Clinical trial NCT03898180
Conditions: Urothelial Carcinoma
Keywords: Advanced or metastatic urothelial cancer Lenvatinib Pembrolizumab Programmed Cell Death-1 (PD1, PD-1) Programmed Cell Death 1 Ligand 1 (PDL1, PD-L1) Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)
Sponsor: Merck Sharp & Dohme LLC
Start date: 2019-05-06; Completion date: 2024-05-20
Enrollment: 505 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of lenvatinib (MK-7902/E7080) in combination with pembrolizumab (MK-3475) in the treatment of cisplatin-ineligible participants with a Programmed Cell Death-Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10, or in participants ineligible for any platinum-containing chemotherapy regardless of CPS, with advanced/unresectable or metastatic urothelial carcinoma (UC).

The primary hypotheses for this study are that:

1. Pembrolizumab + lenvatinib is superior to pembrolizumab + placebo with respect to Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by blinded independent central review (BICR), and
2. Pembrolizumab + lenvatinib is superior to pembrolizumab + placebo with respect to Overall Survival (OS).

Based on recommendation of the external Data Monitoring Committee (eDMC), Amendment 3 (effective: September \[Sep\]-24-2021) was implemented to unblind the study and discontinue lenvatinib and placebo treatment. The eDMC was then disbanded.

With Amendment 4 (effective: December-5-2022) second course pembrolizumab will no longer be offered. Any participant receiving second course pembrolizumab treatment prior to initiation of Amendment 4 will be able to complete treatment as planned. Study participation will end after the final administration of pembrolizumab. Participants who either complete 35 administrations of pembrolizumab or discontinue pembrolizumab will discontinue from the study following the safety follow-up visit. AEs and spontaneously reported pregnancies will be reported and followed per protocol. The overall study ends when the last participant completes the last study-related contact or visit, withdraws from the study, or is lost to follow-up.

Detailed description:

Arms: arm 1: Participants receive pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to \~2 years) PLUS lenvatinib 20 mg via oral capsule once daily (QD) until progressive disease or discontinuation. With protocol amendment 3 (effective: Sep-24-2021), participants discontinue lenvatinib. arm 2: Participants receive pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to \~2 years) PLUS placebo for lenvatinib via oral capsule QD until progressive disease or discontinuation. With protocol amendment 3 (effective: Sep-24-2021), participants discontinue placebo.
Interventions: intervention 1: Pembrolizumab intervention 2: Lenvatinib intervention 3: Placebo for lenvatinib
Intervention descriptions: intervention 1: IV infusion intervention 2: oral capsule intervention 3: oral capsule

Protocol documents:
SAP_002.pdf: 
Official Protocol Title:
NCT number:
Document Date:
NCT03898180
MK-7902-ssap-p011-04-amend03_final-
redaction
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MK-7902 PROTOCOL 011-004
Supplemental Statistical Analysis Plan (sSAP)
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TABLE OF CONTENTS
TABLE OF CONTENTS.........................................................................................................2
LIST OF TABLES ...................................................................................................................4
LIST OF FIGURES .................................................................................................................5
1
INTRODUCTION............................................................................................................6
2
SUMMARY OF CHANGES ...........................................................................................6
3
STATISTICAL ANALYSIS PLAN ................................................................................6
3.1 Statistical Analysis Plan Summary .................................................................................6
3.2 Responsibility for Analyses/In-house Blinding ..............................................................8
3.3 Hypotheses/Estimation.....................................................................................................8
3.4 Analysis Endpoints.........................................................................................................11
3.4.1
Efficacy Endpoints ...................................................................................................11
3.4.2
Safety Endpoints ......................................................................................................11
3.4.3
Patient-reported Outcome Endpoints........................................................................12
3.5 Analysis Populations ......................................................................................................12
3.5.1
Efficacy Analysis Population ...................................................................................12
3.5.2
Safety Analysis Population.......................................................................................12
3.5.3
Patient-reported Outcome Analysis Populations ......................................................12
3.5.4
Pharmacokinetic Analysis Population......................................................................13
3.6 Statistical Methods .........................................................................................................13
3.6.1
Statistical Methods for Efficacy Analyses................................................................13
Progression-free Survival.................................................................................13
Overall Survival ...............................................................................................16
Objective Response Rate..................................................................................16
Analysis Strategy for Key Efficacy Endpoints.................................................17
Duration of Response.......................................................................................17
Disease Control Rate........................................................................................18
3.6.2
Statistical Methods for Safety Analyses...................................................................18
3.6.3
Analysis Methods for Patient-reported Outcome Endpoints ....................................20
PRO Compliance Summary .............................................................................20
Mean change from baseline..............................................................................21
Time-to-Deterioration (TTD)...........................................................................22
Analysis Strategy for Key PRO Endpoints.......................................................23
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3.6.4
Demographic and Baseline Characteristics..............................................................23
3.7 Interim and final Analyses ............................................................................................23
3.7.1
Efficacy and Futility Interim Analyses.....................................................................24
3.7.2
Safety Interim Analyses ...........................................................................................25
3.8 Multiplicity......................................................................................................................25
3.8.1
Futility Analysis.......................................................................................................26
3.8.2
Objective Response Rate..........................................................................................28
3.8.3
Progression-free Survival.........................................................................................28
3.8.4
Overall Survival .......................................................................................................29
3.8.5
Safety Analyses........................................................................................................31
3.9 Sample Size and Power Calculations............................................................................32
3.10
Subgroup Analyses.....................................................................................................33
3.11
Compliance (Medication Adherence) .......................................................................33
3.12
Extent of Exposure.....................................................................................................34
4
REFERENCES..............................................................................................................34
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LIST OF TABLES
Table 1
Censoring Rules for Primary and Sensitivity Analyses of Progression-free Survival
................................................................................................................................. 15
Table 2
Analysis Methods for Key Efficacy Endpoints ....................................................... 17
Table 3
Censoring Rules for Duration of Response............................................................. 18
Table 4
Analysis Strategy for Safety Parameters ................................................................. 20
Table 5
PRO Data Collection Schedule and Mapping of Study visit to Analysis Visit....... 21
Table 6
Censoring Rules for Time-to-Deterioration............................................................. 23
Table 7
Analysis Strategy for Key PRO Endpoints ............................................................. 23
Table 8
Summary of Interim and Final Analysis Strategy ................................................... 25
Table 9
Futility Scenarios for PFS (Superiority in Progression Free Survival – Combo vs
Pembro in All Subjects) .................................................................................................. 27
Table 10
Futility Scenarios for ORR (Superiority in Objective Responsive Rate – Combo 
vs Pembro in All Subjects with Imagine by BICR per RECIST 1.1) ............................. 27
Table 11
Possible α Levels and Approximate Objective Response Rate Difference Required 
to Demonstrate Efficacy for Objective Response at Interim Analysis............................ 28
Table 12
Efficacy Boundaries and Properties for Progression-free Survival Analyses ..... 29
Table 13
Efficacy Boundaries and Properties for Overall Survival Analyses ................... 30
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LIST OF FIGURES
Figure 1
Multiplicity Diagram for Type I Error Control ....................................................26
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1
INTRODUCTION
This supplemental SAP (sSAP) is a companion document to the protocol. In addition to the 
information presented in the protocol SAP which provides the principal features of 
confirmatory analyses for this trial, this supplemental SAP provides additional statistical 
analysis details/data derivations and documents modifications or additions to the analysis 
plan that are not “principal” in nature and result from information that was not available at 
the time of protocol finalization.
2
SUMMARY OF CHANGES
The sSAP has been amended to include the following change:

Add second non-binding futility analysis timing and rules for ORR and PFS to 
Sections 3.1, 3.7.1, and 3.8.1

Sections 3.3, 3.4.3, 3.4.4, 3.6.3, 3.6.3.1 – 3.6.3.4 narrowed the scope of 
ePRO’s TLF’s to include only those specific items which are required for 
Disclosure tables and clinicaltrials.gov
3
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but before any unblinding/final database lock, changes are made to primary 
and/or key secondary hypotheses, or the statistical methods related to those hypotheses, then 
the protocol will be amended (consistent with ICH Guideline E9). Changes to exploratory or 
other nonconfirmatory analyses made after the protocol has been finalized, but before 
unblinding/final database lock, will be documented in this supplemental statistical analysis 
plan (sSAP) and referenced in the clinical study report (CSR) for the study. Post hoc 
exploratory analyses will be clearly identified in the CSR. Other planned analyses (ie, those 
specific to PK data and PROs) will be documented in separate analysis plans.
3.1
STATISTICAL ANALYSIS PLAN SUMMARY
Key elements of the statistical analysis plan (SAP) are summarized below. The 
comprehensive plan is provided in Sections 3.2 through 3.12.
Study Design Overview
A Phase 3, Randomized, Double-blind Study to Compare the Efficacy and Safety 
of Pembrolizumab (MK-3475) in Combination with Lenvatinib (E7080/MK-
7902) Versus Pembrolizumab and Placebo as First Line Treatment for Locally 
Advanced or Metastatic Urothelial Carcinoma in Cisplatin-ineligible Participants 
Whose Tumors Express PD-L1, and in Participants Ineligible for Any Platinum-
containing Chemotherapy Regardless of PD-L1 Expression (LEAP-011)
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Treatment Assignment
Approximately 694 participants will be randomized in a 1:1 ratio between 
2 treatment arms: (1) pembrolizumab + lenvatinib and (2) pembrolizumab + 
placebo.
Stratification factors are as follows:

Ineligible for any platinum-containing chemotherapy, PD-L1 CPS ≥10, 
ECOG PS 2

Ineligible for any platinum-containing chemotherapy, PD-L1 CPS <10, 
ECOG PS 2

Cisplatin-ineligible, PD-L1 CPS ≥10, ECOG PS 2

Cisplatin-ineligible, PD-L1 CPS ≥10, ECOG PS 0 or 1.
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Analysis Populations
Efficacy: Intention to Treat (ITT)
Safety: All Participants as Treated (APaT)
Primary Endpoints

PFS per RECIST 1.1 by BICR

OS
Key Secondary 
Endpoint

ORR per RECIST 1.1 by BICR
Statistical Methods for 
Key Efficacy Analyses
The primary hypotheses will be evaluated by comparing pembrolizumab + 
lenvatinib to pembrolizumab + placebo with respect to PFS and OS using a 
stratified log-rank test. HR will be estimated using a stratified Cox regression 
model. Event rates over time will be estimated within each treatment group using 
the Kaplan-Meier method. The difference in ORR will be estimated using the 
stratified Miettinen and Nurminen method with strata weighted by sample size.
Statistical Methods for 
Key Safety Analyses
The analysis of safety results will follow a tiered approach. The tiers differ with 
respect to the analyses that will be performed. There are no events of interest that 
warrant elevation to Tier 1 in this study. Tier 2 parameters will be assessed via 
point estimates with 95% CIs provided for between-group comparisons; only point 
estimates by treatment group are provided for Tier 3 safety parameters. The 95% 
CIs for the between-treatment differences in percentages will be provided using 
the Miettinen and Nurminen method.
Interim Analyses
Two interim efficacy analyses and two interim futility analysis will be performed 
in this study. Results will be reviewed by an external DMC. These interim analyses 
are summarized below. Details are provided in Section 3.7.

Futility Analysis 1
o
Timing: To be performed when 297 participants have been 
enrolled, and ≥151 PFS events (27% of targeted events) are 
observed.
o
Analysis: A non-binding futility analysis on PFS and ORR will 
be performed.

