluate health status with 
lenvatinib + pembrolizumab combination 
therapy, SOC chemotherapy and lenvatinib 
monotherapy as assessed using the 
EuroQoL EQ-5D-5L questionnaire, and to 
generate utility scores for use in economic 
models.
Health status and health utilities assessed 
using the EuroQoL EQ-5D-5L.
Objective: to identify molecular (genomic, 
metabolic, and/or proteomic) biomarkers, 
including HPV status, that may be 
indicative of clinical response/resistance, 
safety, and/or the mechanism of action of 
pembrolizumab and lenvatinib.
Molecular (genomic, metabolic, and/or 
proteomic) determinants of response or 
resistance to treatments, using blood and/or 
tumor tissue.
Objective: to assess the PK of lenvatinib 
monotherapy and when co-administered 
with pembrolizumab.
Plasma concentration of lenvatinib versus 
time.
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4
STUDY DESIGN
4.1
Overall Design
Original protocol text that is contained in this section has been retained for reference.
NOTE: Based on a periodic review of safety data (data cutoff 31-MAY-2024) for LEAP-
009, OS Kaplan-Meier curves did not favor pembrolizumab + lenvatinib versus SOC 
chemotherapy, and it was considered that additional follow-up OS outcomes in favor of the 
combination are unlikely to support a clinically meaningful favorable benefit-risk ratio. The 
prespecified interim and final analyses of the study described in Section 9 will not be 
performed. Selected analyses of safety endpoint will be performed at the end of the study; 
there will be no further planned analyses for efficacy and ePRO endpoints. Updated analyses 
are described in Section 9.
In alignment with the study-specific investigator letter dated 05-SEP-2024, all participants 
should discontinue the combination of lenvatinib + pembrolizumab or lenvatinib 
monotherapy, as applicable. On a case-by-case basis, investigators may contact the Sponsor 
for consideration of continuing lenvatinib plus pemrolizumab or lenvatinib monotherapy if 
they assess the participant is deriving clinical benefit. Treatment with SOC chemotherapy 
(Arm 2) can continue at the discretion of the investigator until a protocol specified 
discontinuation criterion is met. Participants who are continuing study treatment should 
follow the modified protocol study procedures as specified in this amendment.
All participants beyond the 30-day Safety Follow-up Visit in the initial treatment or 
Crossover treatment phases should be discontinued from the study; however, standard safety 
reporting should continue, as applicable. As of Amendment 07, participants who are still on 
study treatment will no longer require ePRO assessments or tumor response assessments by 
BICR to be performed. Scans will no longer be required to be submitted to the iCRO; 
however, tumor imaging with investigator assessment should continue per protocol. 
Biomarker specimen collection is discontinued. The 30-day Safety Follow-up Visit is the last 
required visit.
This is a Phase 2, randomized, open-label, multicenter, study of lenvatinib + pembrolizumab, 
SOC chemotherapy and lenvatinib monotherapy. Participants with R/M HNSCC who have 
progressed after platinum chemotherapy at any time (with or without cetuximab) and after 
treatment with immunotherapy (PD-1/PD-L1 inhibitors) will be enrolled in this study. This 
study will be conducted in participants with measurable disease, per RECIST 1.1 by BICR, 
regardless of PD-L1 status.
The site’s study team must have reviewed and submitted pre-study images that are of 
diagnostic quality from at least 2 dates to determine that radiographic progression has 
occurred per RECIST 1.1 following initiation of the PD-1/PD-L1 inhibitor. These images 
include at a minimum, the baseline image for prior anti-PD-1/PD-L1 or an image showing 
nadir during prior anti-PD-1/PD-L1 treatment and an image showing progression on prior
anti-PD-1/PD-L1 treatment (within 12 weeks of last doses of anti-PD-1/PD-L1 treatment). 
These pre-study images will be submitted to the iCRO to verify that the images are of 
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diagnostic quality prior to randomization (see Section 8.2.1.1). The baseline tumor image 
collected during the Screening period must be also submitted to the iCRO for verification of 
measurable disease per RECIST 1.1 for eligibility prior to randomization.
Note: The pre-study scan demonstrating progression on prior PD-1/PD-L1 treatment can be 
used as screening tumor imaging for the study if it is performed within 28 days before the 
date of randomization and can be assessed by the iCRO.
An archival or newly obtained (within 90 days prior to start of study treatment) tumor 
specimen for PD-L1 biomarker analysis will be required prior to randomization. 
Participants will be stratified prior to randomization according to ECOG PS and PD-L1 
status (see Section 6.3.2). 
Initial Treatment
Eligible participants will be centrally randomized to receive lenvatinib + pembrolizumab 
(Arm 1), SOC chemotherapy (Arm 2) or lenvatinib monotherapy (Arm 3).

Lenvatinib + pembrolizumab combination therapy (Arm 1), in which participants will 
be enrolled and treated with the combination of pembrolizumab (200 mg 30-minute 
IV infusion Q3W) for 35 cycles + lenvatinib (20 mg PO QD) until centrally verified 
PD, or until a discontinuation criterion is met. 

SOC chemotherapy (Arm 2), in which participants will be enrolled and treated with 
investigator's choice of SOC chemotherapy (docetaxel, paclitaxel, cetuximab, or 
capecitabine) until centrally verified disease progression or a discontinuation criterion 
is met.

Lenvatinib monotherapy (Arm 3), in which participants will receive lenvatinib 
monotherapy (24 mg orally PO, QD) until centrally verified disease progression or a 
discontinuation criterion is met.
The study design is shown in Figure 1 (Initial Treatment). 
A single-arm futility analysis (Figure 1) for the lenvatinib monotherapy arm will be 
conducted after 30 participants have been randomized to lenvatinib monotherapy (Arm 3) 
and have been followed up for approximately 12 weeks after study entry. Randomization to 
this arm will be paused after the 30th participant is randomized. If the number of responses 
by BICR is ≥3, randomization to the lenvatinib monotherapy arm will be resumed such that a 
total of N=100 participants will be enrolled in this arm. If the number of responses is ≤2, 
randomization to the lenvatinib monotherapy arm will be permanently stopped. If the number 
of responses by BICR ≥3 is observed prior to the 30th participant, the randomization to the 
lenvatinib monotherapy arm will not be paused. 
Overall, approximately 400 participants will be randomized, with approximately 100 
participants randomized to the lenvatinib arm and 150 participants to each of the SOC 
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chemotherapy and lenvatinib + pembrolizumab treatment arms. Enrollment was completed 
on 05-SEP-2024.
Participants will be evaluated with radiographic imaging to assess response to study 
intervention every 6 weeks from the date of randomization. After 1 year (48 weeks), imaging 
will occur every 9 weeks until centrally verified PD or initiation of a new anticancer regimen. 
Schedule should be followed regardless of treatment delays. All imaging obtained during the 
study will be submitted to the iCRO for BICR, which will assess the images using RECIST 
1.1 (Section 4.2.1.1.1) for determination of ORR and PFS. The tumor imaging showing site-
assessed PD should be submitted immediately for verification by BICR. Treatment beyond 
centrally verified radiographic PD per RECIST 1.1 may be permitted at the discretion of the 
investigator after consultation with the Sponsor and obtaining documented informed consent.
Survival Follow-up will continue after centrally verified PD, discontinuation of study 
intervention, and the start of new anticancer treatment. In addition, upon Sponsor request, 
participants may be contacted for survival status at any time during the study.
AE monitoring will be ongoing throughout the study. AEs will be graded in severity 
according to the guidelines outlined in the National Cancer Institute (NCI) CTCAE, version 
5.0.
Participants in the lenvatinib + pembrolizumab combination arm may continue receiving 
pembrolizumab for up to 35 cycles (approximately 2 years), until centrally verified PD, or 
until a discontinuation criterion is met. Participants may continue to receive lenvatinib 
monotherapy until disease progression or unacceptable toxicity. Either pembrolizumab or 
lenvatinib may be interrupted or discontinued due to toxicity and the participant may 
continue in the study receiving the remaining study treatment intervention.
Participants receiving lenvatinib monotherapy may add pembrolizumab to lenvatinib upon 
centrally verified PD by RECIST 1.1 with Sponsor consultation. As per Section 4.3.2, 
lenvatinib monotherapy dose (24 mg) should be decreased to 20 mg daily or at the last dose 
level when given in combination with pembrolizumab. Treatment with SOC chemotherapy 
may continue until a discontinuation criterion (see Section 7.1) is met. Participants receiving 
SOC chemotherapy may start pembrolizumab and lenvatinib upon centrally verified 
radiographic PD by RECIST 1.1 with Sponsor consultation. As of Amendment 07, 
participants in the SOC chemotherapy arm or lenvatinib monotherapy arm may not crossover 
to receive lenvatinib + pembrolizumab at the time of disease progression.
All decisions to continue intervention beyond centrally verified radiographic PD by RECIST 
1.1 require consultation with the Sponsor.
Crossover Treatment
Participants who experience centrally verified PD in the lenvatinib monotherapy or SOC 
chemotherapy arms can cross over to receive lenvatinib + pembrolizumab at time of disease 
progression with Sponsor consultation. All screening evaluations must be completed and 
reviewed to confirm potential participants meet all treatment eligibility criteria. For 
participants who were randomized initially to lenvatinib monotherapy, lenvatinib treatment 
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may be continued during Crossover screening at the discretion of the investigator after 
consultation with the Sponsor and if the study is ongoing. As of Amendment 07, participants 
in the SOC chemotherapy arm or lenvatinib monotherapy arm may not crossover to receive 
lenvatinib + pembrolizumab at the time of disease progression.
Second Course Treatment
NOTE: As of Amendment 07, there will be no Second Course Treatment. This section is no 
longer applicable.  
The study will be conducted in conformance with Good Clinical Practice (GCP).
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This is an open-label, randomized study with 3 treatment arms to assess the safety and 
efficacy of lenvatinib + pembrolizumab, SOC chemotherapy and lenvatinib monotherapy in 
participants with R/M HNSCC who progressed after platinum-containing chemotherapy at 
any time (with or without cetuximab) and a PD-1/PD-L1 inhibitor. The study is open label 
because of the different infusion times needed for Arms 1 and 2.
In order to provide a direct comparison of OS between the lenvatinib + pembrolizumab arm 
and SOC chemotherapy arm, 150 participants will be enrolled in each of these arms. As 
lenvatinib monotherapy has not been studied in patients with R/M HNSCC patient 
population, a lenvatinib monotherapy arm has been included to provide an estimation of the 
safety and efficacy of this treatment in this patient population. In order to accomplish this, 
the sample size for this arm will be 100 participants with interim futility analysis to be 
conducted for this lenvatinib monotherapy arm. The preliminary results detailed in Section 
2.2.3, for an open-label, Phase 1b/2 study (Study E7080-A001-111 [Study 111/KN-146]) to 
assess the safety and preliminary antitumor activity of the combination of lenvatinib + 
pembrolizumab in participants with selected solid tumors including R/M HNSCC 
demonstrated promising clinical activity, supporting further evaluation of the combination of 
lenvatinib + pembrolizumab in participants with R/M HNSCC [Taylor, M. H., et al 2018a].  
Given the lack of treatment options and high unmet medical need for patients with R/M 
HNSCC who progress on immune checkpoint inhibitor therapy, the safety and efficacy of 
lenvatinib + pembrolizumab will be assessed in this patient population. If the safety profile is 
acceptable and this combination improves OS compared to SOC chemotherapy, this study 
could support the regulatory approval of the combination of lenvatinib + pembrolizumab in 
participants with R/M HNSCC who progress after treatment with an anti-PD-1/PD-L1 mAb.
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4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
Primary Efficacy Endpoint
This study will use OS as the primary endpoint. OS has been recognized as the gold standard 
for the demonstration of superiority of a new antineoplastic therapy in randomized clinical 
studies. In addition, this change in primary endpoint is based on the updated statistical 
assumptions secondary to emerging external data for this patient population. 
Secondary Efficacy Endpoints
PFS is an acceptable measure of clinical benefit for a late stage study that demonstrates 
superiority of a new antineoplastic therapy, especially if the magnitude of the effect is large 
and the therapy has an acceptable risk/benefit profile. The use of BICR and RECIST 1.1, to 
assess PFS is typically considered acceptable by regulatory authorities. 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. Expedited verification 
of radiologic progression as determined by central review will be communicated to the site.
OR based on RECIST 1.1 as assessed by BICR will serve as an additional efficacy endpoint. 
The use of BICR and RECIST 1.1 to assess OR is typically considered acceptable by 
regulatory authorities. Images will be submitted to an iCRO and read by an independent 
central reviewer blinded to treatment assignment to minimize bias in the response 
assessments.
DOR per RECIST 1.1 assessed by BICR will serve as an additional measure of efficacy and 
is a commonly accepted endpoint by both regulatory authorities and the oncology 
community.
4.2.1.1.1
RECIST 1.1
RECIST 1.1 will be used by BICR when assessing images for efficacy measures. 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 Section 8.2.1.7 for additional detail.
4.2.1.2
Safety Endpoints
Safety parameters frequently used for evaluating investigational-systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of AEs/SAEs, and changes in vital signs and laboratory values. AEs 
will be assessed as defined by CTCAE, Version 5.0.
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4.2.1.3
Exploratory Endpoints
4.2.1.3.1
Rationale for Patient Reported Outcomes Endpoints
Changes in HRQoL using PRO assessments can provide important information on clinical 
benefit and are accepted clinical endpoints by health authorities. Participants will provide 
information regarding their HRQoL using the EORTC QLQ-C30 and EORTC QLQ-H&N35 
PRO instruments. Health utilities will be evaluated using the EuroQoL-5D-5L (EQ-5D-5L) 
PRO instrument. 
The EORTC QLQ-C30 and EORTC QLQ-H&N35 are psychometrically and clinically 
validated instruments appropriate for assessing HRQoL in participants with HNSCC 
[Bjordal, K., et al 1994] [Bjordal, K., et al 2000]. These instruments have been widely used 
in Phase 3 studies of participants with R/M HNSCC [Mesia, R., et al 2010] [Machiels, J. P., 
et al 2015] [Harrington, K. J., et al 2017] [Cohen, E. E. W., et al 2018].
EORTC QLQ-C30
EORTC QLQ-C30 is the most widely used cancer specific health-related quality of life 
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].
EORTC QLQ-H&N35
The EORTC QLQ-H&N35 is a disease specific questionnaire developed to measure QoL in 
head and neck cancer. The EORTC QLQ-H&N35 consists of 7 multi-item scales (pain in the 
mouth, problems with swallowing, senses, speech, social eating, social contact, and 
sexuality), and 11 single-item scales (problems with teeth, mouth opening, dry mouth, sticky 
saliva, coughing, feeling ill, use of analgesics, use of nutritional supplements, use of feeding 
tube, weight gain, and weight loss) [Bjordal, K., et al 1994].
EuroQoL EQ-5D-5L
The EuroQoL EQ-5D-5L is a standardized instrument for use as a measure of health outcome 
and will provide data to develop health utilities for use in health economic analyses [Rabin, 
R. and de Charro, F. 2001]. The 5 health state dimensions in the EQ 5D-5L include the 
following: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each 
dimension is rated on a 5-point scale from 1 (no problem) to 5 (unable to/extreme problems). 
The EQ-5D-5L also includes a graded (0 to 100) vertical visual analog scale on which the 
participant rates their 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] [Pickard, A. S., et al 2007a].
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4.2.1.3.2
Pharmacokinetic Endpoints
Based on PK data obtained in this study and from other studies, a population PK analysis
may be performed to characterize PK parameters of lenvatinib when co-administered with 
pembrolizumab to support the proposed dosing regimen.
4.2.1.3.3
Rationale for Anti-drug Antibody (ADA) Assessment
To evaluate the immunogenicity and exposure of pembrolizumab in this indication, sample 
collections for analysis of ADA may be performed in participants receiving lenvatinib + 
pembrolizumab (Arm 1). Sampling may be reduced or discontinued upon alignment with 
health authorities.
4.2.1.3.4
Pharmacodynamic Endpoints
No pharmacodynamic endpoints are planned for this study.
4.2.1.3.5
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 
combination 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 
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tumor microenvironment. Increased mutational burden (sometimes referred to as a ‘hyper-
mutated’ state) may generate neo-antigen presentation in the tumor microenvironment. To 
conduct this type of research, it is important to identify tumor-specific mutations that occur 
across all genes in the tumor genome. Evaluation of molecular targets and signaling 
pathways including angiogenesis- or and growth factor related signaling pathways related to 
pembrolizumab and lenvatinib may also be explored. Thus, genome-wide approaches may be 
used for this effort. Note that in order to understand tumor-specific mutations, it is necessary 
to compare the tumor genome with the germline genome. Circulating tumor DNA and/or 
RNA may also be evaluated from blood samples.
Tumor and blood RNA analyses
Both genome-wide and targeted messenger RNA (mRNA) expression profiling and 
sequencing in tumor tissue and in blood may be performed to define gene signatures that 
correlate to clinical response to treatment with pembrolizumab or other immunotherapies. 
Pembrolizumab induces a response in tumors that likely reflects an inflamed/immune 
phenotype. Specific immune-related gene sets (ie, those capturing interferon-gamma 
transcriptional pathways) may be evaluated and new signatures may be identified. Individual 
genes related to the immune system and growth factor signaling pathways (eg, VEGF and 
FGF) may also be evaluated. MicroRNA profiling may also be pursued as well as exosomal 
profiling.
Proteomics and immunohistochemistry (IHC) using blood or tumor
Tumor and blood samples from this study may undergo proteomic analyses (eg, PD-L1 IHC). 
PD-L1 protein level in tumor sections, assessed by IHC, has been shown to correlate with 
response to pembrolizumab in patients with NSCLC, and an in vitro diagnostic (IVD) device 
has been developed for use with pembrolizumab in NSCLC. Preliminary data indicates that 
this association may also be true in additional cancer types (ie, triple negative breast cancer, 
head and neck, and gastric). Additional tumor or blood-derived proteins may also correlate 
with response to pembrolizumab and lenvatinib combination therapy. Therefore, tumor tissue 
may be subjected to proteomic analyses using a variety of platforms that could include but 
are not limited to immunoassays and liquid chromatography/mass spectrometry. This 
approach could identify novel protein biomarkers that could aid in patient selection for 
pembrolizumab (MK-3475) and lenvatinib combination therapy.
Other blood-derived biomarkers
In addition to expression on the tumor tissue, PD-L1, circulating cytokines and angiogenic 
factors, and other tumor derived proteins can be shed from tumor and released into the blood. 
Assays such as enzyme-linked immunoassay (ELISA) measure such proteins in serum. 
Correlation of expression with response to pembrolizumab and lenvatinib combination 
therapy may identify new approaches for predictive biomarkers in blood, representing a 
major advance from today’s reliance on assessing tumor biomarkers. This research would 
serve to develop such assays for future clinical use.
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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.
4.2.2
Rationale for Selected Standard-of-care Chemotherapies
The proposed choice of docetaxel, paclitaxel, cetuximab, or capecitabine as single-agent, 
SOC chemotherapy is based on the NCCN guidelines for R/M HNSCC recognizing these 
agents as appropriate treatment options in the second-line setting, input from key opinion 
leaders, and prior precedence in 2L registration trials.
Docetaxel
Docetaxel has a registered indication in squamous cell carcinoma of the head and neck for 
locally advanced disease in combination with cisplatin and 5-fluorouracil. However, it is 
commonly given in the R/M setting as a single agent with RR ranging from 6-42%, 
depending on the line of therapy and patient population. For example, significant clinical 
activity of weekly docetaxel in a Phase 2 study of 38 patients was seen with a response rate 
of 42% in the 1L R/M setting [Hitt, R., et al 2006]. In addition, a randomized Phase 2 study 
of weekly docetaxel versus methotrexate showed a higher response rate for docetaxel (27%) 
in the 1L R/M setting, although survival rates were comparable [Guardiola, E., et al 2004]. 
Phase 3 studies using weekly docetaxel as the control arm in the 1L/2L setting have also been 
performed, confirming the activity of docetaxel in the predominantly 2L setting, although 
RRs were more modest at 6.2% [Argiris, A., et al 2013]. Thus, single-agent docetaxel on a 
weekly schedule has been shown to have activity in R/M disease and is utilized particularly 
in head and neck cancer patients who have not been previously exposed to taxanes.
Paclitaxel
Paclitaxel has been shown in several clinical trials to demonstrate clinical efficacy for the 
treatment of R/M HNSCC.  The majority of these studies are in mixed populations of 1L and 
2L R/M HNSCC. In the BERIL-1 study, paclitaxel plus buparlisib was compared versus 
paclitaxel plus placebo for patients with second-line R/M HNSCC. Approximately 78 
participants with second-line R/M HNSCC were enrolled in this trial and received paclitaxel 
80 mg/m2 weekly. ORR was observed to be 14% for the paclitaxel plus placebo arm. For this 
treatment arm, median OS was 6.5 months (5.3-8.8) and median PFS was 3.5 months (2.2-
3.7) [U.S. Prescribing Information 2017].
Cetuximab
Cetuximab has a registered indication for the treatment of recurrent or metastatic squamous 
cell carcinoma of the head and neck progressing after platinum-based therapy.  In an open-
label Phase 2 study of 103 R/M head and neck cancer patients treated with single-agent 
cetuximab after failing to respond to platinum-based therapy, the response rate was 13% 
[Vermorken, J. B., et al 2007]. The activity of single-agent cetuximab in R/M disease has 
also been seen in other studies, with response rates of 8-11% [Fury, M. G., et al 2012].
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Capecitabine
Capecitabine is an active, feasible and well-tolerated mode of palliative treatment for 
advanced head and neck cancer patients who have previously received platinum-based 
chemotherapy. In an open-label Phase 2 study of 40 R/M head and neck cancer patients (33 
patients were evaluable for assessment of response) treated with single-agent capecitabine 
after failing to respond to platinum-based therapy, the ORR was 24.2%. These patients had
documented PD on previous platinum-based therapy in the R/M setting (15%) or received 
platinum-based therapy in the local setting with no documentation of progression (85%). 
17.5% of the patients included in this study could be considered as having primary 
locoregional disease only, and outcomes were not reported separately for the R/M patients. 
The activity of single-agent capecitabine in combination with radiotherapy and/or CT in 
advanced or R/M disease has also been seen in other studies, with response rates of 23.5% to 
68% [Martinez-Trufero, J., et al 2010].
For participants randomized to the SOC chemotherapy arm, the investigator will be allowed 
to select one of the 4 options above that has not been previously administered to the 
participant. When choosing an SOC chemotherapy, the investigator should refer to the 
respective approved product label (with special consideration for any contraindications, 
special warnings and precautions of use), and/or according to local guidelines.
4.3
Justification for Dose
4.3.1
Pembrolizumab
The planned dose of pembrolizumab for this study is 200 mg Q3W. Based on the totality of 
data generated in the pembrolizumab development program, 200 mg Q3W is an appropriate 
dose of pembrolizumab for adults across all indications. As outlined below, this dose is 
justified by:

Clinical data from 8 randomized studies in melanoma and NSCLC indications 
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 
10 mg/kg Q2W representing an approximate 5 to 7.5 fold exposure range (refer to 
pembrolizumab IB, Section 5.2.2)

Population PK analysis showing that both fixed dosing and weight-based dosing 
provides similar control of PK variability with considerable overlap in the 
distributions of exposures, supporting suitability of 200 mg Q3W 

Clinical data showing meaningful improvement in benefit-risk including OS at 
200 mg Q3W across multiple indications

Pharmacology data showing full target saturation in both systemic circulation 
(inferred PK data) and tumor (inferred from PBPK analysis) at 200 mg Q3W.
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4.3.2
Lenvatinib
Monotherapy:
Modeling of PK data in Studies E7080-E044-101 (25 mg QD) and E7080-A001-102 (10 mg 
BID) demonstrated that PFS and PR and SD significantly increased with higher lenvatinib 
exposure (based on Cmax and AUC(0-24)). The MTD from Study E7080-E044-101 (25 mg QD) 
was correlated with higher drug exposure compared with the MTD from Study E7080-A001-
102 (10 mg BID).
Consequently, 25 mg QD was selected for the future studies, as it was determined to be the 
safest dose that provides the highest efficacy. To simplify the dose reduction scheme, a 
dosage of 24 mg QD (two 10 mg capsules + one 4 mg capsule) was selected for continued 
lenvatinib development. Refer to the respective IBs/approved labeling for detailed 
background information on pembrolizumab and lenvatinib. 
Combination therapy:
The dosing regimen for lenvatinib was selected based on the results of Phase 1b portion of 
Phase 1b/2 Study 111/KEYNOTE-146, the primary endpoints of which was to determine the 
MTD and RP2D of lenvatinib in combination with pembrolizumab 200 mg Q3W. Thirteen 
participants (lenvatinib 24 mg/day + pembrolizumab 200 mg Q3W: n=3; lenvatinib 
20 mg/day + pembrolizumab 200 mg Q3W: n=10) were enrolled in the Phase 1b portion of 
the study. Eight of the participants had RCC, 2 had NSCLC, 2 had EC, and 1 had melanoma. 
There were 2 DLTs at the dose of lenvatinib 24 mg/day + pembrolizumab 200 mg Q3W 
(1 participant had Grade 3 arthralgia, and another had Grade 3 fatigue); hence, this dose was 
defined as the toxic dose. No DLTs were reported in the next 10 participants (expansion 
part), all of whom received the lenvatinib 20 mg/day + pembrolizumab 200 mg Q3W dose. 
Based on review of all of the clinical data from these 13 participants, the MTD and RP2D 
were determined to be 20 mg lenvatinib daily in combination with a fixed dose of 200 mg 
pembrolizumab given Q3W. Based on the promising antitumor efficacy and tolerable safety 
profile seen in both the EC and RCC expansion cohorts from Study 111/KEYNOTE-146 
[Makker, V., et al 2018], two Phase 3 studies have been initiated for both of these tumor 
types, Study E7080-G000-309/KEYNOTE-775 and Study E7080-G000-307/KEYNOTE-
581.
4.3.3
SOC Chemotherapy
Doses and regimens for SOC chemotherapy were selected based on standard clinical practice 
and should be prepared per local and institutional guidelines according to the approved 
product labels.
4.3.4
Maximum Dose Exposure for This Study
NOTE: In alignment with the study-specific investigator letter dated 05-SEP-2024, all 
participants should discontinue the combination of lenvatinib + pembrolizumab or lenvatinib 
monotherapy, as applicable. On a case-by-case basis, investigators may contact the Sponsor 
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for consideration of continuing lenvatinib + pembrolizumab or lenvatinib monotherapy if 
they assess the participant is deriving clinical benefit.
The maximum dose/exposure of lenvatinib monotherapy is 24 mg QD and maximum 
dose/exposure of lenvatinib when given in combination with pembrolizumab is 20 mg QD. 
Lenvatinib may be continued until disease progression or until a discontinuation criterion is 
met.
The maximum dose/exposure of pembrolizumab allowed in this study is 200 mg IV Q3W for 
approximately 2 years (35 cycles) of initial treatment (Section 8.1.8). 
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (Section 
7.3), or the last participant on active treatment is consented in the extension study. For 
purposes of analysis and reporting, the overall study ends when the Sponsor receives the last 
laboratory test result or at the time of final contact with the last participant, whichever comes 
last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
The Sponsor estimates that the maximum duration of the study from first participant entered 
through long-term follow-up will be approximately 5 years.
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
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age, race, ethnicity, and sex (as applicable). The collection and use of 
these demographic data will follow all local laws and participant confidentiality guidelines 
while supporting the study of the disease, its related factors, and the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Male or female participants with R/M HNSCC who have progressed after platinum-
containing chemotherapy at any time (with or without cetuximab) and a PD-1/PD-L1 
inhibitor and are at least 18 years of age may be enrolled in this study.
5.1
Inclusion Criteria
An individual is eligible for inclusion in the study if the individual meets all of the following 
criteria:
Type of Participant and Disease Characteristics
Demographics
1. Be male or female and at least 18 years of age on the day of providing documented 
informed consent.
2. Have pathologically confirmed recurrent (not amenable to curative treatment with local 
and/or systemic therapies) or metastatic (disseminated) HNSCC of the oral cavity, 
oropharynx, hypopharynx, and/or larynx that is considered incurable by local therapies.
Note: Other primary tumor sites of HNSCC, including nasopharynx (any histology) or 
unknown primary tumor (including p16+ unknown primary), are not eligible. 
3. Have experienced disease progression at any time during or after treatment with a 
platinum-containing (eg, carboplatin or cisplatin) regimen with or without cetuximab.
4. Have disease progression on or after treatment with an anti-PD-1/PD-L1 mAb 
administered either as monotherapy, or in combination with other checkpoint inhibitors 
or other therapies. Anti-PD-1/PD-L1 treatment progression is defined by meeting all the 
following criteria:

Treatment with an anti-PD-1/PD-L1 mAb.

Has received at least 2 doses of an anti-PD-1/PD-L1 mAb. 

Has demonstrated disease progression on or after an anti-PD-1/PD-L1 mAb as 
defined by RECIST 1.1. 
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
Progressive disease has been documented within 12 weeks from the last dose of anti-
PD-1/PD-L1 mAb. 
Note: Eligible participants may have received anti-PD-1/PD-L1 mAb and platinum-
containing therapy concomitantly. 
5. Have submitted pre-study imaging that demonstrates evidence of disease progression 
based on investigator review of at least 2 pre-study images per RECIST 1.1, following 
initiation of treatment with a PD-1/PD-L1 inhibitor.
Note: These pre-study images must be submitted to the iCRO for verification that they 
are of acceptable diagnostic quality. The iCRO must have received these images and 
verified that they are of acceptable diagnostic quality before randomization. 
Note: The pre-study imaging submitted to the iCRO will be from disease progression on 
or after treatment with an anti-PD-1/PD-L1 mAb; NOT from images associated with 
disease progression on or after platinum-containing chemotherapy given sequentially.
6. Have documentation of results from testing of HPV status for oropharyngeal cancer 
defined as p16 IHC testing using the CINtec® p16 Histology assay and a 70% cutoff 
point. Refer to Section 8.8.2 for details. If HPV status has previously been tested using 
this procedure, no retesting is required.
7. Have provided tissue for PD-L1 biomarker analysis from a core or excisional biopsy (fine 
needle aspirate is not adequate) not previously irradiated. Repeat samples may be 
required if adequate tissue is not provided. A newly obtained biopsy (within 90 days prior 
to start of study treatment) is strongly preferred, but an archival sample is acceptable. 
8. Have measurable disease by CT or MRI based on RECIST 1.1 as verified by BICR. 
Tumor lesions situated in a previously irradiated area are considered measurable if 
progression has been demonstrated in such lesions.
9. Have an ECOG performance status of 0 or 1 assessed within 7 days of the first dose of 
study intervention.
Male Participants
10. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least: 

1 week after the last dose of lenvatinib; 3 months after the last dose of capecitabine and 
paclitaxel; and 6 months after the last dose of docetaxel. No male contraception is needed 
for pembrolizumab and cetuximab.
•
See Appendix 7 for country-specific requirements.

Refrain from donating sperm
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PLUS either:

Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent
OR

Must agree to use contraception unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause [Appendix 5]) as detailed below:
Agree to use a male condom plus partner use of an additional contraceptive method 
when having penile-vaginal intercourse with a WOCBP who is not currently 
pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each episode 
of penile-vaginal penetration.

Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.

If the contraception requirements in the local label for any of the study drugs is less 
stringent than the requirements above, the local label requirements should be followed.
Female Participants
11. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:
is not a WOCBP.
OR

Is a WOCBP randomized to lenvatinib + pembrolizumab (Arm 1) or lenvatinib 
monotherapy (Arm 3) and using a contraceptive method that is highly effective (with 
a failure rate of <1% per year), with lower user dependency, or be abstinent from 
heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-
term and persistent basis), as described in Appendix 5 during the intervention period 
and for at least 120 days post pembrolizumab or 1 month post lenvatinib, 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 randomized to SOC chemotherapy is eligible to participate if she is using 
a contraceptive method that is highly effective with low user dependency or abstinent 
from heterosexual intercourse as her preferred and usual lifestyle and agrees not to 
donate or freeze/store eggs during the intervention period and for at least 6 months 
after the last dose of capecitabine, docetaxel, paclitaxel; and 2 months after the last 
dose of cetuximab.
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
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 5.

Abstains from breastfeeding during the study intervention period and for at least 180 
days after the last dose of chemotherapy, 1 month after the last dose of lenvatinib, or 
120 days after the last dose of pembrolizumab.

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.

If the contraception requirements in the local label for any of the study drugs is less 
stringent than the requirements above, the local label requirements should be 
followed.

Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Informed Consent
12. The participant (or legally acceptable representative if applicable) provides documented 
informed consent for the study.
Additional Categories
13. Have adequately controlled BP with or without antihypertensive medications, defined as 
BP ≤150/90 mm Hg with no change in antihypertensive medications for at least 1 week 
prior to randomization.  
14. Have adequate organ function as defined in Table 1. 

Note: Specimens must be collected within ≤7 days prior to the start of study
intervention. 
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Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/La
Renal
Creatinine OR
Measured or calculatedb creatinine clearance
(GFR can also be used in place of creatinine or 
CrCl)
≤1.5 × ULN OR
≥30 mL/min for participant with creatinine levels 
>1.5 × institutional ULN
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for participants 
with total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with liver 
metastases)
Coagulation
International normalized ratio (INR) OR 
prothrombin time (PT)
Activated partial thromboplastin time (aPTTc)
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants
Abbreviations: ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); CrCl=creatinine clearance; GFR=glomerular filtration rate; 
ULN=upper limit of normal.
a
Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion 
within last 2 weeks.
b
Creatinine clearance (CrCl) should be calculated per institutional standard.
c
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.
15. Participants who are HBsAg positive are eligible if they have received HBV antiviral 
therapy for at least 4 weeks and have undetectable HBV viral load prior to 
randomization.
Note: Participants should remain on anti-viral therapy throughout study intervention and 
follow local guidelines for HBV anti-viral therapy post completion of study intervention.
Hepatitis B screening tests are not required unless: 
-
Known history of HBV infection 
-
As mandated by local health authority 
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16. Participants with history of HCV infection are eligible if HCV viral load is undetectable 
at screening.
Note: Participants must have completed curative anti-viral therapy at least 4 weeks prior 
to randomization. 
Hepatitis C screening tests are not required unless: 
-
Known history of HCV infection 
-
As mandated by local health authority
5.2
Exclusion Criteria
An individual must be excluded from the study if the individual meets any of the following 
criteria:
Medical Conditions
1. Removed, redundant with Inclusion Criterion #2.
2. Has a history of re-irradiation to any head and neck sites of disease including the cervical, 
infraclavicular or supraclavicular lymph nodes for head and neck cancer.
3. Has disease that is suitable for local therapy administered with curative intent.
4. Has a life expectancy of less than 3 months and/or has rapidly progressing disease (eg, 
tumor bleeding, uncontrolled tumor pain), in the opinion of the treating investigator.
5. Has any evidence of symptoms or signs of active tumor bleeding within 6 months prior to
randomization.
6. Has ulceration and/or fungation of disease onto the skin surface. 
7. Has radiographic evidence of major blood vessel invasion/infiltration or tumor 
demonstrates >90-degree abutment or encasement of a major blood vessel. 

Note: The degree of proximity to major blood vessels should be considered because 
of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis 
after lenvatinib therapy.
8. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease.
9. Has an active infection requiring systemic therapy.
10. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study drug.
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11. Has known active 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 (note 
that the repeat imaging should be performed during study screening), clinically stable and 
without requirement of steroid treatment for at least 14 days prior to first dose of study 
intervention. 
12. Has a known additional malignancy that is progressing or has required active systemic 
treatment within the past 3 years.

Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of 
the skin, superficial bladder cancer, or carcinoma in situ (eg, breast carcinoma, 
cervical cancer in situ) that have undergone potentially curative therapy are not 
excluded. Participants with low-risk early stage prostate cancer defined as follows are 
not excluded; Stage T1c or T2a with a Gleason score ≤ 6 and prostatic-specific 
antigen (PSA) <10 ng/mL either treated with definitive intent or untreated in active 
surveillance that has been stable for the past year prior to study enrollment. Other 
exceptions may be considered after consultation with the Sponsor.
13. Has an active autoimmune disease that has required systemic treatment in the past 2 years 
(ie, with use of disease-modifying agents, corticosteroids or immunosuppressive drugs). 