Futility Analysis 2
o
Timing: To be performed when 370 participants have been 
enrolled, and ≥191 PFS events (30% of targeted events) are 
observed.
o
Analysis: A non-binding futility analysis on PFS and ORR will 
be performed.

Interim Analysis 1
o
Timing: To be performed when enrollment is complete and
≥530 PFS events (95% of targeted events) and 386 deaths 
(70% of targeted events) are observed.
o
Testing: Superiority analyses for PFS and OS will be provided. 
Superiority analysis for ORR will be provided if both PFS and 
OS are positive.

Interim Analysis 2
o
Timing: To be performed when enrollment is complete and
≥558 PFS events (100% of targeted events) and 469 deaths 
(85%) of targeted events) are observed.
o
Testing: Superiority analyses for PFS and OS will be provided.

Final Analysis
o
Timing: To be performed when 552 deaths (100%) of targeted 
events) are observed.
o
Testing: Superiority analysis for OS will be provided.
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Multiplicity
The type I error rate over the multiple endpoints will be controlled by the Lan-
DeMets [Ref. 5.4: 03P3QC] and O’Brien-Fleming [Ref. 5.4: 00VPPS] group 
sequential methods using the graphical approach of Maurer and Bretz 
[Ref. 5.4: 045MYM].
Sample Size and Power
The planned sample size is 694 participants. For PFS, the study has 94.7% power 
to demonstrate that pembrolizumab + lenvatinib is superior to pembrolizumab + 
placebo at an overall 1-sided α level of 0.005, if the underlying treatment 
comparison in HR in PFS is 0.7. For OS, the study has 90.1% power to demonstrate 
that pembrolizumab + lenvatinib is superior to pembrolizumab + placebo at an 
overall 1-sided α level of 0.02, if the underlying treatment comparison in HR in 
OS is 0.75.
3.2
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 will be conducted as a double-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics Department will generate the randomized allocation schedule(s) for 
study intervention assignment.
Blinding issues related to the planned interim analyses are described in Section 3.7.
3.3
HYPOTHESES/ESTIMATION
The objectives and endpoints apply to a study population of male or female participants at 
least 18 years of age with a histologically confirmed diagnosis of advanced/unresectable or 
metastatic urothelial carcinoma (UC), who are cisplatin-ineligible and whose tumors express 
programmed death ligand 1 (PD-L1) (combined positive score [CPS] ≥10), or who are 
medically ineligible to receive any platinum-based chemotherapy.
This study will be considered to have met its primary objective if pembrolizumab +lenvatinib 
is superior to pembrolizumab + placebo for either primary endpoint.
Progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), 
and disease control rate (DCR) will be assessed per Response Evaluation Criteria in Solid 
Tumors Version 1.1 (RECIST 1.1) modified to follow a maximum of 10 target lesions and a 
maximum of 5 target lesions per organ.
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Primary Objectives
Primary Endpoints

To compare pembrolizumab + lenvatinib to 
pembrolizumab + placebo with respect to PFS 
per Response Evaluation Criteria in Solid 
Tumors Version 1.1 (RECIST 1.1) by blinded 
independent central review (BICR).

Hypothesis 1: Pembrolizumab + lenvatinib is 
superior to pembrolizumab + placebo with 
respect to PFS per RECIST 1.1 by BICR.

PFS, defined as the time from 
randomization 
to 
the 
first 
documented 
progressive 
disease 
(PD) or death from any cause, 
whichever occurs first.

To compare pembrolizumab + lenvatinib to 
pembrolizumab + placebo with respect to 
overall survival (OS).

Hypothesis 2: Pembrolizumab + lenvatinib is 
superior to pembrolizumab + placebo with 
respect to OS.

OS, defined as the time from 
randomization to the date of death 
from any cause.
Secondary Objectives
Secondary Endpoints
To compare pembrolizumab + lenvatinib to 
pembrolizumab + placebo with respect to 
objective response rate (ORR) per RECIST 1.1 
by BICR.

Hypothesis 3: Pembrolizumab + lenvatinib is 
superior to pembrolizumab + placebo with 
respect to ORR per RECIST 1.1 by BICR.

Objective response (OR), defined as 
a confirmed complete response (CR) 
or partial response (PR).
To evaluate the safety and tolerability of 
treatment with pembrolizumab + lenvatinib 
versus pembrolizumab + placebo.

Adverse
events
(AEs)
and 
discontinuations due to AEs.
To evaluate pembrolizumab + lenvatinib and 
pembrolizumab + placebo with respect to 
duration of response (DOR) per RECIST 1.1 by 
BICR.

DOR, defined as the time from the 
first documented evidence of CR or 
PR to the earliest date of PD or death 
due to any cause, whichever comes 
first, 
for 
individuals 
with 
a 
confirmed CR or PR.
To evaluate pembrolizumab + lenvatinib and 
pembrolizumab + placebo with respect to 
disease control rate (DCR) per RECIST 1.1 by 
BICR.

Disease control, defined as a 
confirmed response of CR or PR 
or stable disease (SD).
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Primary Objectives
Primary Endpoints
To evaluate changes in patient-reported 
outcomes (PROs) from baseline, and to evaluate 
time to deterioration (TTD) in European 
Organization for Research and Treatment of 
Cancer EORTC QLQ-C30 global health 
status/QoL score.

Change from baseline in EORTC 
QLQ-C30 global health status/QoL 
score.

TTD, defined as the time from 
baseline to the first onset of PRO 
deterioration in EORTC QLQ-C30 
global health status/QoL score.
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
To identify molecular (genomic, metabolic, or 
proteomic) biomarkers that may be indicative of 
clinical response/resistance, safety, and/or the 
mechanism of action of pembrolizumab and 
lenvatinib in all participants.

Molecular (genomic, metabolic, or 
proteomic) determinants of response 
or resistance to treatments, using 
blood and/or tumor tissue.
To assess the pharmacokinetics (PK) of 
lenvatinib when co-administered with 
pembrolizumab.
Population PK parameters including 
clearance, volume of distribution, and 
absorption rate constant.
To compare pembrolizumab + lenvatinib to 
pembrolizumab + placebo with respect to PFS 
per iRECIST (RECIST 1.1 for immune-based 
therapeutics) by investigator.
PFS, 
defined 
as 
the 
time 
from 
randomization to the first documented 
progressive disease (PD) or death from 
any cause, whichever occurs first.
To evaluate changes in PROs from baseline using 
the following instruments:

EORTC QLQ-C30
Change in PROs from baseline in

Scores for the QoL of the 
EORTC QLQ-C30
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3.4
ANALYSIS ENDPOINTS
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below, followed by descriptions of the derivations of selected 
endpoints.
3.4.1
Efficacy Endpoints 
Primary

Progression-free Survival (PFS): PFS is defined as the time from randomization to 
the first documented disease progression (PD) per RECIST 1.1 by BICR, or death due 
to any cause, whichever occurs first. See Section 3.6.1.1 for the definition of 
censoring.

Overall Survival (OS): OS is defined as the time from randomization to death due to 
any cause.
Secondary

Objective Response Rate (ORR): ORR is the percentage of participants with a 
confirmed complete response (CR) or partial response (PR) per RECIST 1.1 by 
BICR.

Duration of Response (DOR): DOR is defined as the time from the first documented 
evidence of CR or PR to PD per RECIST 1.1 by BICR or death due to any cause, 
whichever occurs first.

Disease Control Rate (DCR): DCR is defined as the percentage of participants with 
a confirmed response of CR, PR, or SD per RECIST 1.1 by BICR. Stable disease 
must be achieved at ≥6 weeks after randomization to be considered a best overall 
response.

Progression-free Survival (PFS): PFS is defined as the time from randomization to 
the first documented disease progression (PD) per iRECIST 1.1 by investigator, or 
death due to any cause, whichever occurs first. See Section 3.6.1.1 for the definition 
of censoring.
3.4.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, SAEs, fatal AEs, laboratory tests, and vital signs. Furthermore, specific events will be 
collected and designated as ECIs as described in protocol Section 8.4.7.
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3.4.3
Patient-reported Outcome Endpoints
The following secondary PRO endpoints will be evaluated the PRO instruments are 
EORTC QLQ-C30 as described protocol Section 4.2.1.3.

Change in patient-reported outcomes from baseline in Global health status/QoL.