Note: Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency) is not considered a form of 
systemic treatment and is allowed.
14. Has had an allogeneic tissue/solid organ transplant.
15. Has a known history of human immunodeficiency virus (HIV) infection. 
Note: No HIV testing is required unless mandated by local health authority.
16. Removed, not relevant due to addition of Inclusion Criteria #15 and #16.
17. Has a history of any contraindication or has a severe hypersensitivity to any components 
of pembrolizumab (≥Grade 3), lenvatinib or SOC chemotherapy.
18. Has pre-existing ≥Grade 3 gastrointestinal or non-gastrointestinal fistula
19. Has a history of a gastrointestinal malabsorption or any other condition or procedure that 
may affect oral study drug absorption.
20. 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. 
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
Note: Participants must have recovered adequately from the toxicity and/or 
complications from the intervention prior to starting study therapy.
21. Has clinically significant cardiovascular impairment within 12 months of the first dose of 
study drug, such as history of congestive heart failure greater than New York Heart 
Association (NYHA) Class II, unstable angina, myocardial infarction or cerebrovascular 
accident /transient ischemic attack (TIA)/stroke, cardiac revascularization, or cardiac 
arrhythmia associated with hemodynamic instability.

Note: Medically controlled arrhythmia that is stable with medication is permitted.
22. Has active tuberculosis.
23. Has difficulty swallowing capsules or ingesting a suspension orally or by a feeding tube.
Prior/Concomitant Therapy
24. Participants previously treated to one of the 4 SOC agents in this trial (ie, docetaxel, 
paclitaxel, capecitabine, or cetuximab) may not receive the same agent if randomized to 
the SOC chemotherapy arm. 
25. Has had prior treatment with lenvatinib as monotherapy or in combination with an 
PD-1/PD-L1 inhibitor or other therapies.
26. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 
2 weeks prior to Study Day 1 or has not recovered (ie, ≤ Grade 1 or baseline) from AEs 
due to a previously administered agent. Participants with endocrine-related AEs Grade ≤2 
requiring treatment or hormone replacement may be eligible.

Note: Events of ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia or laboratory values 
listed in Table 1 are allowed.

Note: Participants must have recovered from all radiation-related toxicities and not 
have had radiation pneumonitis.

Note: As per section 6.5.1, anticancer therapies are prohibited during screening.
27. Has received a live or live attenuated vaccine within 30 days prior to the first dose of 
study intervention.
Note: Administration of killed vaccines is allowed.
Refer to Section 6.5.1 for information on COVID-19 vaccines.
28. Was previously treated with 4 or more systemic regimens given for R/M disease.
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Prior/Concurrent Clinical Study Experience
29. Has received an investigational agent or has used an investigational device within 4 
weeks prior to study intervention administration.
Diagnostic Assessments
30. Has urine protein ≥1 g/24 hours.
Note: Participants with proteinuria ≥2+ (≥100 mg/dL) on urine dipstick testing
(urinalysis) will undergo 24-hour urine collection for quantitative assessment of 
proteinuria. 
31. Has prolongation of QTc interval (calculated using Fridericia’s formula) to >480 msec.
32. Has a LVEF below the institutional (or local laboratory) normal range, as determined by 
MUGA or ECHO.
Other Exclusions
33. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that may confound the results of the study, interfere with the participant’s participation 
for the full duration of the study, or is not in the best interest of the participant, in the 
opinion of the treating investigator.
34. Has a known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the study.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen-failure information is 
required to ensure transparent reporting of screen-failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen-failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws consent will not be 
replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (pembrolizumab, lenvatinib and SOC chemotherapy) will be packaged to 
support enrollment as required. Clinical supplies will be affixed with a clinical label in 
accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
NOTE: In alignment with the study-specific investigator letter dated 05-SEP-2024, all 
participants should discontinue the combination of lenvatinib + pembrolizumab or lenvatinib 
monotherapy, as applicable. On a case-by-case basis, investigators may contact the Sponsor 
for consideration of continuing lenvatinib + pembrolizumab or lenvatinib monotherapy if 
they assess the participant is deriving clinical benefit. Treatment with SOC chemotherapy 
(Arm 2) can continue at the discretion of the investigator until a protocol specified 
discontinuation criterion is met.
The study intervention(s) to be used in this study are outlined in Table 2.
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Table 2
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Arm 1 Experimental
Lenvatinib
Drug
Capsule
10 mg
4 mg
20 mg
Oral
Once daily
Test 
Product
IMP
Central
Arm 1 Experimental
Pembrolizumab Biological/Vaccine Solution
25 mg/mL
200 mg
IV Infusion
Day 1 of each 3-
week cycle
Test 
Product
IMP
Central
Arm 2 Active 
Comparator
Docetaxel
Drug
Solution
20 mg/mL
75 
mg/m2
IV Infusion
Day 1 of each 3-
week cycle
Comparator IMP
Provided 
centrally by 
the Sponsor 
or locally by 
the study 
site.
Arm 2 Active 
Comparator
Capecitabine
Drug
Tablet
150 mg
500 mg
1250 
mg/m2
Oral
BID (Twice a 
day) on Day 1 to 
14 of each 3-
week cycle
Comparator IMP
Provided 
centrally by 
the Sponsor 
or locally by 
the study 
site.
Arm 2 Active 
Comparator
Paclitaxel
Drug
Solution
6 mg/mL
80 
mg/m2
IV Infusion
Day 1, 8, and 15 
of each 3-week 
cycle
Comparator IMP
Provided 
centrally by 
the Sponsor 
or locally by 
the study 
site.
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Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Arm 2 Active 
Comparator
Cetuximab
Biological/Vaccine Solution
2 mg/mL
5 mg/mL
400 
mg/m2
loading 
dose 
followed 
by 250 
mg/m2
IV Infusion
Day 1, 8, and 15 
of each 3-week 
cycle
Comparator IMP
Provided 
centrally by 
the Sponsor 
or locally by 
the study 
site.
Arm 3 Experimental
Lenvatinib
Drug
Capsule
10 mg
4 mg
24 mg
Oral
Once daily
Test 
Product
IMP
Central
EEA=European Economic Area; IMP=investigational medicinal product; NIMP/AxMP=noninvestigational/auxiliary medicinal product.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences 
with respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
NOTE: Unit dose strength of SOC chemotherapy may vary based on the local guidelines.
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All supplies indicated in Table 2 will be provided per the “Sourcing” column depending on
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual.
Lenvatinib is provided as capsules for oral administration and does not require preparation. 
For participants unable to swallow capsule, a suspension can be prepared. If a lenvatinib dose 
is missed and cannot be taken within 12 hours of the scheduled dosing time, the participant 
should skip this dose and take the next dose at the scheduled time the next day. Refer to the 
Lenvatinib Pharmacy Manual for additional information.
Chemotherapy should be prepared per local and institutional guidelines according to the 
approved product labels.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
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The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention allocation will occur centrally using an IRT system. Participants will be 
assigned randomly in a 3:3:2 ratio to the lenvatinib + pembrolizumab, SOC chemotherapy or 
lenvatinib monotherapy arms, respectively. Randomization will continue until the planned 
number of participants in each arm receive at least 1 dose of study medication.
6.3.2
Stratification
Randomization will be stratified according to the following factors: 
1. PD-L1 tumor expression as determined by PD-L1 immunohistochemistry (TPS <50% 
versus ≥50%)
2. ECOG performance status (0 versus 1)
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the study intervention administered.
However, the independent radiologist(s) who perform the central imaging review will be 
blinded to the participant’s treatment group assignment.
The investigator will be blinded to the participant-level biomarker results.
6.4
Study Intervention Compliance
If there are interruptions in the study intervention schedule or infusion/injection was stopped, 
the details of and reason for any interruption or infusion/injection cessation of study 
intervention will be documented in the participant’s medical record.
Interruptions from the protocol-specified intervention plan for >28 days for lenvatinib or 
>12 weeks due to toxicity reasons for pembrolizumab and >6 weeks from the last dose due to 
administrative reasons for pembrolizumab require consultation between the investigator and 
the Sponsor and written documentation of the collaborative decision on participant 
management. Please refer to Section 8.1.8.2 for compliance of study drug administration.
6.5
Concomitant Therapy
If there is a clinical indication for any medications or vaccinations prohibited, the 
investigator must discuss any questions regarding this with the Sponsor’s Clinical Director. 
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
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the participant’s primary physician. However, the decision to continue the participant on 
study intervention requires the mutual agreement of the investigator and the Sponsor.
The following medications and vaccinations are prohibited during the study:
Live or live-attenuated vaccines within 30 days before the first dose of study intervention and 
while participating in the study.
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, replication-
incompetent adenoviral vaccines, or inactivated vaccines. These vaccines will be treated 
just as any other concomitant therapy.
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not 
allowed.
If the investigator determines that a participant requires any of the following prohibited 
medications and vaccinations for any reason during the study, study intervention must be 
discontinued:
•
Systemic antineoplastic chemotherapy, immunotherapy, or biological therapy not 
specified in this protocol
•
Investigational agents other than those specified in this protocol
•
Radiation therapy
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed 
at the investigator’s discretion.
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medications will be recorded on the eCRF including all 
prescriptions, OTC products, herbal supplements, and IV medications, and fluids. If changes 
occur during the study period, documentation of drug dosage, frequency, route, and date 
should also be included on the eCRF.
All concomitant medications received within 30 days prior to the first dose of study 
intervention and up to 30 days after the last dose of study intervention should be recorded. 
All concomitant medications administered during SAEs or ECIs are to be recorded. SAEs 
and ECIs are defined in Section 8.4.
Note: All prior anticancer agents will be collected and recorded on the case report form 
(CRF) during the Screening visit (eg, first-line, second-line, third-line, etc).
Additionally, all diagnostic, therapeutic, or surgical procedures relating to malignancy should 
be recorded.
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6.5.1
Prohibited Concomitant Medications
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment periods of this study:
1. Concurrent anticancer therapies not specified in this protocol such as chemotherapy, 
targeted therapies, antitumor interventions (surgical resection, surgical debulking of 
tumor, etc), or cancer immunotherapy.

Note: Topical anticancer agents to treat skin lesions (eg, in situ melanoma or 
squamous cell carcinoma) are allowed, excluding skin metastasis of melanoma.
2. Other concurrent investigational drugs.
3. Live or live attenuated vaccines within 30 days before the first dose of study intervention 
and while participating in the study. Administration of killed vaccines is allowed.
4. Systemic glucocorticoids are permitted only for the following purposes:

Physiologic doses of corticosteroids not exceeding 10 mg daily of prednisone 
equivalent may be used during the study. 

Brief, limited use (≤7 days) of systemic corticosteroids is permitted when considered 
Standard of Care (eg, for exacerbation of chronic obstructive pulmonary disease).

To modulate symptoms of an AE that is suspected to have an immunologic etiology

As needed for the prevention of emesis

Premedication of IV contrast allergies
•
In addition, the following glucocorticoid use is allowed:

For topical or ocular use

Intraarticular joint use

For inhalation in the management of asthma or COPD

Note: For participants on lenvatinib monotherapy or SOC chemotherapy arms, 
the use of systemic glucocorticoids on-study treatment is acceptable.
5. Radiation therapy. 
Participants who, in an assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be discontinued from study 
treatment.
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If participants receive additional anticancer therapies, this will be judged to represent 
evidence of disease progression, and study medication will be discontinued. These 
participants should complete all end-of-treatment assessments and continue to be followed 
for survival in the follow-up period.
See Appendix 7 for country-specific requirements.
Please refer to USPI (or local product label) for additional guidance.
6.5.2
Drug Interactions
There are no DDI-related concomitant medication prohibitions or restrictions.
Lenvatinib is not expected to clinically meaningfully alter exposure to CYP3A4/Pgp
substrates based on results from a lenvatinib DDI study with midazolam (a sensitive CYP3A 
and Pgp substrate). 
Clinical studies also showed that co-administration of lenvatinib with either inducers or 
inhibitors of CYP3A4/Pgp are not of clinical concern.
See Appendix 7 for country-specific requirements.
Please refer to USPI (or local product label) for additional guidance.
6.5.3
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. For participants receiving lenvatinib + pembrolizumab, suggested 
supportive care measures for the management of AEs with potential immunologic etiology 
are outlined in Table 4 along with the lenvatinib dose modification guidelines in Table 3. 
Where appropriate, these guidelines include the use of oral or IV treatment with 
corticosteroids, as well as additional anti-inflammatory agents if symptoms do not improve 
with administration of corticosteroids. Note that several courses of steroid tapering may be 
necessary as symptoms may worsen when the steroid dose is decreased. For each disorder, 
attempts should be made to rule out other causes such as metastatic disease or bacterial or 
viral infection, which might require additional supportive care. The treatment guidelines are 
intended to be applied when the investigator determines the events to be related to 
pembrolizumab or lenvatinib.
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the pembrolizumab treatment guidance. Refer to 
Table 3 for guidelines regarding lenvatinib dose modification and supportive care.
Premedication(s) for docetaxel, paclitaxel, cetuximab, or capecitabine will be given as per 
SOC. Corticosteroid pretreatment or post-treatment of docetaxel and paclitaxel is acceptable 
in concordance with the local label or SOC. It may be necessary to perform conditional
procedures such as bronchoscopy, endoscopy, or skin photography as part of evaluation of 
the event.
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6.6
Dose Modification (Escalation/Titration/Other)
NOTE: In alignment with the study-specific investigator letter dated 05-SEP-2024, all 
participants should discontinue the combination of lenvatinib + pembrolizumab or lenvatinib 
monotherapy, as applicable. On a case-by-case basis, investigators may contact the Sponsor 
for consideration of continuing lenvatinib plus pemrolizumab or lenvatinib monotherapy if 
they assess the participant is deriving clinical benefit. Treatment with SOC chemotherapy 
(Arm 2) can continue at the discretion of the investigator until a protocol specified 
discontinuation criterion is met. Participants who are continuing study treatment should 
follow the modified protocol study procedures as specified in this amendment.  
Adverse events will be graded using NCI CTCAE version 5.0. Investigators will decide the 
probability of the event being related to one or both drugs as to whether dose modification of 
one or both drugs is required.  
Refer to Section 6.6.2 for dose modification guidance for overlapping toxicity for the 
pembrolizumab + lenvatinib combination.
Participants who interrupt or discontinue 1 drug in the lenvatinib-pembrolizumab 
combination due to toxicity can continue with the other drug in the combination until criteria 
for treatment discontinuation are met (eg, unacceptable toxicity, disease progression).
6.6.1
Lenvatinib Dose Modification and Toxicity Management
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 3. An interruption of study intervention for more 
than 28 days will require Sponsor approval before treatment can be resumed.
The starting dose of lenvatinib is 24 mg/day for monotherapy (Arm 3) and 20 mg/day in 
combination with pembrolizumab (Arm 1). Dose reductions of lenvatinib occur in succession 
based on the previous dose level (Arm 3: 24, 20, 14, and 10 mg/day; Arm 1: 20, 14, 10, and 8 
mg/day). Any dose reduction below 8 mg/day must be discussed with the Sponsor.  Once the 
lenvatinib dose has been reduced, it may not be increased at a later date, unless the dose has 
been mistakenly decreased; in this situation, the Sponsor’s approval is required to increase 
the dose.
Refer to the 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), PRES/RPLS (Section 6.6.1.6), hypocalcemia 
(Section 6.6.1.7), hemorrhage (Section 6.6.1.8), gastrointestinal perforation of fistula 
formulation (Section 6.6.1.9), QT prolongation (Section 6.6.1.10) and ONJ (Section 6.6.1.11)
as appropriate, before consulting the dose modification table (Table 3).
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Table 3
Dose Modification Guidelines for Lenvatinib-Related Adverse Events 
Treatment-Related Toxicitya,b
Management
Dose Adjustment
Grade 1 or Tolerable Grade 2
Continue treatment
No change
Intolerable Grade 2c, d or Grade 3e,g
First occurrence
Interrupt lenvatinib until resolved 
to Grade 0-1, or tolerable Grade 2
Arm 3: Reduce lenvatinib dose to 
20 mg once a day (1-level 
reduction) 
Arm 1:  Reduce lenvatinib dose to 
14 mg once a day (1-level 
reduction) 
Second occurrence (same 
toxicity or new toxicity)
Interrupt lenvatinib until resolved 
to Grade 0-1, or tolerable Grade 2
Arm 3: Reduce lenvatinib dose to 
14 mg once a day (1-level 
reduction) 
Arm 1:  Reduce lenvatinib dose to 
10 mg once a day (1-level 
reduction) 
Third occurrence (same toxicity 
or new toxicity)
Interrupt lenvatinib until resolved 
to Grade 0-1, or tolerable Grade 2
Arm 3: Reduce lenvatinib dose to 
10 mg once a day (1-level 
reduction) 
Arm 1:  Reduce lenvatinib dose to 
8 mg once a day (1-level 
reduction) 
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 5.0. Collect all AE grades (ie, decreasing and increasing CTCAE grade). 
a
An interruption of study treatment 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 intervention at a lower dose once 
their weight remains stable for at least 1 week and they have a minimum 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 treatment should be discussed with Sponsor.
f
Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3.
g
For Grade 3 thromboembolic event, permanently discontinue lenvatinib. See Section 6.6.1.5.
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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 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 therapy for at least 1 week 
before C1D1.  Early detection and effective management of hypertension are important to 
minimize the need for lenvatinib dose interruptions and reductions.
Regular assessment of BP should be as detailed in the SoA (Sections 1.3.1, 1.3.2, and 1.3.3). 
Hypertension will be graded using NCI CTCAE v5.0, based on BP measurements only (and 
not on the number of antihypertensive medications).
If the participant’s first BP measurement of the current assessment 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 (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 those participants already on antihypertensive medication, treatment 
modification may be necessary if hypertension persists.  
Lenvatinib should be withheld in any instance where a participant is at imminent risk to 
develop a hypertensive crisis or has uncontrolled hypertension with significant risk factors 
for severe complications (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 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.
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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 drug 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.
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 1 dose level reduction 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 administration should be interrupted and 
restarted at an additional dose reduction 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 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 administration should be interrupted and 
restarted at a third dose reduction 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.
-
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 study drug
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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 or urinalysis per the SoA (Section 1.3.1, 1.3.3 and 
1.3.4). Urine dipstick testing is the preferred method for testing for urinary protein, 
however, urinalysis may be used if the use of urine dipsticks is not feasible.
2. A 24-hour urine collection initiated as soon as possible and at least within 72 hours 
(or an immediate spot [UPCR] test is required) in the following situations:
-
The first (initial) occurrence of ≥2+ (≥100 mg/dL) proteinuria on urine dipstick or 
urinalysis while the participant is receiving lenvatinib.
-
A subsequent increase in severity of urine dipstick or urinalysis proteinuria 
occurring on the same lenvatinib dose level.
-
When there has been a lenvatinib dose reduction and at the new dose level the 
urine protein dipstick or urinalysis result is ≥2+ (≥100 mg/dL).
3. A 24-hour urine collection (initiated as soon as possible and at least within 72 hours) 
to verify the grade of proteinuria is required when UPCR is ≥2.4.
Grading of Proteinuria
-
Grading according to NCI CTCAE v5.0 will be based on the 24-hour urinary protein 
result if one has been obtained. If the participant has 4+ proteinuria by dipstick
(≥1000 mg/dL by urinalysis), a 24-hour urinary protein result is required to confirm 
Grade 3 proteinuria. Management of lenvatinib administration will be based on the 
grade of proteinuria according to Table 3.
Monitoring
-
Urine dipstick or urinalysis testing for participants with proteinuria ≥2+ (≥100 
mg/dL) should be performed on Day 15 (or more frequently as clinically indicated) 
until the results have been 1+ (30 mg/dL) 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 must be discontinued
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6.6.1.3
Management of Diarrhea
An anti-diarrheal agent should be recommended to the participant at the start of study 
treatment, and participants should be instructed and educated to initiate anti-diarrheal 
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 3 should be followed.
6.6.1.4
Management of Hepatotoxicity
Liver function tests (ALT, 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 3 should be followed. Appropriate supportive care should be 
provided together with close monitoring. If hepatic failure occurs, the study drug must be 
discontinued. If hepatic failure (any grade per CTCAE version 5) occurs, lenvatinib 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, 
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 such symptoms promptly to the treating physician.  
If a thromboembolic event is confirmed, instructions contained in Table 3 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 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 
treatment discontinuation. 
6.6.1.6
Management of 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 3 should be followed.
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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 v5.0, 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 situations, the total (uncorrected) serum calcium should be used instead. 
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 3 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. Refer to Appendix 7 for country-specific 
requirement.
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 
participants at higher risk. For participants requiring invasive dental procedures, 
discontinuation of bisphosphonate treatment may reduce the risk of ONJ. Withhold 
lenvatinib if ONJ develops and restart based on clinical judgment of adequate resolution (See 
Section 6.6.4).
6.6.2
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 
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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 drug 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, TIDM) and other 
supportive care should be taken promptly.
3. Participants receiving the combination therapy (lenvatinib + pembrolizumab) 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 4, but 
lenvatinib may be administered at a reduced dose by the time this criterion is met 
and must be permanently discontinued immediately.
b. ALT or AST >3 X ULN and (TBL >2 X ULN or INR >1.5).
Although Table 4 advises pembrolizumab to be withheld (interrupted), and 
Table 3 advises lenvatinib to have no dose modification or a reduction, if this 
criterion is met, both drugs must be permanently discontinued immediately.
Participants who experience a toxicity that is attributable to lenvatinib should modify, 
interrupt, or discontinue lenvatinib as per the Dose Modification Guidelines for Lenvatinib-
Related Adverse Events, but may continue in the trial receiving pembrolizumab, unless or 
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until unacceptability toxicity or progression occurs. Participants who experience a toxicity 
attributable to pembrolizumab should interrupt or discontinue pembrolizumab as per Dose 
Modification Guidelines for Pembrolizumab Related Adverse Events, but may continue in 
the trial receiving lenvatinib, unless or until unacceptable toxicity or progression occurs.
6.6.3
Pembrolizumab Dose Modifications
Pembrolizumab dose reductions are not permitted. Pembrolizumab treatment may be 
interrupted or discontinued due to toxicity. Pembrolizumab may be interrupted for a 
maximum of 12 weeks. An interruption of study treatment for more than 12 weeks due to 
toxicity or more than 6 weeks from the last dose due to administrative reasons will require 
Sponsor approval before study intervention can be resumed (see Section 6.4). 
6.6.3.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation. 
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 4.
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Table 4
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated With 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if 
the irAEs are not controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 
after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAE v5.0)
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 to 
2 mg/kg prednisone or 
equivalent) followed by 
taper
Add prophylactic 
antibiotics for 
opportunistic infections
Monitor participants for signs and symptoms of 
pneumonitis
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment
Recurrent Grade 2, 
or Grade 3 or 4 
Permanently discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Diarrhea/Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids 
(initial dose of 1 to 
2 mg/kg prednisone or 
equivalent) followed by 
taper
Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (ie, peritoneal signs 
and ileus)
Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion
Recurrent Grade 3 
or Grade 4
Permanently discontinue
AST or ALT 
Elevation or 
Increased Bilirubin
Grade 2 a
Withhold
Administer corticosteroids 
(initial dose of 0.5 to 
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 b or 4 c
Permanently discontinue
Administer corticosteroids 
(initial dose of 1 to 
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 -cell 
failure
Withhold d
Initiate insulin replacement 
therapy for participants 
with T1DM
Administer 
antihyperglycemic in 
participants with 
hyperglycemia
Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypophysitis
Grade 2
Withhold
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4
Withhold or permanently 
discontinued
Hyperthyroidism
Grade 2
Continue
Treat with nonselective 
beta-blockers (eg, 
propranolol) or 
thionamides as appropriate
Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or permanently 
discontinue d
Hypothyroidism
Grade 2
Continue
Initiate thyroid 
replacement hormones (eg, 
levothyroxine or 
liothyronine) per standard 
of care
Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or permanently 
discontinue d
Nephritis:
grading according 
to increased 
creatinine or acute 
kidney injury
Grade 2
Withhold
Administer corticosteroids 
(prednisone 1 to 2 mg/kg 
or equivalent) followed by 
taper
Monitor changes of renal function
Grade 3 or 4
Permanently discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Neurological 
Toxicities
Grade 2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 3 or 4
Permanently discontinue
Myocarditis
Assymptomatic
cardiac enzyme 
elevation with 
clinical suspicion of 
myocarditis (which 
was previously 
myocarditis Grade 1
using CTCAE v4.0)
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
Exfoliative 
Dermatologic 
Conditions
Suspected SJS, 
TEN, or DRESS
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
or exclude other causes
Confirmed SJS, 
TEN, or DRESS
Permanently discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
All Other irAEs
Persistent Grade 2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
or exclude other causes
Grade 3
Withhold or discontinue 
based on the event e
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
AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal
b
AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline 
if baseline abnormal
c
AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal
d
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.
e
Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis).
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6.6.3.2
Dose Modification and Toxicity Management of Infusion Reactions Related 
to Pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines for pembrolizumab-associated 
infusion reaction are provided in Table 5.
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Table 5
Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the investigator.
None
Grade 2
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 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
Abbreviations: h = hour; hrs = hours; IV = intravenous(ly); NSAIDs = nonsteroidal anti-inflammatory drugs; PO = oral(ly); 
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 version 5.0 (CTCAE) at http://ctep.cancer.gov
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6.6.4
Other Allowed Dose Interruptions
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.
•
For scheduled dental surgery or invasive dental procedures, stop lenvatinib for at least 1 
week before the procedure, then restart lenvatinib when deemed clinically appropriate.
Pembrolizumab may be interrupted for situations other than treatment-related AEs, such as 
medical/surgical events or logistical reasons not related to study intervention. Participants 
should be placed back on study intervention within 6 weeks of the last dose administered, 
unless otherwise discussed with the Sponsor. The reason for interruption should be 
documented in the participant’s study record. Imaging should not be delayed for delays in 
treatment cycles.
6.6.5
Dose Modification for Standard Treatment Chemotherapy
Doses of SOC chemotherapy below should be based upon actual body weight, not ideal body 
weight. If the participant’s weight increases or decreases by >10% from baseline during the 
course of the study, the drug dose should be re-calculated.
6.6.5.1
Dose Selection for Docetaxel (Preparation)
The preparation and administration of docetaxel should follow local treatment guidelines. 
Refer to the USPI (or local product label) for additional supportive care guidance.
Corticosteroid use with docetaxel
In order to reduce the incidence and severity of fluid retention as well as the severity of 
hypersensitivity reaction, all participants randomized to receive docetaxel must be 
premedicated with oral corticosteroids such as dexamethasone 16 mg per day (eg, 8 mg BID) 
for 3 days starting 1 day prior to docetaxel administration.
6.6.5.2
Dose Modifications for Docetaxel 
Participants who are dosed initially at 75 mg/m2 and who experience either febrile 
neutropenia, neutrophils <500 cells/mm3 for more than one week, severe or cumulative 
cutaneous reactions, or other Grade 3/4 non-hematological toxicities during docetaxel 
treatment should have treatment withheld until resolution of the toxicity and then resumed at 
55 mg/m2. Participants who develop Grade 3 peripheral neuropathy should have docetaxel 
treatment discontinued entirely.
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Docetaxel should be administered only if ANC >1500/mm3 (1.5 x 109/L) and platelets 
>100,000/mm3 (100 x 109/L).
Docetaxel should not be given to participants with bilirubin >ULN, or to participants with 
AST and/or ALT >1.5 x ULN with concomitant alkaline phosphatase >2.5 x ULN as 
participants with laboratory values above these limits are at increased risk of SAEs (refer to 
local product label).  
For additional guidance regarding treatment modification of docetaxel, please refer to the 
USPI (or local prescribing information) for dose modifications for hematologic and other 
non-hematologic toxicities as recommended for monotherapy with docetaxel in participants 
with non-small cell lung cancer.
6.6.5.3
Dose Selection for Paclitaxel (Preparation)
The preparation and administration of paclitaxel should follow local treatment guidelines. 
Refer to the USPI (or local product label) for additional supportive care guidance.
Premedication for paclitaxel
All participants should be premedicated prior to paclitaxel administration in order to prevent 
severe hypersensitivity reactions. Such premedication may consist of dexamethasone 20 mg 
PO administered approximately 12 and 6 hours before paclitaxel, diphenhydramine (or its 
equivalent) 50 mg IV 30 to 60 minutes prior to paclitaxel, and cimetidine (300 mg) or 
ranitidine (50 mg) IV 30 to 60 minutes before paclitaxel.
6.6.5.4
Dose Modifications for Paclitaxel
The following guidelines should be followed for dose modifications for AEs that are 
suspected to be caused by paclitaxel. 
•
Paclitaxel should be administered only if ANC >1500/mm3 (1.5 x 109/L) and platelets 
>100,000/mm3 (100 x 109/L). 
•
In case of a life-threatening event, consider discontinuing paclitaxel.
In case of Grade 3 or 4 AEs despite medical management: 
•
Hold paclitaxel until the event has resolved to Grade 1 or better, then re-introduce at the 
reduced dose of 65 mg/m2. 
•
In case of a second episode of the same event at Grade 3 or 4, consider discontinuing 
paclitaxel.
•
In cases of Grade 2 non-hematologic AE (except alopecia) that are persistent despite 
medical management, consider holding paclitaxel until event resolves to Grade 1 or 
better, then re-introduce at a reduced dose. 
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•
The minimum paclitaxel dose allowed on study and the first dose reduction level is 
65 mg/m2 (ie., only one dose reduction of paclitaxel is permitted to 65 mg/m2). 
For additional guidance regarding treatment modification of paclitaxel, please refer to the 
USPI (or local prescribing information) for dose modifications for hematologic and other 
non-hematologic toxicities. 
6.6.5.5
Dose Selection for Cetuximab (Preparation)
Participants receiving cetuximab should be premedicated with an H1 antagonist (eg, 50 mg 
of diphenhydramine) intravenously 30-60 minutes prior to the first dose. Premedication for
subsequent doses of cetuximab should be given per medical judgment and history of prior
infusion reactions. See Appendix 7 for country-specific requirements.
Guidelines for medical therapy for infusion reactions detailed in Table 6 are provided below 
for reactions due to cetuximab.
Refer to the USPI (or local product label) for additional supportive care guidance.
6.6.5.6
Dose Modifications for Cetuximab
Reduce, delay, or discontinue cetuximab to manage adverse reactions as described in 
Table 6 below. 
Table 6
Cetuximab Dose Modifications for Adverse Reactions
Adverse Reaction
Severitya
Dosage Modification
Infusion reactions [see USPI 
Warnings and Precautions 
(5.1)]
Grade 1 or 2
Reduce the infusion rate by 50%.
Grade 3 or 4
Immediately and permanently, 
discontinue cetuximab.
Dermatologic toxicities and 
infections sequelae (eg, 
acneiform rash, 
mucocutaneous disease) [see 
USPI Warnings and 
Precautions (5.4)]
1st occurrence; Grade 3 or 4
Delay infusion 1 to 2 weeks; if 
condition improves, continue at 
250 mg/m2. If no improvement, 
discontinue cetuximab.
2nd occurrence; Grade 3 or 
4
Delay infusion 1 to 2 weeks; if 
condition improves, continue at 
200 mg/m2. If no improvement, 
discontinue cetuximab.
3rd occurrence; Grade 3 or 4
Delay infusion 1 to 2 weeks; if 
condition improves, continue at 
150 mg/m2. If no improvement, 
discontinue cetuximab.
4th occurrence; Grade 3 or 4
Discontinue cetuximab.
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Adverse Reaction
Severitya
Dosage Modification
Pulmonary toxicity [see 
USPI Warnings and 
Precautions (5.3)]
Acute onset or worsening 
pulmonary symptoms
Delay infusion 1 to 2 weeks; if 
condition improves, continue at the 
dose that was being administered at 
the time of occurrence.
If no improvement in 2 weeks or 
interstitial lung disease (ILD) is 
confirmed, discontinue cetuximab.
a
National Cancer Institute (NCI) Common Toxicity Criteria (CTC) version 2.0.
Source: Adapted from ERBITUX® USPI: ImClone LLC a wholly-owned subsidiary of Eli Lilly and 
Company.
For additional guidance regarding treatment modification of cetuximab, please refer to the 
USPI (or local prescribing information) for dose modifications for hematologic and other 
non-hematologic toxicities. 
6.6.5.7
Dose Selection for Capecitabine (Preparation)
The preparation and administration of capecitabine should follow local treatment guidelines. 
Capecitabine should be administered at 1250 mg/m2 twice daily orally (ie., total daily dose of 
2500 mg/m2), for 14 days continuously, followed by 7 days with no dosing in a 3-week 
cycle.
Capecitabine can induce diarrhea, sometimes severe, including necrotizing enterocolitis 
(typhlitis). Therefore, for participants who experience capecitabine-associated diarrhea, 
aggressive supportive management with anti-diarrheals, including loperamide and lomotil, 
according to local SOC treatment guidelines are indicated. Refer to the USPI (or local 
product label) for additional supportive care guidance.
6.6.5.8
Dose Modifications for Capecitabine
Recommended dose modifications for capecitabine are outlined in Table 7.
Table 7
Recommended Dose Modifications for Capecitabine
Toxicity NCIC 
Grades
During a Course of Therapy
Dose Adjustment for Next 
Treatment (% of Starting Dose)
Grade 1
Maintain dose level
Maintain dose level
Grade 2

1st appearance
Interrupt until resolved to Grade 0-
1
100%

2nd appearance
75%

3rd appearance
50%

4th appearance
Discontinue treatment 
permanently
-
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Toxicity NCIC 
Grades
During a Course of Therapy
Dose Adjustment for Next 
Treatment (% of Starting Dose)
Grade 3

1st appearance
Interrupt until resolved to Grade 0-
1
75%

2nd appearance
50%

3rd appearance
Discontinue treatment 
permanently
-
Grade 4

1st appearance
Discontinue permanently 
OR
If physician deems it to be in the 
participant’s best interest to 
continue, interrupt until resolved 
to Grade 0-1
50%
NCIC=National Cancer Institute of Canada.
Source: XELODA® USPI; Hoffmann-La Roche, Inc.© 2019 Genentech, Inc.
If unscheduled laboratory assessments during a treatment cycle show Grade 3 or 4 
hematologic toxicity, treatment with capecitabine should be interrupted.
For additional guidance regarding treatment modification of capecitabine, please refer to the 
USPI (or local prescribing information) for dose modifications for hematologic and other 
non-hematologic toxicities.
6.7
Intervention After the End of the Study
Upon study termination, participants are to be discontinued and may be enrolled in an 
extension study using pembrolizumab in combination with lenvatinib or lenvatinib 
monotherapy, if available.  
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention is included in the label text; random 
code/disclosure envelopes or lists are not provided.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Original protocol text that is contained in this section and the following sections has been 
retained for reference.
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period will still continue to be monitored in the study and participate in the study visits and 
procedures as specified in Section 1.3 and Section 8.10.4 unless the participant has 
withdrawn from the study (Section 7.2).
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
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 1.3 and Section 
8.10.4.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
Participants receiving the combination therapy (lenvatinib + pembrolizumab) 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 4 but 
lenvatinib may be administered at a reduced dose by the time this criterion is met and 
must be permanently discontinued immediately.
o
ALT or AST >3 × ULN and (TBL >2 × ULN or INR >1.5)
Although Table 4 advises pembrolizumab to be withheld (interrupted), Table 3 advises 
lenvatinib to have no dose modification or a reduction, if this criterion is met, both drugs 
must be permanently discontinued immediately.

The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
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
The participant has a confirmed positive serum pregnancy test.

Progressive disease is radiographically documented per RECIST 1.1 and centrally 
verified. 
o
As of Amendment 07, central tumor response assessments will no longer be performed. 
Participants receiving study treatment will be assessed locally by the investigator for 
disease progression per the protocol schedule. Scans will not be sent to the iCRO.
o
Participants with RECIST 1.1 disease progression per local investigator 
assessment must discontinue study treatment.  