TTD in EORTC QLQ-C30 Global health status/QoL.
Time to deterioration (TTD) is defined as the time from baseline to the first onset of PRO 
deterioration. TTD in the EORTC QLQ-C30 global health status/QoL score has been used as 
a key PRO endpoint in the UC study, KEYNOTE-045 [Ref. 5.4: 050DSW]. Deterioration in 
the global health status/quality of life is defined as a 10 points or greater worsening from 
baseline, with or without subsequent confirmation, under a right-censoring rule.
[Ref. 5.4: 00TWVP].
All ePRO analyses will be conducted using database cutoff date of 26JUL2021 to align with 
CSR P011V01MK7902.
3.4.4 Derivation of PRO Endpoints
The derivation of overall improvement and overall improvement + stability is based on the 
assessment for possible PRO response at a time point considering subsequent confirmation,
defined as follows:
Assessment 
Category at a 
time point (one 
analysis visit)
Change from baseline at a time point 
(one analysis visit)
Change from baseline at the 
subsequent time point (the next 
consecutive analysis visit)
Improvement
score improved from baseline by ≥10 
points 
score improved from baseline by ≥10 
points
Stability
score improved from baseline by ≥10 
points 
score improved or worsened from 
baseline by <10 points
score improved or worsened from 
baseline by <10 points
score improved or worsened from 
baseline by <10 points
score improved or worsened from 
baseline by <10 points
score improved from baseline by ≥10 
points
Worsening
score worsened from baseline by ≥10 
points 
not required
Unconfirmed
A time point assessment that doesn’t meet any of the above criteria.
The overall improvement is defined as the best observed PRO response that is an  improvement 
among all post-baseline assessments by timepoint. The overall improvement + stability is 
defined as the best observed PRO response that is an improvement or stability among all post-
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baseline assessments by timepoint.
Based on prior literature Osoba et al. (1998) [Osoba, D., et al 1998] and King (1996) [King, M. 
T. 1996], a 10 points or greater worsening from baseline for each scale of the EORTC QLQ-
C30 represents a clinically relevant deterioration. Changes from baseline in EORTC QLQ-C30 
scores will also be interpreted according to recent subscale-specific guidelines, which indicate 
that clinically meaningful differences vary by scale (Cocks et al., 2012).
3.5
ANALYSIS POPULATIONS
3.5.1
Efficacy Analysis Population
The analyses of the primary efficacy endpoints are based on the intention-to-treat (ITT) 
population. All randomized participants will be included in this population. Participants will 
be analyzed in the treatment group to which they are randomized. Details of the approach to 
handling missing data are provided in Section 3.6.
3.5.2
Safety Analysis Population
Safety analyses will be conducted in the All Participants as Treated (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 
receive incorrect study intervention for the entire treatment period; such participants will be 
included in the treatment group corresponding to the study intervention actually received.
Any participant who receives the incorrect study intervention for one cycle, but receives the 
randomized study intervention for all other cycles, will be analyzed according to the 
randomized treatment group, and a narrative will be provided for any events that occur 
during the cycle for which the participant is incorrectly dosed.
At least one laboratory, vital sign, or ECG 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.
3.5.3
Patient-reported Outcome Analysis Populations
The analyses of PRO endpoints will be based on a quality of life-related full analysis set (FAS) 
population following the ITT principle and ICH E9 guidelines. This population consists of all
randomized participants who have received at least 1 dose of study intervention and have 
completed at least 1 PRO assessment.
3.5.4
Pharmacokinetic Analysis Population
The population PK analysis set includes all participants who have received at least one dose 
of study intervention with documented dosing history in the pembrolizumab + lenvatinib 
arm, and have measurable plasma levels of lenvatinib or serum levels of pembrolizumab.
3.6
STATISTICAL METHODS
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3.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary efficacy 
objectives. Efficacy results that are deemed to be statistically significant after consideration 
of the type I error control strategy are described in Section 3.8. Nominal p-values will be 
computed for other efficacy analyses but should be interpreted with caution because of 
potential issues of multiplicity.
The stratification factors used for randomization (see protocol Section 6.3.2) will be applied 
to all stratified analyses, in particular, the stratified log-rank test, stratified Cox model, and 
stratified Miettinen and Nurminen method [Ref. 5.4: 00VMQY]. In the event that there are 
small strata, for the purpose of analysis, strata will be combined to ensure sufficient number 
of participants, responses and events in each stratum. Details regarding the pooling strategy 
will be pre-specified in a future sSAP amendment prior to the database lock for the first 
analysis when each applicable endpoint will be analyzed, and decisions regarding the pooling 
will be based on a blinded review of response and event counts by stratum.
The efficacy analyses for ORR, DOR and PFS will include responses and documented 
progression events that occur prior to second course treatment or protocol specified treatment 
crossover.
Progression-free Survival
The nonparametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment arm. The hypotheses of treatment difference in PFS will be tested by the stratified 
log-rank test. A stratified Cox proportional hazard model with Efron’s method of tie handling 
will be used to estimate the magnitude of the treatment comparison (ie, HR) between the 
treatment arms. The HR and its 95% CI from the stratified Cox model with a single treatment 
covariate will be reported. The stratification factors used for randomization (protocol
Section 6.3.2) will be applied to both the stratified log-rank test and the stratified Cox model.
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. For the primary analysis, for the participants who have PD, the true date of 
disease progression will be approximated by the date of the first assessment at which PD is 
objectively documented per RECIST 1.1 by BICR, regardless of discontinuation of study
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drug. Additional analyses will be performed for comparison of PFS based on the 
investigator’s assessment and PFS analysis for PD per RECIST 1.1 by BICR.
To evaluate the robustness of the PFS endpoint per RECIST 1.1 by BICR, one primary and 
two sensitivity analyses with a different set of censoring rules will be performed. For the 
primary analysis, if the events (PD or death) are after more than 1 missed disease assessment, 
the data are censored at the last disease assessment before missing visits. Also data after new 
anticancer therapy are censored at the last disease assessment before the initiation of new 
anticancer therapy. The first sensitivity analysis follows ITT principles (ie, PDs/deaths are 
counted as events regardless of missed study visits or initiation of new anticancer therapy).
The second sensitivity analysis considers discontinuation of treatment or initiation of an 
anticancer treatment subsequent to discontinuation of study-specified treatments, whichever 
occurs later, to be a PD event for participants without documented PD or death. If a 
participant meets multiple criteria for censoring, the censoring criterion that occurs earliest 
will be applied. The censoring rules for primary and sensitivity analyses are summarized in 
Table 1.
The proportional hazards assumption on PFS may be examined using both graphical and 
analytical methods if warranted. The log [-log] of the survival function vs. time for PFS will 
be plotted for the comparison between the two arms. If the curves are not parallel, indicating 
that hazards are not proportional, supportive analyses may be conducted to account for the 
possible non-proportional hazards effect associated with immunotherapies: for example, 
using the Restricted Mean Survival Time method [Ref. 5.4: 045X5X].
The RMST is the population average of the amount of event-free survival time experienced 
during a fixed study follow-up time. This quantity can be estimated by the area under the 
Kaplan-Meier curve up to the follow-up time. The clinical relevance and feasibility should be 
taken into account in the choice of follow-up time to define RMST (e.g., near the last 
observed event time assuming that the period of clinical interest in the survival experience is 
the whole observed follow-up time for the study, but avoiding the very end of the tail where 
variability may be high); a description of the RMST as a function of the cutoff time may be 
of interest. The difference between two RMSTs for the two treatment groups will be 
estimated and 95% CI will be provided.
A sensitivity analysis may be performed based on the MaxCombo test with logrank(FH(0,0)), 
FH (0, 1), FH (1, 1) at the final analysis of PFS to account for the potential loss of power
with logrank test when the proportional hazard assumption is violated.
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Table 1
Censoring Rules for Primary and Sensitivity Analyses of Progression-free 
Survival
Situation
Primary 
Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
No PD and no death; new 
anticancer treatment is not 
initiated
Censored at last 
disease
assessment
Censored at last 
disease assessment
Progressed
at
treatment 
discontinuation due to reasons other 
than complete response; otherwise, 
censored at last disease assessment 
if still receiving study intervention 
or completed study intervention
No PD and no death; new 
anticancer 
treatment 
is 
initiated
Censored at last 
disease 
assessment before 
new
anticancer 
treatment
Censored at last 
disease assessment
Progressed at date of new anticancer 
treatment
PD or death documented 
after ≤1 missed disease 
assessment and before new 
anticancer treatment
Progressed at date 
of 
documented 
PD or death
Progressed at date 
of documented PD 
or death
Progressed at date of documented 
PD or death
PD or death documented 
immediately 
after 
≥2 
consecutive missed disease 
assessments or after new 
anticancer treatment
Censored at last 
disease 
assessment prior 
to the earlier date 
of ≥2 consecutive 
missed
disease 
assessments and 
new
anticancer 
treatment
Progressed at date 
of documented PD 
or death
Progressed at date of documented 
PD or death
Abbreviation: PD = progressive disease.
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Overall Survival
The nonparametric Kaplan-Meier method will be used to estimate the OS curve in each 
treatment arm. The hypotheses of treatment difference in OS will be tested by the stratified 
log-rank test. A stratified Cox proportional hazard model with Efron’s method of tie handling 
will be used to estimate the magnitude of the treatment comparison (ie, HR) between the 
treatment arms. The HR and its 95% CI from the stratified Cox model with a single treatment 
covariate will be reported. The stratification factors used for randomization (protocol 6.3.2) 
will be applied to both the stratified log-rank test and the stratified Cox model. Participants 
without documented death at the time of analysis will be censored at the date of last known 
contact.
The proportional hazards assumption on OS may be examined using both graphical and 
analytical methods if warranted. The log [-log] of the survival function vs. time for OS will 
be plotted for the comparison between the two arms. If the curves are not parallel, indicating 
that hazards are not proportional, supportive analyses may be conducted to account for the 
possible non-proportional hazards effect associated with immunotherapies: for example, 
using the Restricted Mean Survival Time method [Ref. 5.4: 045X5X].
The RMST is the population average of the amount of event-free survival time experienced 
during a fixed study follow-up time. This quantity can be estimated by the area under the 
Kaplan-Meier curve up to the follow-up time. The clinical relevance and feasibility should be 
taken into account in the choice of follow-up time to define RMST (e.g., near the last 
observed event time assuming that the period of clinical interest in the survival experience is 
the whole observed follow-up time for the study, but avoiding the very end of the tail where 
variability may be high); a description of the RMST as a function of the cutoff time may be 
of interest. The difference between two RMSTs for the two treatment groups will be 
estimated and 95% CI will be provided.
A sensitivity analysis may be performed based on the MaxCombo test with logrank, FH (0, 
1), FH (1, 1) at the final analysis of OS to account for the potential loss of power with 
logrank test when the proportional hazard assumption is violated.
Objective Response Rate
The stratified Miettinen and Nurminen method will be used for comparison of ORR between 
the treatment groups. The difference in ORR and its 95% CI from the stratified Miettinen and 
Nurminen method with strata weighting by sample size will be provided. The same 
stratification factors used for randomization (protocol Section 6.3.2) will be used as 
stratification factors in the analysis.
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Analysis Strategy for Key Efficacy Endpoints
A summary of the primary analysis strategy for the key efficacy endpoints is provided in 
Table 2.
Table 2
Analysis Methods for Key Efficacy Endpoints
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Analyses
PFS per RECIST 1.1
by BICR
Testing: stratified log-rank test
Estimation: Stratified Cox model 
with Efron’s tie handling method
ITT
Censored according to rules in 
Table 1
OS
Testing: stratified log-rank test
Estimation: Stratified Cox model 
with Efron’s tie handling method
ITT
Censored at last known alive date
Key Secondary Analyses
ORR per RECIST 1.1
by BICR
Testing and estimation: stratified 
Miettinen and Nurminen method
ITT
Participants with missing data are 
considered nonresponders
Abbreviations: BICR = blinded independent central review; ITT = intent-to-treat; ORR = objective response 
rate; OS = overall survival; PFS = progression-free survival; RECIST 1.1 = Response Evaluation Criteria in 
Solid Tumors.
The strategy to address multiplicity issues with regard to multiple endpoints and interim 
analyses is described in Section 3.7 (Interim Analyses) and Section 3.8 (Multiplicity).
Duration of Response
If sample size permits, DOR will be summarized descriptively using the Kaplan-Meier 
method. Range and median survival time will be reported. 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 3. For the DOR analysis, a corresponding 
summary of the reasons responding participants are censored will also be provided.
Responding participants who are alive, have not progressed, have not initiated new 
anticancer treatment, have not been determined to be lost to follow-up, and have had a 
disease assessment within ~5 months of the data cutoff date are considered ongoing 
responders at the time of analysis. If a participant meets multiple criteria for censoring, the 
censoring criterion that occurs earliest will be applied.
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Table 3
Censoring Rules for Duration of Response
Situation
Date of Progression or 
Censoring
Outcome
No progression nor death, no new 
anticancer treatment initiated
Last adequate disease 
assessment
Censor (non-event)
No progression nor death, new 
anticancer treatment initiated
Last adequate disease 
assessment before new 
anticancer treatment initiated
Censor (non-event)
Death or progression immediately 
after ≥2 consecutive missed disease 
assessments or after new anticancer 
therapy, if any
Earlier date of last adequate 
disease assessment prior to ≥ 
2 missed adequate disease 
assessments and new 
anticancer treatment, if any
Censor (non-event)
Death or progression after ≤1 missed 
disease assessment and before new 
anticancer treatment, if any
PD or death
End of response (event)
Abbreviation: PD = progressive disease.
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for 
evaluation of response.
Disease Control Rate
The stratified Miettinen and Nurminen method will be used for comparison of DCR between 
the treatment arms. The difference in DCR and its 95% CI from the stratified Miettinen and 
Nurminen method with strata weighting by sample size will be provided. The same 
stratification factors used for randomization (protocol Section 6.3.2) will be used as 
stratification factors in the analysis.
3.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, vital signs, and ECG measurements.
The analysis of safety results will follow a tiered approach (Table 4). The tiers differ with 
respect to the analyses that will be performed. AEs (specific terms as well as system organ 
class terms) and events that meet predefined limits of change in laboratory, vital signs, and 
ECG parameters are either prespecified as Tier 1 endpoints or will be classified as belonging 
to Tier 2 or Tier 3 based on observed proportions of participants with an event.
Tier 1 Events
Safety parameters or AEs of special interest that are identified a priori constitute Tier 1 safety 
endpoints that will be subject to inferential testing for statistical significance. AEs that are 
immune-mediated or potentially immune-mediated are well documented and will be 
evaluated separately; however, these events have been characterized consistently throughout 
the pembrolizumab clinical development program, and determination of statistical
significance is not expected to add value to the safety evaluation. Similarly, the combination 
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of pembrolizumab and lenvatinib has not been associated with any new safety signals.
Therefore, there are no Tier 1 events for this protocol.
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events using the Miettinen and Nurminen method, an 
unconditional, asymptotic method [Ref. 5.4: 00VMQY].
Membership in Tier 2 requires that at least 10% of participants in any treatment group exhibit 
the event; all other AEs and predefined limits of change will belong to Tier 3. The threshold 
of at least 10% of participants was chosen for Tier 2 events because the population 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, Grade 3 to 5 AEs (≥5% of 
participants in 1 of the treatment groups) and SAEs (≥5% of participants in 1 of the treatment 
groups) will be considered Tier 2 endpoints. Because many 95% CIs may be provided 
without adjustment for multiplicity, the CIs should be regarded as a helpful descriptive 
measure to be used in safety review, not as a formal method for assessing the statistical 
significance of the between-group differences.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment group are provided for Tier 3 safety parameters.
Continuous Safety Measures
For continuous measures such as changes from baseline in laboratory, vital signs, and ECG 
parameters, summary statistics for baseline, on-treatment, and change from baseline values 
will be provided by treatment group in table format.
To properly account for the potential difference in follow-up time between the study arms, 
which is expected to be longer in the combo arm, AE incidence adjusted for treatment 
exposure analyses may be performed as appropriate.
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Table 4
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE (≥10% of participants in one of the treatment 
groups)
X
X
Any Grade 3 to 5 AE (≥5% of participants in one of 
the treatment groups)
X
X
Any serious AE (≥5% of participants in one of the 
treatment groups)
X
X
Tier 3
Any AE
X
Change from baseline results (laboratory test toxicity 
grade)
X
Abbreviations: AE = adverse event; CI = confidence interval; X = results will be provided.
3.6.3
Analysis Methods for Patient-reported Outcome Endpoints
This section describes the planned analyses for the PRO endpoints.
EORTC QLQ-C30 Scoring: Each scale or item is scored between 0 and 100, according to the 
EORTC QLQ-C30 standard scoring algorithm {04HN7P}. For global health status/quality of 
life, a higher value indicates a better level of function.
PRO Scoring Algorithm 
The QLQ-C30 is composed of both multi-item scales and single-item measures. These include 
five functional scales, three symptom scales, a global health status / QoL scale, and six single 
items. Each of the multi-item scales includes a different set of items - no item occurs in more 
than one scale.
EORTC QLQ-C30 Scoring: All the scales and single-item measures range in score from 0 to 
100. A high scale score represents a higher response level.
Thus, a high score for a functional scale represents a high / healthy level of functioning,
a high score for the global health status / QoL represents a high QoL, but a high score for a 
symptom scale / item represents a high level of symptomatology / problems., according to the 
EORTC QLQ-C30 standard scoring algorithm [Scott, N. W., et al 2008]. For global health 
status/QoL and all functional scales, a higher value indicates a better level of function; for 
symptom scales and single items, a higher value indicates increased severity of symptoms.
According to the QLQ-C30 Manuals, if items I1, I2, …, In are included in a scale, the linear 
transformation procedure is as follows:
1. Compute the raw score: 
2. Linear transformation to obtain the score S:
n
I
I
I
RS
n /)
...
(
2
1




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Function scales: 
Symptom scales/items: 
Global health status/QoL: 
100
1

Range
RS
S
Range is the difference between the maximum possible value of RS and the minimum possible 
value. If more than half of the items within one scale are missing, then the scale is considered 
missing, otherwise, the score will be calculated as the average score of those available items. 
PRO Compliance Summary
Completion and compliance of EORTC QLQ-C30/QoL by visit and by treatment will be 
described. Numbers and percentages of complete and missing data at each visit will be 
summarized. An instrument is considered complete if at least one valid is available 
according to the missing item rules outlined in the scoring manual for the instrument.
Completion rate of treated participants (CR-T) at a specific time point is defined as the 
number of treated participants who complete at least one item over the number of treated 
participants in the PRO analysis population.
CR-T = Number of treated participants wℎo complete at least one item 
Number of treated participants in tℎe PRO analysis population
The completion rate is expected to shrink in the later visit during study period due to the 
participants who discontinued early. Therefore, another measurement, compliance rate of 
eligible participants (CR-E) will also be employed as the support for completion rate. CR-E 
is defined as the number of treated participants who complete at least one item over number 
of eligible participants who are expected to complete the PRO assessment, not including the 
participants missing by design such as death, discontinuation, translation not available.
CR-E = Number of treated participants wℎo complete at least one item 
Number of eligible participants wℎo are expected to complete
100
1
1