Continuing initial treatment beyond centrally verified radiographic PD per RECIST 1.1 
may be permitted, following Sponsor consultation, only for participants randomized to 
the lenvatinib + pembrolizumab arm. This is also applicable for participants on Crossover 
treatment receiving lenvatinib + pembrolizumab that have experienced locally assessed 
radiographic PD per RECIST 1.1. As of Amendment 07, participants continuing 
lenvatinib + pembrolizumab on initial or crossover treatment may be permitted to 
continue treatment beyond locally assessed radiographic PD per RECIST 1.1, following 
Sponsor consultation.
NOTE: The participant must be deriving clinical benefit from the study therapy per 
investigator assessment and meet these additional criteria:
o
Absence of unacceptable toxicity
o
Absence of clinical symptoms or signs indicating clinically significant disease 
progression
o
No decline in performance status
o
Absence of rapid disease progression or threat to vital organs or critical 
anatomical sites (e.g., CNS metastasis, respiratory failure due to tumor 
compression, spinal cord compression) requiring urgent alternative medical 
intervention

NOTE: Participants who experience centrally verified PD in the lenvatinib monotherapy 
or SOC chemotherapy arms can crossover to receive lenvatinib + pembrolizumab at time 
of disease progression with Sponsor consultation. As of Amendment 07, participants in 
the SOC chemotherapy arm or lenvatinib monotherapy arm may not crossover to receive 
lenvatinib + pembrolizumab at the time of disease progression. 

Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment. 

NOTE: Exceptions to second malignancy include basal cell carcinoma of the skin, 
squamous cell carcinoma of the skin, new nonulcerated primary melanoma <1 mm in 
depth with no nodal involvement, or carcinoma in situ (eg, breast carcinoma, cervical 
cancer in situ) that have undergone potentially curative therapy. Exceptions should be 
discussed with the Sponsor before continuing therapy or follow-up.

The participant has 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.
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
Administrative reasons requiring cessation of treatment.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, are outlined in Section 8.1.9. The procedures to be performed should a participant 
repeatedly fail to return for scheduled visits and/or if the study site is unable to contact the 
participant are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical (or dental) decisions must be made by an investigator who is a 
qualified physician (or dentist when appropriate).
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before providing documented informed consent may be used for 
screening or baseline purposes provided the procedures meet the protocol-specified 
criteria and were performed within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
•
The maximum amount of blood collected from each participant over the duration of the 
study will be provided.
•
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study. If there are changes to 
the participant’s status during the study (eg, health or age of majority requirements), the 
investigator or medically qualified designee must ensure the appropriate documented 
informed consent is in place.
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8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
Prior to entering Cross over, participant must provide documented informed consent.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention 
allocation/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
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The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed within the prior 
10 years that the investigator considers to be clinically important. Details regarding the 
disease for which the participant has enrolled in this study will be recorded separately and 
not listed as medical history.
If a medical condition is diagnosed at the time of screening due to the physical examination, 
laboratory tests, radiologic assessment, other assessment, and/or a combination of these 
evaluations, the medical condition is to be recorded as a baseline condition along with the 
participant’s other medical history unless due to any protocol-specified intervention (eg, 
procedure, washout, or run-in treatment including placebo run-in).
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before the first dose of study intervention.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the Safety Follow-up Visit. Concomitant medications will be 
recorded for 30 days after the last dose of study intervention.
8.1.5.3
Prior Anticancer Therapy for HNSCC
The investigator or qualified designee will review and record all prior anticancer treatments 
including systemic treatments, radiation, and surgeries, regardless of the time before the first 
dose of study intervention. This will include platinum-containing chemotherapy with or 
without an anti-PD-1/PD-L1 therapy.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
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8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Study intervention should begin within 3 days of randomization. Lenvatinib may be 
administered at home except on C1D1, C1D15 and C2D1; on these days, lenvatinib will be 
taken in the clinic. Administration of study interventions will be monitored by the 
investigator and/or study staff. Study intervention will be administered by the investigator 
and/or study staff according to the specifications within the Pharmacy Manual. An 
extemporaneous suspension of lenvatinib capsules should be used for participants unable to 
swallow capsules, as detailed in the Pharmacy Manual. Please refer to Section 8.1.8.1 for 
further details. 
Investigators must choose a standard treatment (docetaxel, paclitaxel, cetuximab, or 
capecitabine) prior to randomization and document the selection in the trial database (See 
data entry guidelines). When choosing a standard therapy, the investigator should refer to the 
USPI or local product label (with special consideration for any contraindications, special 
warnings and precautions of use).
8.1.8.1
Timing of Dose Administration
Lenvatinib
Lenvatinib is provided as capsules for oral administration and does not require preparation.
Lenvatinib 24 mg (two 10-mg capsules and one 4-mg capsule) for monotherapy and 
lenvatinib 20 mg (two 10-mg capsules) for combination therapy will be taken orally with 
water (with or without food) once daily at approximately the same time each day in each 21-
day cycle. However, on C1D1 and C2D1, lenvatinib will be administered in the clinic 0-4 
hours after completion of pembrolizumab administration. Participants should not take their 
study medication on C2D1 before their appointment. 
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.
Lenvatinib capsules should be swallowed whole. Alternatively, the capsules can be dissolved 
in a small glass of liquid (ie, water or apple juice) if a participant is unable to swallow or has 
feeding tube.  See the Pharmacy Manual for additional information.
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Pembrolizumab
Pembrolizumab will be administered as a 30-minute IV infusion on Day 1 of each 21-day 
cycle. Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window of –5 
minutes to +10 minutes is permitted (ie, infusion time is 30 minutes: –5 min/+10 min).
After C1D1, pembrolizumab may be administered up to 3 days before or after the scheduled 
Day 1 of each subsequent cycle due to administrative reasons.
Docetaxel
Docetaxel can be administered on Day 1 of each 3-week cycle.

Day 1 of each 3-week cycle:
Trial treatment of docetaxel should be administered on Day 1 of each 3-week cycle 
after all procedures/assessments have been completed as detailed on the SoA (Section 
1.3.2). Docetaxel 75 mg/m2 will be administered as an IV infusion administered over 
1 hour or following local SOC.
Paclitaxel
Trial treatment of paclitaxel should be administered on Days 1, 8 and 15 of each 3-week 
cycle after all procedures/assessments have been completed as detailed on the SoA (Section 
1.3.2). Paclitaxel 80 mg/m2 will be administered as an IV infusion administered over 1 hour 
or following local SOC.
Cetuximab
Trial treatment of cetuximab should be administered on Days 1, 8 and 15 of each 3-week 
cycle after all procedures/assessments have been completed as detailed on the SoA (Section 
1.3.2).  
Cetuximab will be given as an initial loading dose on C1D1 of 400 mg/m2 infused over 120 
minutes (maximum infusion rate 10 mg/min). For all subsequent doses, starting with C1D8, 
administer 250 mg/m2 infused over 60 minutes (maximum infusion rate 10 mg/min) or 
follow local SOC.
Capecitabine
Trial treatment of capecitabine should be administered twice daily on Days 1 to 14 of each 3-
week cycle after all procedures/assessments have been completed as detailed on the SoA 
(Section 1.3.2).  
Capecitabine will be administered at an initial dose of 1250 mg/m2. Administration of 
capecitabine dissolved in water or through a feeding tube will be allowed for participants 
unable to swallow tablets.
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8.1.8.2
Compliance
Lenvatinib
Sites should collect and record the number of lenvatinib capsules returned, per the SoA 
(Section 1.3). Lenvatinib compliance will be calculated by the Sponsor based on the drug 
accountability documented by the site staff and monitored by the Sponsor/designee. The 
objective is 100% compliance, and investigators and their staff should evaluate compliance at 
each visit and take appropriate steps to optimize compliance.
Pembrolizumab, docetaxel, paclitaxel or cetuximab:
Study intervention will be administered by the investigator and/or study staff according to the 
specifications within the protocol and Pharmacy Manual, as applicable. The total volume of 
study intervention infused will be compared with the total volume prepared to determine 
compliance with each dose administered.
Capecitabine: 
Site staff will perform tablet counts at regular intervals during treatment, per the SoA 
(Section 1.3.2). Capecitabine compliance will be calculated by the Sponsor, based on the 
drug accountability documented by the site staff and monitored by the Sponsor/designee. 
Investigators and their staff should evaluate compliance at each visit and take appropriate 
steps to optimize compliance. 
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the treatment period 
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA and Section 8.10.4.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the discontinuation visit (EOT visit) should be performed at the time 
of withdrawal. Any AEs that are present at the time of withdrawal should be followed in 
accordance with the safety requirements outlined in Section 8.4.
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
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8.1.12
Demographics
Participant demography information will be collected at the Screening visit. Demography 
information includes date of birth (or age), sex, and race/ethnicity.
8.1.13
Tumor Tissue for Biomarker Status
During the Screening period, a tissue sample is required for each participant consisting of:

A newly obtained core or incisional biopsy of a tumor lesion, which was not previously 
irradiated
or

An archival tumor tissue sample if a new biopsy is unavailable (depending on protocol 
requirements)
FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived 
tissue.
Details pertaining to tumor tissue submission can be found in the Central Laboratory Manual. 
The PD-L1 result will be masked to the site.
8.2
Efficacy Assessments
8.2.1
Tumor Imaging and Assessment of Disease
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.
As of Amendment 07: All participants who are still on study treatment should continue tumor 
imaging and investigator assessments of imaging per protocol. Tumor response assessments 
by BICR will no longer be performed and scans will no longer be sent to the iCRO.
Original protocol text that is contained in this section has been retained for reference.
In addition to survival, efficacy will be assessed based on evaluation of scan changes in 
tumor burden over time, until the participant is discontinued from the study or goes into 
survival follow-up. The process for scan collection and transmission to the iCRO can be 
found in the SIM. Tumor scans by CT are strongly preferred. For the abdomen and pelvis, 
contrast-enhanced MRI may be used when CT with iodinated contrast is contraindicated, or 
when mandated by local practice. The same scan technique 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 response assessment based on scans.
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Note: For the purposes of assessing tumor scans, the term “investigator” refers to the local 
investigator at the site and/or the radiological reviewer at the site or at an offsite facility. 
If brain scans are performed, magnetic resonance imaging is preferred; however, CT imaging 
will be acceptable, if MRI is medically contraindicated.
Bone scans may be performed to evaluate bone metastases. Any supplemental scans 
performed to support a positive or negative bone scan, such as plain x-rays acquired for 
correlation, should also be submitted to the iCRO.
Scans should include the head and neck, chest, and abdomen at all timepoints specified in 
Section 1.3. Scans of the brain and pelvis are optional (if clinically indicated). For an 
individual participant, scans should be consistent at all timepoints, (ie, follow-up scans 
should image the same areas as the baseline area, using the same imaging modality).
At screening, participant eligibility will require radiographic documentation of at least one 
lesion that meets the requirements for selection as a target lesion, as defined by RECIST 1.1 
verified by BICR, prior to participant randomization. 
All scheduled scans for participants from the sites will be submitted to the iCRO. In addition, 
a scan (including via other modalities) that is obtained at an unscheduled time point for any 
reason (including suspicion of progression or other clinical reason) should also be submitted 
to the iCRO if it shows disease progression, or if it is used to support a response assessment. 
All scans acquired within the protocol-specified window of time around a scheduled scan 
visit are to be classified as pertaining to that visit.
When the investigator identifies radiographic progression per RECIST 1.1, the iCRO will 
perform expedited verification of radiologic PD and communicate the results to the study site 
and Sponsor via email. In clinically stable participants, scans should continue until PD has 
been verified by BICR (if initial site-assessed PD was not verified by BICR, each subsequent 
scan must be submitted to iCRO with verification of PD request until PD has been verified 
by BICR). Once PD is verified centrally, subsequent scans (if acquired) should not be 
submitted to the iCRO.
8.2.1.1
Pre-study Scans to Confirm Disease Progression
The site’s study team must have reviewed and submitted pre-study scans that are of 
diagnostic quality from at least 2 dates to determine that radiographic progression has 
occurred per RECIST 1.1 following initiation of prior PD-1/PD-L1 inhibitor treatment. Scans 
should include:

The baseline scan for prior anti-PD-1/PD-L1 or a scan showing nadir during prior anti-
PD-1/PD-L1 treatment.

Scans showing PD on or after an anti-PD-1/PD-L1 mAb (minimum of 2 doses; within 12 
weeks of last dose of pre-study treatment).
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The iCRO must have received these scans prior to randomization in this study and must also 
verify that the scans are of diagnostic quality prior to randomization. These scans will be 
collected by the iCRO for possible retrospective independent review of response.
8.2.1.2
Initial Tumor Scans
Initial scans must be performed within 28 days prior to the date of randomization. The site 
study team must review screening scans to confirm that the participant has measurable 
disease per RECIST 1.1. Additionally, expedited verification of measurable disease based on 
RECIST 1.1 by BICR at screening will be used to determine participant eligibility prior to 
randomization. Verification by the BICR that the participant’s scans show at least 1 lesion 
that is appropriate for selection as a target lesion per RECIST 1.1 is required prior to 
participant randomization.
If brain scans are required to document the stability of existing metastases, the brain MRI 
should be acquired during Screening period.  Scans performed as part of routine clinical 
management is acceptable for use as a baseline tumor scan if it is of diagnostic quality and 
performed within 28 days prior to the date of randomization and can be assessed by the 
iCRO. 
Note: The pre-study scan demonstrating progression on prior PD-1/PD-L1 treatment can be 
used as the screening scan for the study if it is performed within 28 days before the date of 
randomization and can be assessed by the iCRO.
8.2.1.3
Tumor Scans During the Study
The first on study scan assessment should be performed at Week 6 (42-49 days) from the 
date of randomization. Subsequent scans should be performed every 6 weeks (42 days ±7 
days) or more frequently if clinically indicated. After 1 year (48 weeks), participants who 
remain on study intervention will have their scans performed every 9 weeks (63 days ±7 
days). Scan timing should follow calendar days from randomization and not be adjusted for 
delays in cycle starts. Scans should continue to be performed until PD is identified by the 
investigator and verified by BICR (unless the investigator elects to continue study 
intervention and the Sponsor is consulted), the start of new anticancer treatment, withdrawal 
of consent, or death, whichever occurs first. All supplemental scans must be submitted to the 
iCRO if imaging shows PD or to support response assessments.
Treatment beyond centrally verified radiographic PD per RECIST 1.1 may be permitted at 
the discretion of the investigator after consultation with the Sponsor and receiving informed 
consent. Participants who continue treatment beyond centrally verified radiographic PD must 
continue assessments as described in the SoA (Section 1.3.1). Investigator assessments are to 
be documented on the eCRF, but scans are not to be submitted to the iCRO. Further 
progression and discontinuation of study intervention are to be determined by the 
investigator.
Scans to confirm PR or CR should be performed at the next scheduled scan or at least 4 
weeks after the first indication of a response is observed. If participants confirmed PR or CR 
outside of their regular scheduled scan, they will then return to the regular scan schedule, 
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starting with the next scheduled scan time point. Participants who receive additional scans for 
confirmation do not need to undergo the next scheduled scan if it is less than 4 weeks later; 
scans may resume at the subsequent scheduled scan time point.
On-study brain scans should be performed if clinically indicated or to confirm CR (if other 
lesions indicate CR and brain lesions existed at baseline.)
8.2.1.4
End of Treatment and Follow-up Tumor Scans
As of Amendment 07: Imaging scans will no longer be submitted to the iCRO nor read by 
BICR. Original protocol text that is contained in this section has been retained for 
reference.For participants who discontinue study intervention, scans should be performed at 
the time of study intervention discontinuation (±4-week window). If a previous scan was 
obtained within 4 weeks prior to the date of discontinuation, a scan at study intervention 
discontinuation is not mandatory. For participants who discontinue study intervention due to 
centrally verified PD, this is the final required scan. All scans should be submitted to the 
iCRO.
For participants who discontinue study intervention without centrally verified PD, every 
effort should be made to continue monitoring disease status by scans using the same scan 
schedule as during study intervention calculated from the date of randomization (every 6 
weeks in Year 1 or every 9 weeks after Year 1), until the start of new anticancer treatment, 
centrally verified PD, pregnancy, death, withdrawal of consent, or the end of the study, or 
notification by the Sponsor, whichever occurs first.
8.2.1.5
Crossover Treatment Tumor Scans
As of Amendment 07: Imaging scans will no longer be submitted to the iCRO. Additionally, 
participants in the SOC chemotherapy arm or lenvatinib monotherapy arm may not crossover 
to receive lenvatinib + pembrolizumab at the time of disease progression. Original protocol 
text that is contained in this section has been retained for reference.
Participants who experience centrally verified PD in the lenvatinib monotherapy or SOC 
chemotherapy arms can cross over to lenvatinib + pembrolizumab at time of centrally 
verified disease progression with Sponsor consultation. The Crossover screening scans (new 
baseline) should be performed within 28 days prior to the first dose as new baseline scan. 
The centrally verified PD scan in initial treatment may also be used as the Crossover baseline 
scan if it is within 28 days prior to the Crossover first dose. During Crossover, the first scan 
should be performed 6 weeks (42-49 days) after Crossover C1D1. Subsequent scans should 
be performed every 6 weeks (42 days ±7 days) or more frequently if clinically indicated. 
After 1 year (48 weeks), participants who remain on study intervention will have their scan 
performed every 9 weeks (63 days ±7 days). Scan timing should follow calendar days from 
Crossover C1D1 and not be adjusted for delays in cycle starts. For participants who 
discontinue Crossover treatment, scans should be performed at the time of study intervention 
discontinuation (±4 week window). If a previous scan was obtained within 4 weeks before 
the date of discontinuation, a scan at study intervention discontinuation is not mandatory. 
Scans should continue to be performed until PD is identified by the investigator per RECIST 
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1.1, the start of new anticancer treatment, withdrawal of consent, or death, whichever occurs 
first. All supplemental scans must be submitted to the iCRO if imaging shows PD or to 
support response assessments. All Crossover scans should be submitted to the iCRO for 
quality control, storage, and possible retrospective review.
8.2.1.6
Second Course Scans
NOTE: As of Amendment 07, there will be no Second Course Scans. This section is no
longer applicable. 
8.2.1.7
RECIST 1.1 Assessment of Disease
As of Amendment 07: Central tumor response assessments will be discontinued. Imaging 
scans will no longer be submitted to the iCRO nor read by BICR. Original protocol text that 
is contained in this section has been retained for reference.
RECIST 1.1 will be used by BICR as the primary measure for assessment of tumor response 
and date of PD, and as a basis for all protocol guidelines related to disease status (eg, 
discontinuation of study intervention). Although RECIST 1.1 references a maximum of 
5 target lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions 
in total and 5 per organ if clinically relevant, to enable a broader sampling of tumor burden. 
Upon investigator-assessed disease progression, the indicative scans are to be submitted 
immediately to iCRO for BICR verification of progression. After submission of scan(s), the 
iCRO will email the assessment to the site and Sponsor.
If disease progression is not verified, the process continues as follows:
•
If participant is clinically stable, continue study intervention per protocol
-
resume imaging per protocol schedule (≥4 weeks to next scan)
-
send scans to iCRO
-
continue local assessment
-
do not change investigator assessment of progression
-
if subsequent scan(s) indicate progression, submit scan(s) to iCRO to request 
verification
•
If the participant is not clinically stable, best medical practice is to be applied
Before stopping study intervention or imaging or starting new anti-cancer therapy in a 
participant who is clinically stable, communication with the Sponsor is required.
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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 iCRO
Figure 2 illustrates the study intervention decision process involving verification of disease 
progression for participants.
•
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
Figure 2
Study Intervention Decision Making Process (PFS)
iCRO = Imaging Contract Research Organization; PFS = Progression-free Survival; RECIST 1.1 = Response Evaluation 
Criteria in Solid Tumors Version 1.1
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8.2.2
Patient Reported Outcomes
As of Amendment 07: ePRO assessments will be discontinued. Original protocol text that is 
contained in this section has been retained for reference.
It is a best practice and strongly recommended that ePROs are administered before any other 
visit procedures and in the order listed in the SoA, starting with EuroQoL EQ-5D-5L.  
Collection begins at C1 and continues until C35 or treatment discontinuation, whichever 
occurs first.
The PRO questionnaires will be administered:

Prior to dosing at C1D1, and then

Day 1 of every cycle from C1 through C9, then

Day 1 of every other cycle through C17 (C9, C11, C13, C15, C17), then

Every 3 cycles through C35 (C20, C23, C26, C29, C32, C35)

Obtain at EOT and Safety FU.
If the EOT visit happens prior to the end of the study, PROs will be administered at EOT 
visit.
PROs will also be administered at the 30-day Safety Follow-up visit. In the event the EOT 
visit is combined with the 30-day Safety Follow-up visit, only the PRO assessments for the 
EOT visit will be completed.
It is best practice and strongly recommended that ePROs are administered to randomized 
participants prior to drug administration, AE evaluation, and disease status notification. If the 
participant does not complete the ePROs at a scheduled time point, the MISS_MODE form 
must be completed to capture the reason the assessment was not performed.
8.3
Safety Assessments
The total amount of blood/tissue to be drawn/collected over the course of the study (from 
prestudy to poststudy visits), including approximate blood/tissue volumes drawn/collected by 
visit and by sample type per participant, can be found in the Central Laboratory Manual.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination including oral examination will be conducted by an 
investigator or medically qualified designee (consistent with local requirements) as per 
institutional standard. Comprehensive physical examinations will be performed as specified 
in the SoA (Section 1.3). A comprehensive physical examination will include evaluations of 
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the head, eyes, ears, nose, throat, neck, chest (including heart and lungs), abdomen, limbs, 
skin, and a complete neurological examination.
A brief directed physical examination including oral examination will be conducted by an 
investigator or medically qualified designee (consistent with local requirements) per 
institutional standard. Directed physical examinations will be performed as specified in the 
SoA (Section 1.3).
Documentation of the physical examination will be included in the source documentation at 
the investigational site. Significant findings prior to participant treatment allocation will be 
recorded on the appropriate CRF. Changes from screening physical examination findings that 
meet the definition of an AE will be recorded on the appropriate CRF. Height will only be 
measured and recorded at Screening.
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 (using a validated method) at 
Screening, before the administration of each dose of study intervention and during the Safety 
Follow-up Period, as specified in the SoA (Section 1.3). Vital signs include body 
temperature, heart rate, respiratory rate, weight, and blood pressure. 
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.
Only 1 BP measurement is needed for participants with systolic BP <140 mm Hg and 
diastolic BP <90 mm Hg. If the participant’s initial BP is elevated (ie, systolic BP ≥140 mm 
Hg or diastolic BP ≥90 mm Hg), the BP measurement should be repeated at least 5 minutes 
later. One BP assessment is defined as the mean value of 2 measurements at least 5 minutes 
apart. If the BP assessment (ie, the mean of the 2 BP measurements obtained at least 5 
minutes apart) shows an elevated BP (systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg), 
a confirmatory assessment should be obtained at least 30 minutes later by performing 2 
measurements (at least 5 minutes apart) to yield a mean value. 
At the C1D8 telephone visit and if required between clinic visits, participants will have BP 
measured. If the participant does not return to the study site for this BP measurement, BP 
may be measured, for example, at home or at a local pharmacy, and the results will be 
reviewed with the investigator or designee. The investigator/site may provide a diary as a 
tool to aid the participant in collecting BP evaluations between clinic visits. The Sponsor will 
not provide diaries to the site. If BP result raises concerns, the investigator may require 
additional follow-up, including an on-site BP re-test, or other clinically appropriate 
intervention(s).
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8.3.3
Electrocardiograms
ECGs will be obtained as designated in the SoA (Section 1.3). Additional time points may be 
performed as clinically necessary. 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. 
QTc prolongation has been seen in some lenvatinib studies. Drugs known to prolong the QTc 
interval (including Class Ia and III antiarrhythmics) must be used cautiously. Please refer to 
lenvatinib prescribing information. Monitor electrocardiograms every cycle (as specified in 
the SoA) in participants 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.
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.
8.3.4
Echocardiograms or Multigated Acquisition Scans
A MUGA scan (using a technetium-based tracer) or an ECHO can be performed to further 
assess LVEF as designated in the SoA (Sections 1.3.1 and 1.3.2). Additional time points may 
be performed as clinically necessary. MUGA or ECHO scans should be performed locally in 
accordance with the institution’s standard practice. MUGA scans are the preferred modality. 
However, whichever modality is used for the initial assessment should be repeated for all 
subsequent LVEF assessments for that participant. LVEFs as assessed by the institution will 
be entered on the eCRF. Investigator assessment will be based on institutional reports.
8.3.5
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the SoA.
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•
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 for all AEs and 90 days for all SAEs (or 30 
days following cessation of treatment if the participant initiates new anticancer therapy, 
whichever occurs first) after the last dose of study intervention, every attempt should be 
made to perform repeat assessments until the values return to normal or baseline or if a 
new baseline is established as determined by the investigator.
8.3.5.1
CBC with Differential and Clinical Chemistry
CBC with differential and clinical chemistry results must be reviewed before administration 
of study intervention. Electrolytes such as potassium, calcium, and magnesium should be 
monitored and abnormalities, when considered clinically significant, should be corrected in 
all participants before starting study intervention.
8.3.5.2
Urine Dipstick Testing/Urinalysis
After Cycle 1, urine dipstick testing will only be performed in participants taking lenvatinib 
as described in SoA (Section 1.3). Urine dipstick testing for participants with ≥2+ proteinuria 
should be monitored as described in Section 6.6.1.2.
8.3.5.3
Thyroid Function Testing
The screening blood sample for thyroid function testing will be obtained within 7 days before 
the first dose of study intervention.
Thyroid function testing will be performed within 7 days of C1D1 and within 3 days of each 
subsequent cycle. Participants may be dosed while thyroid function test results are pending, 
however the results must be reviewed by the investigator when available.
8.3.6
Pregnancy Testing
Pregnancy testing ([urine or serum] as required by local regulations) should be conducted 
according to Section 1.3 (SoA) and at the end of relevant systemic exposure for all arms.
•
Pregnancy testing requirements for study inclusion are described in Section 5.1.
•
Pregnancy testing (urine or serum) should be conducted at monthly intervals during 
intervention.
•
Pregnancy testing (urine or serum) should be conducted for the time it takes to eliminate 
systemic exposure after the last dose of study intervention(s) as noted in Section 5.1, ie, 
120 days following cessation of pembrolizumab, 30 days following cessation of 
lenvatinib, or 180 days following cessation of chemotherapy.
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Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator to establish the absence of pregnancy at any time during the participant's 
participation in the study. 
8.3.7
Eastern Cooperative Oncology Group Performance Status
The ECOG Performance Status is standardized criteria to measure how cancer impacts level 
of functioning (performance status) in terms of ability to care for oneself, daily activity, and 
physical ability (walking, working, etc) with grades 0 to 5.
The investigator or qualified designee will assess ECOG status (see Appendix 8) at 
screening, before the administration of each dose of study intervention and during the 
follow-up period as specified in the SoA (Section 1.3).
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. The investigator, who is a qualified physician, 
will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity/toxicity, and causality.
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.
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•
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 
randomization through the time required to eliminate systemic exposure after cessation of 
study intervention as described in Sections 5.1 and 8.3.6, or 30 days after cessation of 
study intervention if the participant initiates new anticancer therapy must be reported by 
the investigator.
•
Additionally, any SAE brought to the attention of an investigator at any time outside of 
the time period specified above must be reported immediately to the Sponsor if the event 
is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 8.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
Table 8
Reporting Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/
Allocation
Reporting Time 
Period:
Randomization/
Allocation 
through Protocol-
specified Follow-
up Period
Reporting Time 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame 
to Report 
Event and 
Follow-up 
Information to 
Sponsor:
Nonserious Adverse 
Event (NSAE)
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
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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:
Serious Adverse 
Event (SAE) 
including Cancer and 
Overdose
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
– drug/vaccine 
related.
(Follow 
ongoing to 
outcome)
Within 
24 hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if participant 
has been exposed to 
any protocol-specified 
intervention (eg, 
procedure, washout, or 
run-in treatment 
including placebo run-
in)
Exception: A positive 
pregnancy test at the 
time of initial 
screening is not a 
reportable event 
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
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events, 
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities toward the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
Note: To meet EU CTR requirements, the Sponsor will report SUSARs to the Eudravigilance 
database via E2B(R3) electronic ICSR form in compliance with CTR 536/2014.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee), or a pregnancy that occurs during the study in a 
nonparticipant whose sexual partner is a participant capable of producing ejaculate is 
reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
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serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
Pembrolizumab
It is not known whether pembrolizumab is excreted in human milk. No studies have been 
conducted to assess the impact of pembrolizumab on milk production or its presence in breast 
milk. Because many drugs are excreted in human milk, female participants must discontinue 
breastfeeding during treatment with pembrolizumab and for 4 months after the final dose 
[U.S. Prescribing Information 2018].
Lenvatinib
It is not known whether lenvatinib is excreted in human milk. However, lenvatinib and its 
metabolites are excreted in rat milk at concentrations higher than in maternal plasma. 
Because of the potential for SAEs from lenvatinib in nursing infants, female participants are 
advised to discontinue breastfeeding during treatment with lenvatinib [U.S. Prescribing 
Information 2018a].
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 8.4.1.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the study. Any suspected endpoint that upon review is 
not progression of the cancer under study will be forwarded to Global Pharmacovigilance as 
an SAE within 24 hours of determination that the event is not progression of the cancer under 
study.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:
1. An overdose of Sponsor's product, as defined in Section 8.5 lenvatinib overdose without 
an associated adverse event is not considered an ECI. 
2. An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.* 
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*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose exceeding the prescribed 
dose for:

Pembrolizumab: ≥5 times the protocol-specified dose

Lenvatinib: any dose above the protocol-prescribed dose if associated with an adverse 
event 