Range
RS
S
100
1 

Range
RS
S
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The reasons of non-completion and non-compliance will be provided in supplementary table:
–
Completed as scheduled.
–
Not completed as scheduled.
–
Off-study: not scheduled to be completed.
In addition, reasons for non-completion as scheduled of these measures will be collected 
using “miss_mode” forms filled by site personnel and will be summarized in table format.
The schedule (study visits and estimated study times) and mapping of study visit to analysis 
visit for PRO data collection is provided in Table 5.
Table 5
PRO Data Collection Schedule* and Mapping of Study visit to Analysis Visit
Data Collection Visit
Scheduled Day
Window of Day Range
Week 1
1
[-28,1]
Week 5
20
[2,43]
Week 8
55
[44,65]
Week 11
77
[66,87]
Week 14
99
[88,109]
Week 17
121
[110,131]
Week 20
143
[132,153]
Week 25
175
[154,219]
Week 36
252
[220,285]
Week 45
318
[286,351]
Week 56
395
[352,439]
Week 69
483
[440,527]
Week 82
571
[528,615]
Week 94
659
[616,703]
Week 105
736
[704,769]
EoT or Safety FU *
796
[770,822]
* If the D/C visit takes place ≥30 days from the last dose of study intervention, a safety FU visit 
is not required. In that event, all procedures required for both the D/C visit and the safety FU 
visit will be performed at the D/C visit. The D/C date is the date when the participant 
discontinues all study intervention. SoA as detailed in Protocol 7902-011-00.
Mean change from baseline
Change from baseline in the following secondary PRO endpoint from EORTC QLQ C30 will 
be assessed:
•
Global health status/QoL score (EORTC QLQ-C30)
The time point for the mean change from baseline analysis is defined as the latest time point 
at which CR-T ≥60% and CR-E ≥80% based on blinded data review prior to the database 
lock for any PRO analysis and will be documented in a future sSAP amendment.  
To assess the treatment effects on the PRO score change from baseline outcomes, a 
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constrained longitudinal data analysis (cLDA) model proposed by Liang and Zeger 
[Ref. 5.4: 00QJ0M] will be applied, with the PRO score as the response variable, and 
treatment, time, the treatment by time interaction, and stratification factors used for
randomization (see protocol Section 6.3.2) as covariates.
The treatment difference in terms of least square (LS) mean change from baseline will be
estimated from this model together with 95% CI. Model-based LS mean with 95% CI will 
be provided by treatment group for PROscores at baseline and post-baseline time point.  
The cLDA model assumes a common mean across treatment groups at baseline and a 
different mean for each treatment at each of the post-baseline time points. In this model, the 
response vector consists of baseline and the values observed at each post-baseline time point. 
Time is treated as a categorical variable so that no restriction is imposed on the trajectory of 
the means over time. The cLDA model is specified as follows:
E(Y_ijt )=γ_0+γ_jt I(t>0)+βX_i,j=1,2,,3,..,n; t=0,1,2,3,..k
where Yijt is the PRO score for participant i, with treatment assignment j at visit t; γ0 is the 
baseline mean for all treatment groups, γjt is the mean change from baseline for treatment 
group j at time t; Xi is the stratification factor (binary) vector for this participant, and β is the 
coefficient vector for stratification factors. An unstructured covariance matrix will be used to 
model the correlation among repeated measurements. If the unstructured covariance model 
fails to converge with the default algorithm, then Fisher scoring algorithm or other 
appropriate methods can be used to provide initial values of the covariance parameters. In 
the rare event that none of the above methods yield convergence, a structured covariance 
such as Toeplitz can be used to model the correlation among repeated measurements. In this 
case, the asymptotically unbiased sandwich variance estimator will be used. The cLDA 
model implicitly treats missing data as missing at random (MAR).
Line plots for the empirical mean change from baseline will be provided across all time 
points as a supportive analysis.
In addition, the model-based LS mean change from baseline to the specified post-baseline 
time point together with 95% CI will be plotted in bar charts.
Time to Traditional Deterioration (TTD)
The Kaplan-Meier method will be used to estimate the TTD curve for each treatment group. 
The estimate of median time to deterioration and its 95% confidence interval will be obtained 
from the Kaplan-Meier estimates. The treatment difference in TTD will be assessed by the 
stratified log-rank test. A stratified Cox proportional hazard model with Efron's method of 
tie handling and with a single treatment covariate will be used to assess the magnitude of the 
treatment difference (i.e, HR). The HR and its 95% CI will be reported. The same 
stratification factors used for randomization (see protocol Section 6.3.2) will be used as the 
stratification factors in both the stratified log-rank test and the stratified Cox model.
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
Time to Traditional Deterioration (TTD) as measured by EORTC QLQ-C30 global health 
status/quality of life scores. TTD is defined as the time from baseline to the first onset of a 10 or more 
points deterioration from baseline with a subsequent visit of 10 or more points deterioration from 
baseline.
The approach for the TTD analysis will be based on the assumption of non- informative 
censoring. The participants who do not have deterioration on the last date of evaluation will be 
censored. Table 6 provides censoring rule for TTD analysis.
Table 6
Censoring Rules for Time-to-Deterioration
Scenario
Outcome
Deterioration documented
Event observed at time of assessment (first 
deterioration)
Ongoing or discontinued from study without 
deterioration
Right censored at time of last assessment
No baseline assessments
Right censored at treatment start date
Analysis Strategy for Key PRO Endpoints
Table 7
Analysis Strategy for Key PRO Endpoints
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data 
Approach
Mean change from baseline in EORTC QLQ-
C30/QoL
cLDA model
FAS
Model-
based.Table 1
TTD in EORTC QLQ-C30/QoL
stratified log-rank test 
and HR estimation using 
stratified Cox model 
with Efron’s tie handling 
method
FAS
Censored 
according to 
rules in 
Table 6.
3.6.4
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis 
tests will be performed on these characteristics. The number and percentage of participants 
screened and randomized and the primary 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.
3.7
INTERIM AND FINAL ANALYSES
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Blinding to treatment assignments will be maintained at all investigational sites. The results 
of interim analyses will not be shared with investigators prior to completion of the study.
Participant-level unblinding will be restricted to an external unblinded statistician and 
scientific programmer performing the interim analysis, who will have no other 
responsibilities associated with the study.
An external DMC will serve as the primary reviewer of the results of interim efficacy and 
futility analyses and safety analyses, and will make recommendations for discontinuation of 
the study or protocol modifications to the study EOC. If the DMC recommends modifications 
to the design of the protocol or discontinuation of the study, the EOC (and potentially other 
limited Sponsor personnel) may be unblinded to results at the treatment level to act on these
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recommendations. The extent to which individuals are unblinded with respect to results of 
interim analyses will be documented by the unblinded statistician. Additional logistical 
details will be provided in the DMC charter. Key aspects of the interim analyses are 
described below.
Treatment-level results from the interim analysis will be provided to the DMC by the 
unblinded statistician. The unblinded statistician will not be involved in any discussions 
regarding modifications to the protocol, statistical methods, identification of protocol 
deviations, or data validation efforts after the interim analyses.
Access to the allocation schedule for summaries or analyses for presentation to the eDMC 
will be restricted to an unblinded external statistician, and, as needed, an external scientific 
programmer performing the analysis, who will have no other responsibilities associated with 
the study.
If the study is positive at an interim analysis for either primary endpoint, additional analyses, 
including but not limited to the protocol-specified final analysis, may be carried out for 
exploratory purposes or upon regulatory request.
3.7.1
Efficacy and Futility Interim Analyses
Two interim efficacy analyses and two interim futility analysis are planned in addition to the 
final analysis for this study. For the interim and final analyses, all randomized participants 
will be included. Results of the interim analyses will be reviewed by the DMC. Details of the 
boundaries for establishing statistical significance with regard to efficacy are discussed 
further in Section 3.8.
The analyses planned, endpoints evaluated, and drivers of timing are summarized in Table 8.
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Table 8
Summary of Interim and Final Analysis Strategy
Analyses
Key 
Endpoints
Timing
Estimated Time 
after First
Participant 
Randomized
Primary Purpose of 
Analysis
Futility Analysis 1
PFS 
ORR
~297
participants 
enrolled
≥151 PFS events
~16 months
Non-binding 
futility IA for PFS 
and ORR
Futility Analysis 2
PFS 
ORR
~370
participants 
enrolled
≥191 PFS events
~20 months
Non-binding 
futility IA for PFS 
and ORR
IA1
PFS 
OS
ORR if both 
PFS and OS 
are rejected
≥530 PFS events
~386
OS
events 
expected at this time
~24 months
Interim PFS and 
OS analyses
Final ORR 
analysis
IA2
PFS 
OS
≥558 PFS events
~469 OS events
~30 months
Final PFS analysis
Interim OS 
analysis
FA
OS
~552 OS events
~39 months
Final OS analysis
Abbreviations: FA = final analysis; IA = interim analysis; ORR = objective response rate; OS = overall 
survival; PFS = progression-free survival.
3.7.2
Safety Interim Analyses
The DMC will conduct regular safety monitoring. The safety data will be reviewed during a 
safety run-in after 40 participants have been enrolled and have received 2 Cycles of treatment. 
If the DMC notes any safety concerns, the protocol will be amended. It is estimated that this 
review will include approximately 15 participants and no less than 10 patients will have 
ECOG PS 2. If the initial review includes fewer than 10 participants with ECOG PS 2, an 
additional DMC review would be conducted after 15 participants with ECOG PS 2 have 
received 2 Cycles of treatment. The timing and interval of safety monitoring will be specified 
in the DMC charter.
3.8
MULTIPLICITY
The study uses the graphical method of Maurer and Bretz [Ref. 5.4: 045MYM] to control 
multiplicity for multiple hypotheses as well as interim analyses. According to this approach, 
study hypotheses may be tested more than once, and when a particular null hypothesis is 
rejected, the α allocated to that hypothesis can be reallocated to other hypothesis tests.
Figure 1 shows the initial 1-sided α allocation for each hypothesis in the ellipse representing 
the hypothesis. The weights for re-allocation from each hypothesis to the others are shown in 
the boxes on the lines connecting hypotheses.
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Initial α assigned to OS and PFS will be 0.02 and 0.005, respectively. If either hypothesis is 
rejected, α will be reallocated to the other hypothesis. If both are rejected, the ORR 
hypothesis will be tested at 0.025 (Figure 1).
Abbreviations: ORR = objective response rate; OS = overall survival; PFS = progression-free survival.
Note: If both PFS and OS null hypotheses are rejected, the allocation strategy allows testing of ORR at α = 0.025.
Figure 1
Multiplicity Diagram for Type I Error Control
3.8.1
Futility Analysis
After reviewing the safety data at the 3rd DMC safety meeting on August 7, 2020, the DMC 
requested that efficacy data be provided along with safety data at the 4th DMC safety review. 
The DMC made a similar request after the 4th DMC meeting. In order to provide a statistical 
framework for the DMC to evaluate benefit-risk, non-binding futility boundaries have been 
provided for ORR and PFS. The non-binding futility analyses on ORR and PFS will be 
performed at approximately 16 and 20 months from FPI, when approximately 297 and 370 
participants have been enrolled and approximately 151 and 191 PFS events have been 
observed.
All participants randomized as of the last patient last visit for the futility analyses will be 
included in the comparisons of PFS between the 2 randomized treatment groups. An 
observed hazard ratio (combination / pembrolizumab monotherapy) greater than 
approximatey 1.3 and 1.2 would be sufficient for the eDMC to consider futility at each 
analysis. The actual PFS boundaries will be determined by the actual number of PFS events
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at the time of the analysis using the pre-specified Hwang-Shih-DeCani beta-spending 
function with gamma parameter (-9). Table 9 shows the probability of stopping the study for 
futility under different scenarios.
Table 9
Futility Scenarios for PFS (Superiority in Progression Free Survival – Combo 
vs Pembro in All Subjects)
PFS Events
Approx.
Observed HR at 
Boundary
Cumulative Probability (%) of Stopping for Futility 
Under:
HR = 1.3
HR = 1.2
Null HR
= 1
Alternative 
HR = 0.7
151 (27% IF)
1.3
49.1
30.4
5.2
<1
191 (34% IF)
1.2
71.1
50.3
10.6
<1
HSD (-9) Spending function is used
Approximately 252 and 335 participants who have available imaging responses from BICR 
per RECIST 1.1 will be used to compare the ORRs between the 2 randomized treatment 
groups in the two futility anaylses. Approximate observed differences in the ORRs 
(combination – pembrolizumab monotherapy) less than -10% at the first futility analysis and 
less than -5% at the second futility analysis would be sufficient for the eDMC to consider 
futility. The actual ORR futility boundaries will be determined by the actual number of 
participants included in the ORR analysis using a Hwang-Shih-DeCani beta-spending 
function with gamma parameter (-10).
Table 10 shows the probability of stopping the study for futility under different scenarios.
Table 10
Futility Scenarios for ORR (Superiority in Objective Responsive Rate –
Combo vs Pembro in All Subjects with Imagine by BICR per RECIST 1.1)
Sample Size
Approx. 
Observed
∆ORR at 
Boundary
Cumulative Probability (%) of Stopping for Futility 
Under:
∆ORR =
-10%
∆ORR = -
5%
Null ∆ORR
= 0
Alternative
∆ORR= 17%
252 (36% IF)
-10%
60.9
24.3
5.9
<1
335 (48% IF)
-5%
88.7
54.5
17.8
<1
HSD (-10) Spending function is used
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All of the available data (ORR, PFS, and safety) will be considered by the eDMC in their 
deliberations in considering whether to recommend stopping the study for futility.
3.8.2
Objective Response Rate
The study will test the ORR hypothesis at the interim analysis 1 (IA1), at an α level of 0.025 
if both OS and PFS hypotheses are rejected.
Based on the 694 randomized participants with at least 3 months of follow-up, power at 
α=0.025, as well as the approximate treatment difference required to reach the bound 
(ΔORR), are shown in Table 11, assuming underlying 30% and 47% response rates in the 
control and experimental groups, respectively.
If, at IA2, the OS test does not achieve statistical significance but the PFS test achieves 
statistical significance, the p-value of the ORR test from IA2 will be compared to 0.025 if the 
null hypothesis for OS is later rejected.
Table 11
Possible α Levels and Approximate Objective Response Rate Difference 
Required to Demonstrate Efficacy for Objective Response at Interim Analysis
α
~Δ Objective Response Rate 
(ORR)
Power (ΔORR=0.17)
0.025
0.073
0.996
3.8.3
Progression-free Survival
The PFS hypothesis may be tested at α=0.005 (initially allocated α) or α=0.025 (if the OS 
null hypothesis is rejected). Table 12 shows the bounds and boundary properties for PFS 
hypothesis testing derived using a Lan-DeMets O’Brien-Fleming spending function. If the 
actual number of PFS events at the interim and final analyses differs from those specified in 
the table, the bounds will be adjusted using the Lan-DeMets O’Brien-Fleming spending 
function accordingly.
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Table 12
Efficacy Boundaries and Properties for Progression-free Survival Analyses
Analysis
Value
=0.005
=0.025
IA1:95%*
Z
2.654
2.025
N = 694
p (1-sided) a
0.004
0.021
Events: 530
HR at boundb
0.794
0.839
Month: 24
P(Cross) if HR=1c
0.004
0.021
P(Cross) if HR=0.7d
0.927
0.981
Final:
Z
2.657
2.062
N = 694
p (1-sided) a
0.004
0.02
Events: 558
HR at boundb
0.799
0.840
Month: 30
P(Cross) if HR=1c
0.005
0.025
P(Cross) if HR=0.7d
0.947
0.986
Abbreviations: HR = hazard ratio; IA = interim OS analysis (PFS final analysis). 
The number of events and timings are estimated approximately.
*Percentage of the target number of events at final analysis anticipated at interim analysis
ap (1-sided) is the nominal α for testing.
bHR at bound is the approximate HR required to reach an efficacy bound.
cP (Cross if HR=1) is the probability of crossing a bound under the null hypothesis.
dP (Cross if HR=0.7) is the probability of crossing a bound under the alternative hypothesis.
3.8.4
Overall Survival
The OS hypothesis may be tested at α=0.02 (initially allocated α) or α=0.025 (if the PFS null 
hypothesis is rejected). Table 13 shows the bounds and boundary properties for OS 
hypothesis testing derived using a Lan-DeMets O’Brien-Fleming spending function.
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Table 13
Efficacy Boundaries and Properties for Overall Survival Analyses
Analysis
Value
=0.02
=0.025
IA1: 70%*
Z
2.549
2.439
N = 694
p (1-sided) a
0.005
0.007
Events: 386
HR at boundb
0.771
0.780
Month: 24
P(Cross) if HR=1c
0.005
0.007
P(Cross) if HR=0.75d
0.609
0.650
IA2: 85%*
Z
2.326
2.230
N: 694
p (1-sided) a
0.010
0.013
Events: 469
HR at boundb
0.807
0.814
Month: 30
P(Cross) if HR=1c
0.012
0.015
P(Cross) if HR=0.75d
0.794
0.820
Final
Z
2.138
2.050
N: 694
p (1-sided) a
0.016
0.020
Events: 552
HR at boundb
0.834
0.840
Month: 39
P(Cross) if HR=1c
0.020
0.025
P(Cross) if HR=0.75d
0.901
0.915
Abbreviations: HR = hazard ratio; IA = interim analysis.
The number of events and timings are estimated approximately.
*Percentage of the target number of events at final analysis anticipated at interim analysis.
ap (1-sided) is the nominal α for testing.
bHR at bound is the approximate HR required to reach an efficacy bound.
cP (Cross if HR=1) is the probability of crossing a bound under the null hypothesis.
dP (Cross if HR=0.75) is the probability of crossing a bound under the alternative hypothesis.
If the actual number of OS events at the interim and final analyses differs from those 
specified in the table, the bounds will be updated using this spending function evaluated at 
the observed information fraction (fraction of observed over expected final events) at each 
analysis.
The bounds provided in the table above are based on the assumption that the expected 
number of events at IA1, IA2 and FA are 386, 469 and 552, respectively. At the time of an 
analysis, the observed number of events may differ substantially from the expected. To avoid 
overspending at an interim analysis and leave reasonable alpha for the final analysis, the 
minimum alpha spending strategy will be adopted. At an IA, the information fraction used in 
Lan-DeMets spending function to determine the alpha spending at the IA will be based on
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the minimum of the expected information fraction and the actual information fraction at each 
analysis. Specifically,
•
In the scenario that the events accrue slower than expected and the observed number 
of events is less than the expected number of events at a given analysis, the 
information fraction will be calculated as the observed number of events at the 
interim analysis over the target number of events at FA.
•
In the scenario that the events accrue faster than expected and the observed number of 
events exceeds the expected number of events at a given analysis, then the 
information fraction will be calculated as the expected number of events at the
interim analysis over the target number of events at FA.
The final analysis will use the remaining Type I error that has not been spent at the earlier 
analyses. The event counts for all analyses will be used to compute correlations.
Of note, while the information fraction used for spending calculation will be the minimum 
of the actual information fraction and the expected information fraction, the correlations 
required for deriving the bounds will still be computed using the actual information fraction 
based on the observed number of events at each analysis over the target number of events at 
FA.
The minimum spending approach assumes timing is not based on any observed Z-value and 
thus the Z test statistics used for testing conditioned on timing are multivariate normal. Given 
the probabilities derived with the proposed spending method, the correlations based on actual 
event counts are used to compute bounds that control the Type I error at the specified level 
for a given hypothesis conditioned on the interim analysis timing. Since this is true regardless 
of what is conditioned on, the overall Type I error for a given hypothesis unconditionally is 
controlled at the specified level. By using more conservative spending early in the study, 
power can be retained to detect situations where the treatment effect may be delayed.
3.8.5
Safety Analyses
The DMC has responsibility for assessment of overall risk/benefit. When prompted by safety 
concerns, the DMC can request corresponding efficacy data. DMC review of efficacy data to 
assess the overall risk/benefit to study participants will not require a multiplicity adjustment 
typically associated with a planned efficacy interim analysis. However, to account for any 
multiplicity concerns raised by the DMC review of unplanned efficacy data prompted by 
safety concerns, a sensitivity analysis for OR, PFS, and OS adopting a conservative 
multiplicity adjustment will be conducted. For each safety analysis at which an unplanned 
efficacy analysis is performed, an arbitrary small alpha will be assigned for a nominal bound 
of 0.00005. Based on this nominal bound, the final bound for OR, PFS, and OS will be 
adjusted so that final analysis will be controlled within the allocated Type I error.
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3.9
SAMPLE SIZE AND POWER CALCULATIONS
The study will randomize 694 participants in a 1:1 ratio into the pembrolizumab + lenvatinib 
and pembrolizumab + placebo arms, unless a protocol-specified non-binding futility analysis 
leads to suspension of randomized treatment. PFS and OS are primary endpoints for the 
study, with ORR as the key secondary endpoint.
Based on the 694 participants with at least 7 months of follow-up, the power of the ORR 
testing at the allocated α=0.025 is approximately 99.6% to detect a 17-percentage point 
difference between an underlying 30% response rate in the control arm and a 47% response 
rate in the experimental arm.
For the PFS endpoint, based on a target number of 558 events and 1 efficacy interim analyses 
at approximately 95% of the target number of events, the study has approximately 95% 
power to detect an HR of 0.7 at an overall α level of 0.005 (1-sided), and 99% power at an α 
level of 0.025 (1-sided).
For the OS endpoint, based on a target number of 552 events and 2 efficacy interim analyses 
at approximately 70% and 85% of the target number of events, the study has approximately 
90% power to detect an HR of 0.75 at an overall α level of 0.02 (1-sided), and 91.5% power 
at an α level of 0.025 (1-sided).
Based on KEYNOTE-052 and KEYNOTE-361 data, the above sample size and power 
calculations for PFS and OS assume the following:

PFS follows an exponential distribution with a median of 3.2 months for the control 
group.

OS follows an exponential distribution with a median of 10.0 months for the control 
group.

Enrollment period of 17 months

An annual dropout rate of 12% and 5% for PFS and OS, respectively

A follow-up period of 13 and 22 months for PFS and OS, respectively, after the last 
participant enrolls.
The sample size and power calculations were performed using R (“gsDesign” package) and 
EAST 6.4.
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3.10
SUBGROUP ANALYSES
To determine whether the treatment effect is consistent across various subgroups, the 
between-group treatment effect for OS, PFS, and ORR (with a nominal 95% CI) will be 
estimated and plotted by treatment group within each category of the following subgroup 
variables:

Geographic region (US, non-US)

ECOG performance status (0, 1, 2)

Ineligibility for cisplatin versus ineligibility for any platinum-based chemotherapy

PD-L1 CPS (<10, ≥10)

Note: Participants in the any platinum-ineligible subgroup with PD-L1 below 
detectable levels will be included in the CPS <10 category. Cisplatin-ineligible 
participants in the CPS <10 category will be ineligible for this study.

Age category (<65 years, 65 to 74 years, ≥75 years)

Sex (female, male)

Race (white, nonwhite)

Baseline hemoglobin (<10g/dL, ≥10g/dL)

Metastatic location at baseline (visceral disease, lymph node only)

Liver metastasis at baseline (presence, absence)

Number of Bajorin risk factors (0, 1, 2)
The consistency of the treatment effect will be assessed using descriptive statistics for each 
category of the subgroup variables listed above. If the number of participants in a category of 
a subgroup variable is less than 10% of the ITT population, the subgroup analysis will not be 
performed for this category of the subgroup variable, and this subgroup variable will not be 
displayed in the forest plot. The subgroup analyses for PFS and OS will be conducted using 
an unstratified Cox model, and the subgroup analyses for ORR will be conducted using the 
unstratified Miettinen and Nurminen method.
3.11
COMPLIANCE (MEDICATION ADHERENCE)
Drug accountability data for study intervention will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
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3.12
EXTENT OF EXPOSURE
Extent of exposure for a participant is defined as the number of Cycles in which the 
participant receives the study intervention. Summary statistics will be provided for the extent 
of exposure in the APaT population.
4
REFERENCES
[Ref. 5.4: 00QJ0M]
Liang K-Y, Zeger SL. Longitudinal data analysis of continuous
and discrete responses for pre-post designs. Sankhya: The 
Indian Journal of Statistics 2000;62(Series B, Pt. 1):134-48.
[Ref. 5.4: 00TWVP]
Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting
the significance of changes in health-related quality-of-life 
scores. J Clin Oncol 1998;16:139-44.
[Ref. 5.4: 00VMQY]
Miettinen O, Nurminen M. Comparative analysis of two rates.
Stat Med 1985;4:213-26.
[Ref. 5.4: 00VPPS]
O'Brien PC, Fleming TR. A multiple testing procedure for
clinical trials [Abstract]. Biometrics 1979;35(3):549-56.
[Ref. 5.4: 03P3QC]
Lan KKG, DeMets DL. Discrete sequential boundaries for
clinical trials. Biometrika 1983;70(3):659-63.
[Ref. 5.4: 045MYM]
Maurer W, Glimm E, Bretz F. Multiple and repeated testing of
primary, coprimary, and secondary hypotheses. Stat Biopharm 
Res. 2011;3(2):336-52.
[Ref. 5.4: 045X5X]
Uno H, Claggett B, Tian L, Inoue E, Gallo P, Miyata T, et al.
Moving beyond the hazard ratio in quantifying the between-
group difference in survival analysis. J Clin Oncol. 2014 Aug 
1;32(22):2380-5.
[Ref. 5.4: 050DSW]
Vaughn DJ, Bellmunt J, Fradet Y, Lee JL, Fong L, Vogelzang
NJ, et al. Health-related quality-of-life analysis from 
KEYNOTE-045: a phase III study of pembrolizumab versus 
chemotherapy for previously treated advanced urothelial 
cancer. J Clin Oncol. 2018 Jun 1;36(16):1579-87. Authors' 
disclosures of potential conflicts of interest, Acknowledgment; 
3 p.
08TJDH

Prot_001.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 3 Randomized, Double-blind Study to Compare the Efficacy and 
Safety of Pembrolizumab (MK-3475) in Combination with  Lenvatinib 
(E7080/MK-7902) versus Pembrolizumab and Placebo as First Line 
Treatment for Locally Advanced or Metastatic Urothelial Carcinoma in 
Cisplatin-ineligible Participants Whose Tumors Express PD-L1, and in 
Participants Ineligible for Any Platinum-containing Chemotherapy 
Regardless of PD-L1 Expression (LEAP-011)
NCT03898180
05-DEC-2022


PRODUCT: MK-7902  
1
PROTOCOL/AMENDMENT NO.:  011-04/E7080-G000-317
MK-7902-011-04 FINAL PROTOCOL
05-DEC-2022
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3, Randomized, Double-blind Study to Compare the Efficacy and 
Safety of Pembrolizumab (MK-3475) in Combination with Lenvatinib (E7080/MK-7902) 
Versus Pembrolizumab and Placebo as First Line Treatment for Locally Advanced or 
Metastatic Urothelial Carcinoma in Cisplatin-ineligible Participants Whose Tumors Express 
PD-L1, and in Participants Ineligible for Any Platinum-containing Chemotherapy Regardless 
of PD-L1 Expression (LEAP-011)
Protocol Number: 011-04 (E7080-G000-317)
Compound Number: MK-7902
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
The study is co-funded by MSD and Eisai.
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
141237
EudraCT
2018-003752-21
Approval Date: 05 December 2022
08F4G3


PRODUCT: MK-7902  
2
PROTOCOL/AMENDMENT NO.:  011-04/E7080-G000-317
MK-7902-011-04 FINAL PROTOCOL
05-DEC-2022
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
08F4G3