SOC chemotherapy: ≥20% over the prescribed dose
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 participants 
receiving single doses of lenvatinib as high as 40 mg were similar to those in clinical studies 
at the recommended dose for differentiated thyroid cancer, RCC, and HCC.
No specific information is available on the treatment of overdose of pembrolizumab or 
lenvatinib. In the event of overdose, the participant should be observed closely for signs of 
toxicity. Appropriate supportive treatment should be provided if clinically indicated.
All reports of pembrolizumab overdose with and without an AE and all reports of lenvatinib 
overdose with an AE must be reported by the investigator within 24 hours to the Sponsor 
either by electronic media or paper.
Reports of pembrolizumab overdose without any associated clinical symptoms or abnormal 
laboratory results, should be reported using the terminology “accidental or intentional 
overdose without adverse effect.”
All reports of overdose for SOC chemotherapy with and without an AE must be reported by 
the investigator within 24 hours to the Sponsor either by electronic media or paper.
8.6
Pharmacokinetics
As of Amendment 07: Sample collection for PK and/or ADA, RNA analysis, and 
plasma/serum biomarkers is discontinued. Original protocol text that is contained in this 
section has been retained for reference.
Blood samples will be collected as specified in the SoA (Sections 1.3.1 and 1.3.3). Study 
sites must have appropriately trained staff and adequate equipment for procuring and 
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processing specimens. Instructions for collection, handling and shipping of PK samples will 
be provided in the Central Laboratory Manual.
To evaluate the immunogenicity and exposure of pembrolizumab in this indication, blood 
samples for PK and ADA will be collected and may be stored only at this time. Further 
analysis may be performed if required and reported separately if conducted.
If at some point during the study, prospective PK and/or ADA sample collection is deemed to 
be unnecessary by the Sponsor, it may be reduced or discontinued, and sites will be notified 
accordingly.
8.6.1
Blood Collection for Serum Pembrolizumab
To evaluate pembrolizumab immunogenicity and pembrolizumab exposure in this 
combination with lenvatinib, sample collections for analysis of ADA and PK are currently 
planned as shown in the SoA (Section 1.3). Blood samples will be obtained to measure PK 
and ADA of serum pembrolizumab. These samples collected may be stored at this time. 
Analysis may be performed if required. If ongoing ADA and/or PK results are deemed to be 
unnecessary by the Sponsor, it may be decided to discontinue or reduce further sample 
collection in this study. If PK and/or ADA analyses are performed, the results of these 
analyses will be reported separately.
8.6.2
Blood Collection for Plasma Lenvatinib
To evaluate the exposure of lenvatinib when administered as monotherapy and when co-
administered with pembrolizumab blood samples will be collected from all participants as 
specified in the SoA (Section 1.3). Plasma concentrations of lenvatinib will be measured and 
quantified by validated tandem high-performance liquid chromatography/mass spectroscopy 
methods. Data will be analyzed using a PopPK approach.
8.6.3
Blood Collection for RNA Analysis and Plasma and Serum Biomarker 
Analysis
Blood for RNA Analysis: Collect predose on C1D1, C2D1, C3D1, C5D1, and at EOT.
Blood for Plasma Biomarkers: Collect at predose on D1 of C1, C2, C3, C5, C7, C9, C11, 
C13, C15, C17, then on D1 of every 3 cycles until EOT, including at the EOT visit.
Blood for Serum Biomarkers: Collect predose on C1D1, C1D15, C2D1, C3D1, C5D1, and at 
EOT.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
As of Amendment 07: Biomarker sample collections are discontinued. Original protocol text 
that is contained in this section has been retained for reference.
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To identify novel biomarkers, the following biospecimens to support exploratory analyses 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 circulating tumor nucleic acids 
•
Tumor tissue 
Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be provided in the Central Laboratory Manual.
8.8.1
Planned Genetic Analysis Sample Collection
Samples are to be collected for planned analysis of associations between genetic variants in 
germline/tumor DNA and drug response. If a documented law or regulation prohibits (or 
local IRB/IEC does not approve) sample collection for these purposes, then such samples are 
not to be collected at the corresponding sites.
The planned genetic analysis sample should be obtained predose on Day 1 but may be 
collected at the next scheduled blood draw, if needed. Sample collection, storage, and 
shipment instructions for planned genetic analysis samples will be in the Central Laboratory 
Manual.
8.8.2
Human Papilloma Virus Testing
Participants with oropharynx cancer must have assessment of HPV status from tumor tissue 
prior to randomization as per the inclusion criteria (Section 5.1).
Tumor p16 expression must be evaluated by assessment of IHC analysis with CINtec® p16 
Histology assay (Ventana Medical Systems Inc., Tucson AZ) using positive p16 expression, 
which is defined as strong and diffuse nuclear and cytoplasmic staining in 70% or more of 
the tumor cells.
Note: If local p16 testing results are not available, or cannot be assessed by the specified 
method, a tumor tissue sample may be submitted for p16 testing at the designated central 
laboratory.
Note: Oral cavity, hypopharynx, and larynx cancer are not required to undergo HPV testing 
by p16 IHC as by convention they are assumed to be HPV negative.
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8.9
Health Economics Medical Resource Utilization and Health Economics
All-cause hospitalizations and emergency department visits must be reported in the eCRF, 
from the time of treatment 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.
8.10
Visit Requirements
Visit requirements are outlined in SoA (Section 1.3). Specific procedure-related details are 
provided in Section 8.
8.10.1
Screening
Documented informed consent must be provided before performing any protocol-specific 
procedure. Results of a test performed before the participant signing consent as part of 
routine clinical management are acceptable in lieu of a screening test if performed within the 
specified time frame.
Screening procedures are to be completed within 28 days before the first dose of study 
intervention.
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments during the initial screening period are acceptable in lieu of a repeat 
screening test if performed within the specified time frame and the corresponding 
inclusion/exclusion criteria is met. Participants who are rescreened will retain their original 
screening number.
See Appendix 7 for country-specific requirements
8.10.2
Initial Treatment Phase
Visit requirements are outlined in the SoA (Section 1.3). Assessments/procedures are to be 
performed before administration of study intervention.
8.10.2.1
Telephone Contact or Visit
A telephone visit will be scheduled on C1D8 to report blood pressure and record AEs, as 
outlined in the SoA (Section 1.3). At the C1D8 telephone visit and if required between clinic 
visits, participants will have BP measured. If the participant does not return to the study site 
for this BP measurement, BP may be measured, for example, at home or at a local pharmacy, 
and the results will be reviewed with the investigator or designee. The investigator/site may 
provide a diary as a tool to aid the participant in collecting BP evaluations between clinic 
visits. The Sponsor will not provide diaries to the site. If BP result raises concerns, the 
investigator may require additional follow-up, including an on-site BP re-test, or other 
clinically appropriate intervention(s).
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8.10.2.2
Addition of Pembrolizumab Following Progression on Lenvatinib 
Monotherapy
An investigator may add pembrolizumab to lenvatinib monotherapy following centrally 
verified PD by RECIST 1.1 with Sponsor consultation. The lenvatinib dose should be 
decreased to 20 mg daily (from 24 mg monotherapy) when given in combination with 
pembrolizumab. If the lenvatinib dose was reduced during monotherapy, the reduced dose 
should be continued. Visit requirements are outlined in the SoA (Section 1.3.3). As of 
Amendment 07, participants in the lenvatinib monotherapy arm may not crossover to receive 
lenvatinib + pembrolizumab at the time of disease progression.
Participants may receive pembrolizumab alone during Crossover with Sponsor consultation. 
Participants who discontinue lenvatinib prior to initiation of Crossover treatment will not 
restart lenvatinib.
8.10.3
Second Course
NOTE: As of Amendment 07, there will be no Second Course. This section is no longer 
applicable. 
8.10.4
Discontinued Participants Continuing to be Monitored in the Study 
The discontinuation visit should take place at the time study intervention is discontinued for 
any reason. If the discontinuation visit takes place 30 days from the last dose of study 
intervention, at the time of the mandatory Safety Follow-up visit, the safety visit is not 
required. All procedures required at the discontinuation visit and at the 30-day Safety 
Follow-up visit should be performed.
8.10.5
Posttreatment Visit
8.10.5.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before initiation of a new anticancer treatment, whichever 
comes first.
Participants who are eligible for Crossover treatment may have up to 2 Safety Follow-up 
visits, 1 after initial treatment or First Course and 1 after the Crossover treatment.
8.10.5.2
Efficacy Follow-up Visits
As of Amendment 07: Efficacy Follow-up Visits will be discontinued. Therefore, 
participants in efficacy follow-up and survival follow-up should be discontinued from the 
study. Imaging scans will no longer be submitted to the iCRO nor read by BICR. Original 
protocol text that is contained in this section has been retained for reference.
Participants who complete the protocol-required cycles of study intervention or who 
discontinue study intervention for a reason other than centrally verified PD will begin 
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Efficacy Follow-up and should be assessed as outlined in the SoA corresponding to the 
assigned treatment arm (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, 
centrally verified PD, death, end of study, or the participant begins retreatment as detailed in 
Section 8.10.3. Information regarding poststudy anticancer treatment will be collected if new 
treatment is initiated. Participants who completed all efficacy assessments and/or will not 
have further efficacy assessments must enter Survival Follow-up.
8.10.5.3
Survival Follow-up Contacts
As of Amendment 07: Survival Follow-up Visits will be discontinued. Those participants 
remaining on study treatment at the time of Amendment 07 should continue to be monitored 
in the study through the AE reporting period (Section 8.4). Original protocol text that is 
contained in this section has been retained for reference.
Participant survival follow-up status will be assessed approximately every 12 weeks to assess 
for survival status until death, withdrawal of consent, or the end of the study, whichever 
occurs first.
The first survival follow-up assessment should be scheduled as described below:
•
For participants who discontinue treatment intervention and who will not enter Efficacy 
Follow-up, the first survival follow-up contact will be scheduled 12 weeks after the 
Discontinuation Visit and/or Safety Follow-up Visit (whichever is last).
•
For participants who completed assessments in Efficacy Follow-up, the first survival 
follow-up contact will be scheduled 12 weeks after the last efficacy assessment follow-up 
visit has been performed.
8.10.6
Vital Status
To ensure current and complete survival information (vital status) is available at the time of 
database locks, updated vital status may be requested during the study by the Sponsor. For 
example, updated vital status may be requested before but not limited to, an eDMC review, 
interim and/or final analysis. Upon Sponsor notification, all participants who do not/will not 
have a scheduled study visit or study contact during the Sponsor-defined period will be 
contacted for their vital status.
If a participant withdraws consent, vital status (survival information) may be obtained by 
review of public records, in accordance with local regulations.
If a participant is lost to follow-up, vital status (survival information) can be conducted by 
review of medical records or public records when vital status is in question in accordance 
with local regulations.
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9
STATISTICAL ANALYSIS PLAN
NOTE: A periodic review of safety data using a data cutoff date of 31-MAY-2024 was 
conducted by the eDMC. At the request of the eDMC, OS data were provided for review, 
though there was no preplanned statistical analysis for OS. At this safety analysis, the OS 
Kaplan-Meier curves did not favor pembrolizumab + lenvatinib versus SOC chemotherapy. 
Based on these data and the recommendation of the eDMC, Amendment 07 was 
implemented to discontinue the combination of lenvatinib + pembrolizumab or lenvatinib 
monotherapy arms. The prespecified interim and final analyses of the study described in 
Section 9 will not be performed. Selected analyses of safety endpoints will be performed at 
the end of the study; there will be no further analyses of efficacy or ePRO endpoints.
This section outlines the statistical analysis strategy and procedures for the study. Changes to 
analyses made after the protocol has been finalized, but prior to the conduct of any analysis, 
will be documented in an sSAP and referenced in the CSR for the study. Post hoc exploratory 
analyses will be clearly identified in the CSR. The PRO analysis plan will also be included in 
the sSAP. Other planned analyses (ie, those specific to the analysis of PK data) are beyond 
the scope of this document or will be documented in separate analysis plans.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 through 9.12.
Study Design Overview
Phase 2 study of lenvatinib (E7080/MK-7902) with pembrolizumab 
(MK-3475) versus SOC chemotherapy and lenvatinib monotherapy in 
participants with R/M HNSCC who have progressed after platinum 
chemotherapy and after treatment with immunotherapy (PD-1/PD-L1 
inhibitors)
Treatment Assignment
Approximately 400 participants will be randomized in a 3:3:2 ratio into 
3 treatment arms: lenvatinib + pembrolizumab combination therapy 
(Arm 1), SOC chemotherapy (Arm 2) and lenvatinib monotherapy (Arm 
3). As of Amendment 07, 408 participants have been randomized and no 
additional participants will be randomized. 
Stratification factors are as follows:

ECOG performance status (0 vs. 1)

PD-L1 tumor expression as determined by PD-L1 
immunohistochemistry (TPS <50% vs. ≥50%)
This study will be conducted as an open-label study.
Analysis Populations
Efficacy: ITT
Safety: All Participants as Treated (APaT)
Primary Endpoint(s)
OS
Key Secondary Endpoints

PFS per RECIST 1.1 based on BICR

OR per RECIST 1.1 based on BICR
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Statistical Methods for Key 
Efficacy Analyses
The HRs of OS and PFS will be estimated using a stratified Cox 
regression model. Event rates over time will be estimated within each 
treatment group using the Kaplan-Meier method. ORR will be estimated 
by treatment group with 95% CI calculated by Clopper-Pearson exact 
method. The difference in ORR and its 95% CI from the stratified 
Miettinen and Nurminen method with strata weighting by sample size 
will be provided.
Statistical Methods for Key 
Safety Analyses
For analyses in which 95% CIs will be provided for between-treatment 
differences in the percentage of participants with events, these analyses 
will be performed using the unstratified Miettinen and Nurminen method 
[Miettinen, O. and Nurminen, M. 1985].
Interim Analysis
Multiplicity
Sample Size and Power
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study is being conducted as a randomized, open-label study, i.e., participants, 
investigators, and Sponsor personnel will be aware of participant study intervention 
assignments after each participant is enrolled and study intervention is assigned. 
The Sponsor will generate the randomized allocation schedule for study treatment 
assignment for this protocol and the randomization will be implemented in IVRS/IWRS.
Although the trial is open-label, analyses or summaries generated by randomized intervention 
assignment, or actual intervention received will be limited and documented. In addition, the 
independent radiologist(s) will perform the central imaging review without knowledge of 
treatment group assignment.
9.3
Hypotheses/Estimation
Objectives of the study are stated in Section 3.
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated are listed below.
9.4.1
Efficacy Endpoints
Primary

Overall Survival (OS): defined as time from randomization to death due to any cause.
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Secondary

Progression-free Survival (PFS): defined as time from randomization to the first 
documented disease progression per RECIST 1.1 by BICR or death due to any cause, 
whichever occurs first.

Objective Response (OR): the OR is defined as a confirmed complete response (CR) 
or partial response (PR) per RECIST 1.1 as assessed by BICR.

Duration of Response (DOR): for participants who demonstrate CR or PR, DOR is 
defined as the time from first documented evidence of CR or PR until disease 
progression or death due to any cause, whichever occurs first.
9.4.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory values and vital signs.
9.4.3
Patient Reported Outcome Endpoints
As of Amendment 07, PRO endpoints will not be analyzed. 
9.5
Analysis Populations
9.5.1
Efficacy Analysis Population
The efficacy analyses for OS, PFS and ORR will be based on the ITT population. All 
randomized participants will be included in this population. Participants will be analyzed in 
the treatment group to which they are randomized.
The analysis population for DOR consists of all responders.
9.5.2
Safety Analysis Population
Safety Analyses will be conducted in the APaT population, which consists of all randomized 
participants who received at least one dose of study intervention. Participants will be 
included in the treatment group corresponding to the study intervention they actually 
received for the analysis of safety data using the APaT population. This will be the treatment 
group to which they are randomized except for participants who take incorrect study 
intervention for the entire treatment period; such participants will be included in the 
treatment group corresponding to the study intervention actually received.  Participants who 
are randomized to the SOC chemotherapy arm can receive different chemotherapies at 
investigator’s choice, and they will be pooled and analyzed under SOC chemotherapy arm.  
At least one laboratory, or vital sign measurement obtained subsequent to at least one dose of 
study intervention is required for inclusion in the analysis of the respective safety parameter.  
To assess change from baseline, a baseline measurement is also required.
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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.
Nominal p-values may be computed for other efficacy analyses but should be interpreted 
with caution due to potential issues of multiplicity and sample size.
For the lenvatinib monotherapy arm, if it continues to 100 participants following the interim 
futility analysis, summary statistics for the lenvatinib monotherapy will be provided for each 
endpoint according to the plan as outlined below.
The stratification factors used for randomization (see Section 6.3.2) will be applied to all 
stratified analyses, in particular, stratified Cox model.
The efficacy analyses for ORR, DOR and PFS will be based on responses and documented 
progression events that occur prior to protocol-specified treatment Crossover. 
9.6.1.1
Overall Survival
The non-parametric Kaplan-Meier method will be used to estimate the OS curve by treatment 
group.
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 hazard ratio). The hazard ratio and 
its 95% confidence interval from the stratified Cox model with a single treatment covariate 
will be reported. Participants without documented death at the time of analysis will be 
censored at the date the participant was last known to be alive. 
9.6.1.2
Progression-Free Survival
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve by 
treatment group.
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, hazard ratio) between the treatment 
arms. The hazard ratio and its 95% confidence interval from the stratified Cox model with 
Efron's method of tie handling and with a single treatment covariate will be reported. 
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9.6.1.3
Objective Response Rate
The difference in ORR and its 95% CI from the stratified Miettinen and Nurminen method 
with strata weighting by sample size will be provided. 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]. 
9.6.1.4
Duration of Response
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. Censoring rules for DOR are summarized in Table 10. 
For each DOR analysis, a corresponding summary of the reasons why responding 
participants are censored will also be provided. 
 
 
 
 
 
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9.6.1.5
Analysis Strategy for Key Efficacy Variables
A summary of the primary analysis strategy for the key efficacy endpoints for the lenvatinib 
+ pembrolizumab combination therapy and SOC chemotherapy is provided in Table 11.
Table 11
Summary of Analysis Strategy for Efficacy Endpoints
Endpoint
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoint
OS
HR estimation using stratified 
Cox model with Efron’s tie 
handling method
ITT
Censored at last date 
the participant was 
known to be alive 
Secondary Endpoints
PFS per RECIST 1.1, 
BICR
HR estimation using stratified 
Cox model with Efron’s tie 
handling method
ITT
Censored according to 
rules in Table 9. 
ORR per RECIST 1.1 
by BICR  
Estimation:
Clopper-Pearson (exact) 
method
ITT
Participants with 
missing data are 
considered non-
responders
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Endpoint
Statistical Method
Analysis 
Population
Missing Data 
Approach
DOR per RECIST 
1.1, BICR
Summary statistics using 
Kaplan-Meier method
Responders 
in ITT 
population
Censored according to 
rules in Table 10. 
Abbreviations: BICR = Blinded independent central review; DOR = Duration of response; HR= hazard ratio; 
ITT= intention-to-treat; ORR = Objective response rate; OS = Overall survival; PFS = Progression-free 
survival; RECIST = Response Evaluation Criteria In Solid Tumors.
9.6.2
Statistical Methods for Safety Analyses
The primary safety analyses will include only events that occur prior to protocol-specified 
treatment crossover.
9.6.2.1
Overall Safety Assessment 
The overall safety evaluation will include a summary by treatment group of the number and 
percentage of participants with at least one AE, drug-related AE, serious AE, serious drug-
related AE, Grade 3-5 AE, drug-related Grade 3-5 AE, discontinuation from study 
intervention due to an AE, interruption of study intervention due to an AE, an AE resulting in 
dose reduction, and an AE resulting in death. 
The number and percentage of participants with specific AEs will also be provided. Point 
estimate and 95% CIs for the difference between the lenvatinib + pembrolizumab 
combination therapy arm (Arm 1) and SOC chemotherapy arm (Arm 2) in the percentage of 
participants with specific AEs will be provided for AEs that occur in at least 10% of 
participants in any treatment group. The threshold of at least 10% of participants was chosen 
because the population enrolled in this study is in critical condition and usually experiences 
various AEs of similar types regardless of treatment; events reported less frequently than 
10% of participants would obscure the assessment of the overall safety profile and add little 
to the interpretation of potentially meaningful treatment differences. In addition, difference 
between Arm 1 and Arm 2 in the percentage of participants with specific Grade 3-5 AEs (≥
5% of participants in any treatment group), SAEs (≥5% of participants in any treatment 
group), and tumor hemorrhage (incidence ≥4% of participants in 1 of the treatment groups) 
will also be summarized by point estimate and 95% CI. Rainfall plots with point estimates 
and 95% CIs will be displayed for Arm 1 and Arm 2 with specific AEs, specific Grade 3-5 
AEs and specific SAEs that meet the corresponding predefined threshold rules.
CIs for between treatment group differences will be provided using the M&N method 
[Miettinen, O. and Nurminen, M. 1985]. Because many 95% CIs may be provided without 
adjustment for multiplicity, the CIs should be regarded as helpful descriptive measures for 
the review of the safety profile and not as a formal method for assessing the statistical 
significance of the between-group differences. 
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The number and percentage of participants with laboratory toxicity grade increased from 
baseline will be summarized by the post-baseline maximum toxicity grade per CTCAE V5.0 
for each gradable laboratory test.
For continuous safety measures, such as change from baseline in laboratory, vital signs, and 
ECG parameters, summary statistics for baseline, on-treatment, and change from baseline 
values will be provided.
9.6.2.2
Assessment of Safety Topics of Special Interest 
AEs that are immune-mediated or potentially immune-mediated are considered safety topics 
of special interest (AEOSI) in this study. These events have been characterized consistently 
throughout the pembrolizumab clinical development program. Point estimates and 95% CIs 
for between-group difference is not expected to add value to the safety evaluation, and hence 
only number and percentage of participants with such pembrolizumab AEOSI will be 
provided, as well as the number and percentage of participants with corticosteroids 
administration to treat an AEOSI. Summary statistics will be provided for the analysis of 
time from first dose to the onset of an AEOSI.
Table 12 summarizes the analysis strategy for safety endpoints in this study.
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Table 12
Analysis Strategy for Safety Parameters
Analysis Part
Safety Endpoint
Descriptive 
Statistics
95% between-
group CI 
(Graphical 
display)
Overall Safety 
Assessment
Specific AEs (incidence ≥10% of participants 
in any treatment group)
X
X
Specific Grade 3-5 AE (incidence ≥5% of 
participants in any treatment group)
X
X
Specific serious AE (incidence ≥5% of 
participants in any treatment group)
X
X
Tumor hemorrhage (incidence ≥ 4% of 
participants in 1 of the treatment groups)
X
X
Any AE
X
Any Grade 3-5 AE
X
Any serious AE 
X
Any drug-related AE
X
Any serious and drug-related AE
X
Any Grade 3-5 and drug-related AE
X
Discontinuation of study treatment due to AE
X
Interruption of study treatment due to AE
X
AE that resulted in dose reduction
X
AE that resulted in death
X
Laboratory toxicity grade increase from 
baseline
X
Change from baseline results (vital signs)
X
Assessment of 
safety topics of 
special interest
Pembrolizumab AEOSI 
Lenvatinib CSAE
X
Abbreviations: AE = adverse event; AEOSI = adverse event of special interest; CSAE = clinically
significant adverse event; CI = confidence interval.
9.6.3
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis 
tests will be performed on these characteristics. The number and percentage of participants 
screened and randomized and the primary reasons for screening failure and discontinuation 
will be displayed. Demographic variables, baseline characteristics, primary and secondary 
diagnoses, and prior and concomitant therapies will be summarized by treatment either by 
descriptive statistics or categorical tables.
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9.7
Interim Analyses
9.8
Multiplicity
9.9
Sample Size and Power Calculations
9.10
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
treatment effect for OS, PFS, and ORR (with a nominal 95% CI) will be estimated for 
lenvatinib + pembrolizumab combination therapy and SOC chemotherapy arms within each 
category of the following subgroup variables: 

PD-L1 tumor expression as determined by PD-L1 immunohistochemistry (TPS <50% 
vs. ≥50%)

ECOG performance status (0 vs. 1)

Age category (<65 vs. ≥65 years)

Sex (female vs. male)

Race (white vs. all others)

Geographic region of enrolling site (US vs. Western Europe vs. ROW)