PRODUCT: MK-7902  
3
PROTOCOL/AMENDMENT NO.:  011-04/E7080-G000-317
MK-7902-011-04 FINAL PROTOCOL
05-DEC-2022
DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 04
05-DEC-2022
The scope of the study has been reduced. Long-term efficacy/survival data 
will no longer be collected; therefore, upon either completion or 
discontinuation of pembrolizumab, participants will have a final Safety 
Follow-up visit and be discontinued from the study. Participants in Efficacy 
Follow-up will stop efficacy assessments and be discontinued from the 
study. Participants in Survival Follow-up are considered to have completed 
the study.
Amendment 03
24-SEP-2021
To update the dose modification and toxicity management guidelines for 
irAEs. To make updates consistent with recommendations of the external 
Data Monitoring Committee (eDMC) after an interim review of the data; 
specifically, that all participants be unblinded and lenvatinib/placebo 
administration stop. The study will remain open so that participants still on 
study will have continued access to pembrolizumab.
Amendment 02
06-FEB-2020
To allow participants to be enrolled in China while awaiting authorization 
from the HGRAC to collect biomarker specimens.
Amendment 01
22-JUL-2019
Current literature supports use of this class of drugs in a higher age range for 
this patient population.
Original protocol
25-JAN-2019
Original Protocol
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PRODUCT: MK-7902  
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PROTOCOL/AMENDMENT NO.:  011-04/E7080-G000-317
MK-7902-011-04 FINAL PROTOCOL
05-DEC-2022
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 04
Overall Rationale for the Amendments:
The scope of the study has been reduced. Long-term efficacy/survival data will no longer be collected; therefore, upon either 
completion or discontinuation of pembrolizumab, participants will have a final Safety Follow-up visit and be discontinued from the 
study. Participants in Efficacy Follow-up will stop efficacy assessments and be discontinued from the study. Participants in Survival 
Follow-up are considered to have completed the study.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis
1.2 Schema
1.3.1 Initial Treatment
1.3.2 Second Course Treatment
4.1 Overall Design
7.3 Lost to Follow-up
8.1.13 Subsequent Antineoplastic Treatment
8.2.1.3 End of Treatment and Follow-up 
Tumor Imaging
8.10.5.2 Efficacy Follow-up Visits
8.10.6 Survival Follow-up
8.10.7 Survival Status
Reduced the scope of the study. 
Participants who either complete 
administration of pembrolizumab or 
discontinue pembrolizumab will 
discontinue the study following the Safety 
Follow-up visit. Participants in Efficacy 
Follow-up will stop efficacy assessments
and be discontinued from the study.
Participants in Survival Follow-up are 
considered to have completed the study 
and should have a final survival contact.
Revised the Schema and SoA accordingly
to remove Follow-up and Safety Follow-up 
from the Posttreatment phase of the study.
Long-term efficacy/survival data will 
no longer be collected.
08F4G3