PD-L1 tumor expression as determined by PD-L1 immunohistochemistry (CPS < 1 
vs. ≥ 1)

Anti-PD-1/PD-L1 treatment prior to study entry (most recent vs. not most recent)
A forest plot will be produced, which provides the estimated point estimates and CIs for the 
treatment effect across the categories of subgroups listed above. If the number of participants 
in a category of a subgroup variable is less than 10% of the ITT population, the subgroup 
analysis will not be performed for this category of the subgroup variable, and this subgroup 
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variable will not be displayed in the forest plot. The subgroup analyses 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
Extent of Exposure for a participant is defined as the number of cycles and number of days in 
which the participant receives the study intervention. Summary statistics will be provided on 
the extent of exposure for the overall study intervention, and for pembrolizumab, SOC 
chemotherapy and lenvatinib separately, 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 Interventional Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
I.
Introduction
A. Purpose
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD), conducts clinical trials 
worldwide to evaluate the safety and effectiveness of our products. As such, we are 
committed to designing, implementing, conducting, analyzing, and reporting these 
trials in compliance with the highest ethical and scientific standards. Protection of 
participants in clinical trials is the overriding concern in the design and conduct of 
clinical trials. In all cases, MSD clinical trials will be conducted in compliance with 
local and/or national regulations (including all applicable data protection laws and 
regulations), Regulation (EU) 536/2014, the International Council for Harmonisation 
Good Clinical Practice (ICH -GCP), and also in accordance with the ethical principles 
that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical 
interventional investigations sponsored by MSD irrespective of the party (parties) 
employed for their execution (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. Input may be considered from a broad range of stakeholders, including 
patient advocacy groups/patients representing the trial population, caregivers, and 
healthcare providers to ensure operational feasibility. Trial design also includes 
proactive identification of critical to quality factors utilizing a risk-based 
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approach. Plans are then developed to assess and mitigate risks to those factors as 
appropriate during the trial. 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 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.
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.
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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 and ICH Guidelines. Changes to the protocol that are required 
urgently to eliminate an immediate hazard and to protect participant safety may be 
enacted in anticipation of ethics committee approval. MSD will inform regulatory 
authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is 
of primary importance. Potential participants will be informed of the risks and 
benefits of, as well as alternatives to, trial participation. At a minimum, trial designs 
will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only 
after informed consent is obtained. Participants may withdraw from an MSD trial at 
any time, without any influence on their access to, or receipt of, medical care that 
may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent 
possible, as well as all applicable data protection rights. Unless required by law, only 
the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, 
and/or regulatory authorities will have access to confidential medical records that 
might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
IV.Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate 
investigators (or the sponsoring institution) in a fair manner for the work performed 
in support of MSD trials. MSD does not pay incentives to enroll participants in its 
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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 medical record 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 their financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
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10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that their personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
The Sponsor has EU-approved Binding Corporate Rules since 2017, covering all aspects of 
its Global Privacy Program (Corporate Policy 20), and is self-certified pursuant to the EU-US 
Data Privacy Framework.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee, affiliated institution, and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution, and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules, 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
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regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Scientific Advisory Committee (SAC)
This study was developed in collaboration with a SAC. The SAC is comprised of both 
Sponsor and non-Sponsor scientific experts who provide input with respect to study design, 
interpretation of study results, and subsequent peer-reviewed scientific publications.
10.1.4.2
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide upon any recommendations made by the DMC regarding the study.
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 9.7.2) and 
recommend to the EOC whether the study should continue in accordance with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
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Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trials Regulation 536/2014, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu, https://euclinicaltrials.eu, or other local registries. MSD, as 
Sponsor of this study, will review this protocol and submit the information necessary to 
fulfill these requirements. MSD entries are not limited to FDAAA or the EMA clinical trials 
Regulation 536/2014 mandated trials. Information posted will allow participants to identify 
potentially appropriate studies for their disease conditions and pursue participation by calling 
a central contact number for further information on appropriate study locations and study-site 
contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials Regulation 536/2014, or other locally mandated registries 
are that of the Sponsor and agrees not to submit any information about this study or its results 
to those registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol, generally accepted standards of GCP 
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP), and 
all applicable federal, state, and local laws, rules, and regulations relating to the conduct of 
the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority.
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
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conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
For investigators located in countries with serious breach reporting requirements, investigator 
will promptly report to the Sponsor any serious breach or suspected serious breach that 
occurs in compliance with those requirements. Unless more specifically defined in the 
applicable requirements, a serious breach is any breach of the applicable clinical trial 
regulation or of the clinical trial protocol which is likely to affect to a significant degree: (i) 
the safety or rights of a trial participant, or (ii) the reliability and robustness of the data 
generated in the clinical trial.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period 
(eg, EU CTR: 25 years after the end of the study). No records may be destroyed during the 
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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 or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 13 will be performed by the local laboratory.

Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing (urine or serum) should be conducted at monthly intervals during 
intervention.
-
Pregnancy testing (urine or serum) 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, to establish the absence of pregnancy at any time 
during the participant’s participation in the study.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 13
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
WBC count with Differentiala
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUNb
Urea
Uric acid
Creatininec
AST(SGOT)
ALT(SGPT)
Alkaline phosphatase
Total bilirubin 
(and direct 
bilirubin, if total 
bilirubin is 
elevated above the 
upper limit of 
normal)
Potassium
Magnesium
Sodium
Calciumd
Albumin
Bicarbonate or 
Carbon Dioxide 
(CO2)e
Chloride
Phosphorous
Glucose 
(nonfasting)
Total Protein
Lipase
Amylase
Thyroid 
function 
TSH
T3 or FT3
T4
Coagulationf
PT (INR)
aPTT or PTT
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Laboratory 
Assessments
Parameters
Routine 
Urinalysisg

Specific gravity

pH, glucose, proteinh, hemoglobin or blood, ketones, by dipstick
Other Tests

Follicle-stimulating hormone (as needed in WONCBP only)

Highly sensitive serum or urine β human chorionic gonadotropin (β hCG) pregnancy 
test

Serology (HIV antibody, HbsAg, and HCV RNA). Required at baseline only if 
mandated by local health authority.
Abbreviations: ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); aPTT = activated partial 
thromboplastin time; AST (SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic transaminase); β HCG = β 
human chorionic gonadotropin; BUN = blood urea nitrogen; CPK = creatine phosphokinase; FT3 = free triiodothyronine; 
GFR = glomerular filtration rate; HbsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; INR = international normalized ratio; MCH = mean corpuscular hemoglobin; MCV, mean 
corpuscular volume; PT = prothrombin time; PTT = partial thromboplastin time; RBC = red blood cells; RNA = 
ribonucleic acid; T3 = triiodothyronine; T4 = thyroxine, TSH = thyroid-stimulating hormone; ULN = upper limit of 
normal; UPCR = urine protein-to-creatinine; WBC = white blood cell; WOCBP = women of childbearing potential; 
WONCBP = women of non-childbearing potential.
a
Absolute or % acceptable per institutional standard.
b
Urea is acceptable if BUN is not available as per institutional standard
c
GFR (measured or calculated) or creatinine clearance can be used in place of creatinine.
d
Corrected calcium should be checked for participants with hypoalbuminemia.
e
Bicarbonate performed only if considered local standard of care.
f
Performed as part of the screening assessment and as clinically indicated for participants taking anticoagulants
g
If urine dipstick testing suggests a urinary tract infection, or if clinically indicated, a urine microscopy, culture, and 
sensitivity should be performed at the institution’s laboratory. 
h
If urine protein is ≥2+ (first occurrence or a subsequent increase in severity of urine dipstick proteinuria occurring 
on the same lenvatinib dose level), then a 24-hour urine collection or an immediate spot urine protein-to-creatinine 
(UPCR) test should be done to quantify the 24-hour urine protein excretion. A 24-hour urine collection (initiated as 
soon as possible and at least within 72 hours) to verify the grade of proteinuria is required when UPCR is ≥2.4.
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
Definitions of Medication Error, Misuse, and Abuse
Medication error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
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•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
Lenvatinib overdose without an associated adverse event is not reportable as an AE. Refer to 
Section 8.5 for the definition of overdose.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
Hospitalization is defined as an inpatient admission, regardless of length of stay, even if 
the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
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diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the participant or may require medical or surgical intervention to prevent 1 of the 
other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
Additional Events Reported
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
•
Is a new cancer (that is not a condition of the study)
•
Is associated with an overdose
10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
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•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
-
The investigator will make an assessment of intensity for each AE and SAE (and 
other reportable safety event) according to the NCI CTCAE, version 5.0 Any AE that 
changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the AE CRFs/worksheets.
-
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
-
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.
-
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
-
Grade 4: Life threatening consequences; urgent intervention indicated.
-
Grade 5: Death related to AE.
Assessment of causality
-
Did the Sponsor’s product cause the AE?
-
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s 
signed/dated initials on the source document or worksheet that supports the causality 
noted on the AE form, ensures that a medically qualified assessment of causality was 
done. This initialed document must be retained for the required regulatory time frame. 
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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.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) 
Sponsor’s product(s) is/are used only 1 time.)
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NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.
-
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 their 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.)
-
The investigator must review and provide an assessment of causality for each 
AE/SAE and document this in the medical notes.
-
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the Sponsor. However, it is very 
important that the investigator always make an assessment of causality for every 
event before the initial transmission of the SAE data to the Sponsor.
-
The investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
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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.
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
If the electronic system is unavailable for more than 24 hours, then the site will use the 
paper AE Reporting form.
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
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SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure email of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
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 FSH level in the postmenopausal range may be used to confirm a postmenopausal 
state in women not using hormonal contraception or HRT. However, in the absence of 12 
months of amenorrhea, confirmation with two FSH measurements in the postmenopausal 
range is required.
Females on HRT and whose menopausal status is in doubt will be required to use one of the 
nonhormonal highly effective contraception methods if they wish to continue their HRT 
during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment.
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10.5.2
Contraceptive Requirements
• Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantb
•
Intrauterine hormone-releasing system (IUS)
•
Non-hormonal 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.
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).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
Not applicable.
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Canada
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.
10.7.2
UK
5.1 Inclusion Criteria

Inclusion Criterion #10: Male participants are eligible to participate if they agree to at 
least 6 months of contraception after the last dose of paclitaxel.
6.5.1 Prohibited Concomitant Medications

Live vaccines are to be avoided for 120 days after last dose pembrolizumab.
6.5.1 Prohibited Concomitant Medications and 6.5.2 Drug Interactions
Paclitaxel

Caution should be exercised when administering paclitaxel concomitantly with 
medicines known to inhibit either CYP2C8 or CYP3A4 (eg, ketoconazole and other 
imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, 
saquinavir, indinavir, and nelfinavir) or induce CYP2C8 or CYP3A4 (eg, rifampicin, 
carbamazepine, phenytoin, efavirenz, nevirapine).
Docetaxel

Concomitant use of docetaxel with strong CYP3A4 inhibitors (eg, ketoconazole, 
itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin and voriconazole) should be avoided.
Capecitabine

Care should be exercised when capecitabine is co-administered with CYP2C9 
substrates.
6.6.5.5 Dose Selection for Cetuximab (Preparation)

Close monitoring of participants is required during the infusion for cetuximab, 
particularly during the first administration.
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10.7.3
France
6.5.1 Prohibited Concomitant Medications

In participants being treated with lenvatinib, invasive dental procedures should be 
avoided during treatment with lenvatinib.

Caution should be exercised when lenvatinib is used either simultaneously or 
sequentially with antiresorptive therapy (eg, denosumab and bisphosphonates) and/or 
other angiogenesis inhibitors.
8.10.1 Screening

A dental examination and appropriate preventive dental care should be considered 
prior to initiation of lenvatinib.
10.7.4
Romania
5.1 Inclusion Criteria

Inclusion Criterion #10: Male participants are eligible to participate if they agree to at 
least 6 months of contraception after the last dose of paclitaxel.
10.7.5
Portugal
5.1 Inclusion Criteria

Inclusion Criterion #10: Male participants are eligible to participate if they agree to at 
least 6 months of contraception after the last dose of paclitaxel.
10.7.6
Norway
5.1 Inclusion Criteria

Inclusion Criterion #10: Male participants are eligible to participate if they agree to at 
least 6 months of contraception after the last dose of paclitaxel.
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10.8
Appendix 8: ECOG Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all selfcare, but 
unable to carry out any work activities. Up and about >50% of waking 
hours.
3
In bed >50% of the time. Capable of only limited selfcare, confined to 
bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any selfcare. 
Totally confined to bed or chair.
5
Dead.
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity 
And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair.
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10.9
Appendix 9: Abbreviations
Abbreviation
Expanded Term
1L
first-line
2L
second-line
5-FU
5-fluorouracil
β-HCG
β human chorionic gonadotropin
ADA
antidrug antibodies
AE(s)
adverse event(s) 
AJCC
American Joint Committee on Cancer
ALT
alanine aminotransferase
APaT
all participants as treated
AST
aspartate aminotransferase
BICR
blinded independent central review
BID
twice a day
BOR
best overall response
BP
blood pressure
BUN
blood urea nitrogen
CI
confidence interval
Cmax
maximum or peak serum concentration
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
CPS
combined positive score
CR
complete response
CrCl
creatinine clearance
CRF
case report form 
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CTFG
Clinical Trial Facilitation Group 
ctNA
circulating tumor nucleic acid
CXDY
Cycle X Day Y
D/C
discontinuation
DDI
drug-drug interaction
DILI
drug-induced liver injury
DLT(s)
dose-limiting toxicity(ies) 
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid 
DOR
duration of response
EC
endometrial cancer
ECG
electrocardiogram 
ECHO
echocardiogram
ECI
events of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data collection
eDMC
external Data Monitoring Committee
ELISA
enzyme-linked immunoassay
EMA
European Medicines Agency
EOC
Executive Oversight Committee
EORTC
European Organization for Research and Treatment of Cancer
EORTC QLQ-
C30
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 items
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Abbreviation
Expanded Term
EORTC QLQ-
H&N35
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Head and Neck Module
EOT
end of treatment
ePRO
electronic patient reported outcomes
EQ-5D-5L
European Quality of Life Five-Dimensional Five-Level Questionnaire
EuroQol
European Quality of Life
FAS
Full Analysis Set
FDA
Food and Drug Administration (United States of America)
FDAAA
Food and Drug Administration Amendments Act
FGF
fibroblast growth factor
FGFR
fibroblast growth factor receptor
FSH
follicle-stimulating hormone 
FT3
free triiodothyronine
FU
follow-up
GCP
Good Clinical Practice 
GFR
glomerular filtration rate
HbsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HNSCC
head and neck squamous cell carcinoma
HPV
human papilloma virus
HR
hazard ratio
HRQoL
health-related quality of life
HRT
hormone replacement therapy
HUVEC
human umbilical vein endothelial cell
IA
interim analysis
IB
Investigator’s Brochure 
ICF
informed consent form 
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use
iCR
iRECIST complete response
iCRO
imaging contract research organization
ICSR
Individual Case Safety Report
IEC
Independent Ethics Committee
IHC
immunohistochemistry
IMP
investigational medicinal product
INR
international normalized ratio
IO
immuno-oncology
iPR
iRECIST partial response
irAE
immune-related adverse event
IRB
Institutional Review Board 
iRECIST
Response Evaluation Criteria in Solid Tumors Version 1.1 for immune-based 
therapeutics
IRT
interactive response technology
iSD
iRECIST stable disease
ITT
intention-to-treat
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous(ly)
IVD
in vitro diagnostic
LAM
lactational amenorrhea method
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Abbreviation
Expanded Term
LFTs
liver function tests
LVEF
left ventricular ejection fraction
mAb
monoclonal antibody
MAPK
mitogen-activated protein kinase
MCH
mean corpuscular hemoglobin
MCV
mean corpuscular volume
M&N
Miettinen-Nurminen
MRI
magnetic resonance imaging
mRNA
messenger RNA
MTD
maximum tolerated dose 
MUGA
multigated acquisition
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NSCLC
non–small cell lung cancer
ONJ
osteonecrosis of the jaw
OR
objective response
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PBPK
physiologically based PK
PD
progressive disease
PD-1
programmed cell death 1
PDGFR
platelet-derived growth factor receptor
PD-L1
programmed cell death – ligand 1
PFS
progression-free survival
Pgp
P-glycoprotein
PK
pharmacokinetic
PO
oral(ly)
PopPK
population pharmacokinetic
PR
partial response
PRES/RPLS
posterior reversible encephalopathy syndrome/reversible encephalopathy 
syndrome/reversible posterior leukoencephalopathy syndrome
PRO
patient reported outcome
PT
prothrombin time
PTT
partial thromboplastin time
Q2W
every 2 weeks
Q3W
every 3 weeks
Q6W
every 6 weeks
Q9W
every 9 weeks
Q12W
every 12 weeks
QD
once daily
QoL
quality of life
QTc
corrected QT interval
QTcF
QT interval corrected with Fridericia’s formula
R/M
recurrent/metastatic
RBC
red blood cell
RCC
renal cell carcinoma
RECIST 1.1
Response Evaluation Criteria in Solid Tumors Version 1.1
RNA
ribonucleic acid
RP2D
recommended Phase 2 dose
RR
response rates
RTKi
receptor tyrosine kinase inhibitor
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Abbreviation
Expanded Term
RUQ
right upper quadrant
SAE
serious adverse event 
SD
stable disease
SGOT
serum glutamate oxaloacetate transaminase
SGPT
serum glutamate pyruvate transaminase
SIM
Site Imaging Manual
SoA
schedule of activities
SOC
standard of care
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
T3
triiodothyronine
T4
thyroxine
TAM
tumor-associated macrophage
TBL
total bilirubin level
TPS
tumor proportion score
TRAEs
treatment-related adverse events
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
UPCR
urine protein-to-creatinine ratio
USPI
United States Prescribing Information
VEGF
vascular endothelial growth factor
VEGFR
vascular endothelial growth factor receptor
WBC
white blood cell
WOCBP
woman/women of childbearing potential 
WONCBP
woman/women of non-childbearing potential
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11
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[Bjordal, K., et al 2000]
Bjordal K, de Graeff A, Fayers PM, 
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