PRODUCT: MK-7902  
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PROTOCOL/AMENDMENT NO.:  011-04/E7080-G000-317
MK-7902-011-04 FINAL PROTOCOL
05-DEC-2022
Section # and Name
Description of Change 
Brief Rationale 
1.3.1 Initial Treatment
1.3.2 Second Course Treatment
6.5 Concomitant Therapy
8.1.5.2 Concomitant Medications
8.3.1 Physical Examination
8.3.2 Vital Signs
8.3.5.1 Hematology and Clinical Chemistry
8.3.5.3 Thyroid Function Testing
8.3.6 Eastern Cooperative Oncology Group 
Performance Status
Reduced the frequency that information on 
concomitant medication, safety laboratory 
parameters, physical examination, vital 
sign measurements, and ECOG 
performance status are collected for 
participants still receiving pembrolizumab 
treatment.
Revised the SoA accordingly to reduce the 
frequency concomitant medication, safety 
laboratory parameters, physical 
examination, vital sign measurements, and 
ECOG performance status are collected.
Revision to align with the current 
standard of care for pembrolizumab 
administration and to ease the burden 
on participants and investigational 
sites.
1.1 Synopsis
1.3.2 Second Course Treatment
4.1 Overall Design
8.2.1.4 Second Course Treatment Tumor 
Imaging
8.2.1.4.1 Bone Imaging During Second 
Course
8.10.3 Second Course Treatment
Added a note that Second Course treatment 
will no longer be offered; however, any 
participant receiving Second Course prior 
to initiation of Amendment 011-04 can 
continue as planned.
Revision in alignment with reducing 
the scope of the study.
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Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis
1.3.1 Initial Treatment
1.3.2 Second Course Treatment
8.2.1.2 Tumor Imaging During the Study
8.2.1.2.1 Bone Imaging During the Study
8.2.1.4 Second Course Treatment Tumor 
Imaging
8.2.1.4.1 Bone Imaging During Second 
Course
Removed the requirement of recording the 
date and assessment of imaging performed 
as part of standard of care.
Revision to clarify that the date and 
assessment of imaging performed as 
part of standard of care is no longer 
needed as Second Course treatment is 
no longer an option.
1.3.1 Initial Treatment
1.3.2 Second Course Treatment
8.2.1.3 End of Treatment and Follow-up 
Tumor Imaging
Removed the requirement for imaging at 
the time of discontinuation (end of 
treatment visit).
Imaging is no longer required at the 
time of discontinuation.
1.3.1 Initial Treatment
1.3.2 Second Course Treatment
Added “local” to laboratory tests that were 
previously required to be performed at the 
central laboratory.
Revision to allow investigational sites 
the option of sending samples to the 
local laboratory for all required 
laboratory testing while participants are 
on-treatment.
10.2 Appendix 2: Clinical Laboratory Tests
Removed language stipulating that, if a 
local laboratory is used, samples need to be 
collected and sent to the central laboratory 
in parallel.
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Section # and Name
Description of Change 
Brief Rationale 
4.4.1 Clinical Criteria for Early Study 
Termination
Added language regarding decision to stop 
providing pembrolizumab.
Revision to clarify that the Sponsor 
will provide ample notification in the 
event of a decision to no longer supply 
pembrolizumab.
6.5.2 Prohibited Concomitant Medications
Added a note regarding the concomitant 
use of COVID-19 vaccines.
Revision to clarify that licensed 
COVID-19 vaccines (including those 
for emergency use) are not prohibited.
8.2.1.2 Tumor Imaging During the Study
Added imaging to the list of conditions that 
would stop on-study imaging.
Revision to clarify that imaging would 
stop in the event of a pregnancy. 
4.2.1.6 Planned Exploratory Biomarker 
Research
Text was revised to remove specific 
references to pembrolizumab, lenvatinib, 
and immunotherapy/immune-oncology.
Revision to allow more flexibility with 
planned exploratory biomarker 
research.
Title Page
10.1.1 Code of Conduct for Clinical Trials
Throughout
Sponsor entity name and address change.
Merck Sharp & Dohme Corp. 
underwent an entity name and address 
change to Merck Sharp & Dohme LLC, 
Rahway, NJ, USA. This conversion 
resulted only in an entity name change 
and update to the address.
Throughout Document
Minor administrative, formatting, 
grammatical, and/or typographical changes 
were made throughout the document.
To ensure clarity and accurate 
interpretation of the intent of the 
protocol.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................15
1.1
Synopsis.................................................................................................................15
1.2
Schema ..................................................................................................................20
1.3
Schedule of Activities (SoA)................................................................................23
1.3.1
Initial Treatment...........................................................................................23
1.3.2
Second Course Treatment............................................................................29
2
INTRODUCTION..........................................................................................................33
2.1
Study Rationale....................................................................................................33
2.2
Background ..........................................................................................................36
2.2.1
Pharmaceutical and Therapeutic Background .............................................37
2.2.2
Preclinical and Clinical Studies ...................................................................40
2.2.3
Ongoing Clinical Studies With Pembrolizumab and Lenvatinib.................40
2.3
Benefit/Risk Assessment......................................................................................41
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................41
4
STUDY DESIGN............................................................................................................44
4.1
Overall Design......................................................................................................44
4.2
Scientific Rationale for Study Design.................................................................45
4.2.1
Rationale for Endpoints ...............................................................................46
4.2.2
Rationale for the Use of Placebo .................................................................50
4.3
Justification for Dose...........................................................................................51
4.3.1
Lenvatinib ....................................................................................................51
4.3.2
Pembrolizumab ............................................................................................51
4.3.3
Maximum Dose/Exposure for This Study ...................................................52
4.4
Beginning and End of Study Definition .............................................................52
4.4.1
Clinical Criteria for Early Study Termination .............................................53
5
STUDY POPULATION ................................................................................................53
5.1
Inclusion Criteria.................................................................................................53
5.2
Exclusion Criteria................................................................................................58
5.3
Lifestyle Considerations......................................................................................62
5.3.1
Meals and Dietary Restrictions....................................................................62
5.4
Screen Failures.....................................................................................................62
5.5
Participant Replacement Strategy......................................................................62
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6
STUDY INTERVENTION............................................................................................63
6.1
Study Intervention(s) Administered...................................................................63
6.1.1
Medical Devices...........................................................................................65
6.2
Preparation/Handling/Storage/Accountability .................................................65
6.2.1
Dose Preparation..........................................................................................65
6.2.2
Handling, Storage, and Accountability........................................................65
6.3
Measures to Minimize Bias: Randomization and Blinding..............................66
6.3.1
Intervention Assignment..............................................................................66
6.3.2
Stratification.................................................................................................66
6.3.3
Blinding........................................................................................................66
6.4
Study Intervention Compliance..........................................................................67
6.5
Concomitant Therapy..........................................................................................67
6.5.1
Allowed Concomitant Medications .............................................................68
6.5.2
Prohibited Concomitant Medications ..........................................................69
6.5.3
Drug Interactions .........................................................................................70
6.5.4
Rescue Medications and Supportive Care ...................................................70
6.6
Dose Modification (Escalation/Titration/Other)...............................................70
6.6.1
Pembrolizumab ............................................................................................70
6.6.2
Other Allowed Dose Interruptions for Pembrolizumab...............................78
6.7
Intervention After the End of the Study............................................................78
6.8
Clinical Supplies Disclosure................................................................................78
6.9
Standard Policies..................................................................................................78
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................78
7.1
Discontinuation of Study Intervention...............................................................78
7.2
Participant Withdrawal From the Study...........................................................80
7.3
Lost to Follow-up .................................................................................................81
8
STUDY ASSESSMENTS AND PROCEDURES........................................................81
8.1
Administrative and General Procedures ...........................................................82
8.1.1
Informed Consent.........................................................................................82
8.1.2
Inclusion/Exclusion Criteria ........................................................................83
8.1.3
Participant Identification Card.....................................................................83
8.1.4
Medical History ...........................................................................................83
8.1.5
Prior and Concomitant Medications Review...............................................83
8.1.6
Assignment of Screening Number...............................................................84
8.1.7
Assignment of Treatment/Randomization Number.....................................84
8.1.8
Study Intervention Administration ..............................................................84
8.1.9
Discontinuation and Withdrawal .................................................................84
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8.1.10
Participant Blinding/Unblinding..................................................................85
8.1.11
Calibration of Equipment.............................................................................85
8.1.12
Demographics ..............................................................................................86
8.1.13
Subsequent Antineoplastic Treatment .........................................................86
8.2
Efficacy Assessments ...........................................................................................86
8.2.1
Tumor Imaging and Assessment of Disease................................................86
8.2.2
Patient-reported Outcomes...........................................................................92
8.3
Safety Assessments...............................................................................................93
8.3.1
Physical Examinations.................................................................................93
8.3.2
Vital Signs....................................................................................................93
8.3.3
Electrocardiograms ......................................................................................94
8.3.4
Echocardiograms or Multiple Gated Acquisition Scans..............................94
8.3.5
Clinical Safety Laboratory Assessments .....................................................94
8.3.6
Eastern Cooperative Oncology Group Performance Status.........................95
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................95
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................96
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......98
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...98
8.4.4
Regulatory Reporting Requirements for SAE .............................................98
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................98
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................99
8.4.7
Events of Clinical Interest (ECIs)................................................................99
8.5
Treatment of Overdose........................................................................................99
8.6
Pharmacokinetics...............................................................................................100
8.6.1
Blood Collection for Serum Pembrolizumab.............................................100
8.6.2
Blood Collection for Plasma Lenvatinib....................................................100
8.7
Pharmacodynamics............................................................................................101
8.8
Biomarkers .........................................................................................................101
8.8.1
Planned Genetic Analysis Sample Collection............................................101
8.9
Medical Resource Utilization and Health Economics.....................................101
8.10
Visit Requirements.............................................................................................102
8.10.1
Screening....................................................................................................102
8.10.2
Initial Treatment.........................................................................................103
8.10.3
Second Course Treatment..........................................................................103
8.10.4
Discontinued Participants Continuing to be Monitored in the Study ........103
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8.10.5
Post-treatment Visits..................................................................................104
8.10.6
Survival Follow-up ....................................................................................104
8.10.7
Survival Status ...........................................................................................105
9
STATISTICAL ANALYSIS PLAN ...........................................................................105
9.1
Statistical Analysis Plan Summary...................................................................106
9.2
Responsibility for Analyses/In-house Blinding ...............................................107
9.3
Hypotheses/Estimation ......................................................................................107
9.4
Analysis Endpoints.............................................................................................107
9.4.1
Efficacy Endpoints.....................................................................................107
9.4.2
Safety Endpoints........................................................................................108
9.4.3
Patient-Reported Outcome Endpoints........................................................108
9.5
Analysis Populations..........................................................................................108
9.5.1
Efficacy Analysis Populations...................................................................108
9.5.2
Safety Analysis Populations ......................................................................108
9.6
Statistical Methods.............................................................................................108
9.6.1
Statistical Methods for Efficacy Analyses.................................................108
9.6.2
Statistical Methods for Safety Analyses ....................................................110
9.6.3
Demographic and Baseline Characteristics ...............................................111
9.7
Interim Analyses ................................................................................................111
9.8
Multiplicity .........................................................................................................111
9.9
Sample Size and Power Calculations ...............................................................112
9.10
Subgroup Analyses.............................................................................................112
9.11
Compliance (Medication Adherence)...............................................................113
9.12
Extent of Exposure.............................................................................................113
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................114
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......114
10.1.1
Code of Conduct for Clinical Trials...........................................................114
10.1.2
Financial Disclosure...................................................................................116
10.1.3
Data Protection...........................................................................................116
10.1.4
Committees Structure.................................................................................117
10.1.5
Publication Policy......................................................................................118
10.1.6
Compliance with Study Registration and Results Posting Requirements .118
10.1.7
Compliance with Law, Audit, and Debarment ..........................................119
10.1.8
Data Quality Assurance .............................................................................119
10.1.9
Source Documents .....................................................................................120
10.1.10
Study and Site Closure...............................................................................121
10.2
Appendix 2: Clinical Laboratory Tests............................................................122
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................125
10.3.1
Definition of AE ........................................................................................125
10.3.2
Definition of SAE ......................................................................................126
10.3.3
Additional Events Reported in the Same Manner as SAE.........................127
10.3.4
Recording AE and SAE .............................................................................127
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................131
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................133
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................134
10.5.1
Definitions..................................................................................................134
10.5.2
Contraception Requirements......................................................................135
10.5.3
Pregnancy Testing......................................................................................136
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................137
10.7
Appendix 7: Country-specific Requirements..................................................138
10.7.1
Germany-specific Requirements................................................................138
10.7.2
UK-specific Requirements.........................................................................138
10.8
Appendix 8: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................139
10.9
Appendix 9: Eastern Cooperative Oncology Group (ECOG) Performance 
Status...................................................................................................................143
10.10 Appendix 10: Abbreviations .............................................................................144
11
REFERENCES.............................................................................................................148
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values .................................................58
Table 2
Study Interventions..........................................................................................64
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated With Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ...............................................................72
Table 4
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ........................................................................................................76
Table 5
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease.............................................................................................................91
Table 6
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................97
Table 7
Censoring Rules for Primary Analyses of Progression-free Survival ...........109
Table 8
Analysis Methods for Key Efficacy Endpoints .............................................110
Table 9
Analysis Strategy for Safety Parameters........................................................111
Table 10
Protocol-required Safety Laboratory Assessments........................................123
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LIST OF FIGURES
Figure 1
Initial Treatment (Original Study Design).......................................................21
Figure 2
Second Course (Original Study Design)..........................................................22
Figure 3
Initial Treatment (Amendment 011-04)...........................................................22
Figure 4
Second Course (Amendment 011-04)..............................................................22
Figure 5
Imaging and Treatment for Clinically Stable Participants Treated with 
Pembrolizumab After First Radiologic Evidence of Progressive Disease 
Assessed by the Investigator............................................................................92
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Randomized, Double-blind Study to Compare the Efficacy and 
Safety of Pembrolizumab (MK-3475) in Combination with Lenvatinib (E7080/MK-7902) 
Versus Pembrolizumab and Placebo as First Line Treatment for Locally Advanced or 
Metastatic Urothelial Carcinoma in Cisplatin-ineligible Participants Whose Tumors Express 
PD-L1, and in Participants Ineligible for Any Platinum-containing Chemotherapy Regardless 
of PD-L1 Expression (LEAP-011)
Short Title: Phase 3 Study of First-line Pembrolizumab With or Without Lenvatinib in 
Urothelial Carcinoma in Cisplatin-ineligible Participants Whose Tumors Express PD-L1 and 
Participants Ineligible for Any Platinum-containing Chemotherapy
Acronym: MK-7902-011
Hypotheses, Objectives, and Endpoints:
The objectives and endpoints apply to a study population of male or female participants at 
least 18 years of age with a histologically confirmed diagnosis of advanced/unresectable or 
metastatic urothelial carcinoma (UC), who are cisplatin-ineligible and whose tumors express 
programmed death ligand 1 (PD-L1) (combined positive score [CPS] ≥10), or who are 
medically ineligible to receive any platinum-based chemotherapy.
This study will be considered to have met its primary objective if pembrolizumab +lenvatinib 
is superior to pembrolizumab + placebo for either primary endpoint.
Progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), 
and disease control rate (DCR) will be assessed per Response Evaluation Criteria in Solid 
Tumors Version 1.1 (RECIST 1.1) modified to follow a maximum of 10 target lesions and a 
maximum of 5 target lesions per organ.
NOTE: As of Amendment 011-03, formal comparisons between study treatment arms will no 
longer be conducted. Imaging, ePROs, biomarkers, and PK/ADA samples are no longer 
being collected. Updated analyses are described in Section 9.
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Primary Objectives
Primary Endpoints
To compare pembrolizumab + lenvatinib to 
pembrolizumab + placebo with respect to 
PFS per Response Evaluation Criteria in 
Solid Tumors Version 1.1 (RECIST 1.1) by 
blinded independent central review (BICR).
Hypothesis 1: Pembrolizumab + lenvatinib is 
superior to pembrolizumab + placebo with 
respect to PFS per RECIST 1.1 by BICR.
PFS, defined as the time from 
randomization to the first documented 
progressive disease (PD) or death from any 
cause, whichever occurs first.
To compare pembrolizumab + lenvatinib to 
pembrolizumab + placebo with respect to 
overall survival (OS).
Hypothesis 2: Pembrolizumab + lenvatinib is 
superior to pembrolizumab + placebo with 
respect to OS.
OS, defined as the time from 
randomization to the date of death from 
any cause.
Secondary Objectives
Secondary Endpoints
To compare pembrolizumab + lenvatinib to 
pembrolizumab + placebo with respect to 
objective response rate (ORR) per RECIST 
1.1 by BICR.
Hypothesis 3: Pembrolizumab + lenvatinib is 
superior to pembrolizumab + placebo with 
respect to ORR per RECIST 1.1 by BICR.
Objective response (OR), defined as a 
confirmed complete response (CR) or 
partial response (PR).
To evaluate the safety and tolerability of 
treatment with pembrolizumab + lenvatinib 
versus pembrolizumab + placebo.
Adverse events (AEs) and discontinuations 
due to AEs.
To evaluate pembrolizumab + lenvatinib and 
pembrolizumab + placebo with respect to 
duration of response (DOR) per RECIST 1.1 
by BICR.
DOR, defined as the time from the first 
documented evidence of CR or PR to the 
earliest date of PD or death due to any 
cause, whichever comes first, for 
individuals with a confirmed CR or PR.
To evaluate pembrolizumab + lenvatinib and 
pembrolizumab + placebo with respect to 
disease control rate (DCR) per RECIST 1.1 
by BICR.
Disease control, defined as a confirmed 
response of CR or PR or stable disease 
(SD).
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To evaluate changes in patient-reported 
outcomes (PROs) from baseline, and to 
evaluate time to deterioration (TTD) in 
European Organisation for Research and 
Treatment of Cancer (EORTC) Quality of 
Life Questionnaire Core 30 items (QLQ-
C30) global health status/quality of life 
(QoL). 
EORTC QLQ-C30 global health 
status/QoL score.
TTD, defined as the time from baseline to 
the first onset of PRO deterioration in 
EORTC QLQ-C30 global health 
status/QoL score.
Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Advanced/unresectable or metastatic urothelial carcinoma
Population
Cisplatin-ineligible participants with CPS ≥10, or participants
ineligible for any platinum-containing chemotherapy regardless of 
CPS, with advanced/unresectable or metastatic UC
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Note: As of Amendment 011-03, all participants will be 
unblinded and receive study treatment with pembrolizumab 
monotherapy.
Type of Control
Placebo
Note: As of Amendment 011-03, placebo has been removed.
Study Blinding
Double-blind with in-house blinding
Note: As of Amendment 011-03, the study is unblinded, open-
label.
Masking
Participant or Subject
Investigator
Sponsor
Note: As of Amendment 011-03, the study is unblinded, open-
label.
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Estimated Duration 
of Study
The Sponsor estimates that the study will require approximately 5 
years from the time the first participant signs the informed consent 
until the last participant’s last study-related contact or visit.
Number of Participants:
Approximately 694 participants will be randomized. As of Amendment 011-03, 
approximately 487 participants have been randomized and no additional participants will be 
randomized.
Intervention Groups and Duration:
Intervention 
Groups
NOTE: As of Amendment 011-03, lenvatinib and placebo are removed. 
All participants remaining in the study will receive open-label
pembrolizumab only.
Intervention 
Group 
Name
Drug
Dose 
Strength
Dose 
Frequency
Route 
of 
Admin
Treatment 
Period
Use
Arm 1 and 2
Pembrolizumab
200 mg
Q3W
IV
Infusion
~2 years
(initial 
treatment)
~1 year
(Second 
Course)
Background 
Treatment
Abbreviations: Admin = administration; IV = intravenous; Q3W = every 3 weeks.
Total 
Number
Note: As of Amendment 011-03, all participants will receive open-label 
pembrolizumab only.
2 arms
Duration of 
Participation
NOTE: As of Amendment 011-03, lenvatinib and placebo are removed 
from study intervention. All participants remaining in the study will 
receive open-label pembrolizumab only.
Each participant will participate in the study from the time the participant 
signs the informed consent form (ICF) through the final protocol-specified 
contact.
After a screening phase of up to 28 days, each participant will be assigned 
to receive pembrolizumab for up to 35 cycles or until a discontinuation 
criterion (Section 7.1) is met.
Participants will be permitted to continue study intervention beyond 
RECIST 1.1-defined PD as long as the treating investigator considers that 
the participant may experience clinical benefit, and the participant is 
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tolerating study intervention. All decisions to continue study intervention
beyond confirmed PD by RECIST must be approved by the Sponsor.
Participants who have been receiving study intervention for ≥24 weeks 
(8 cycles) and who attain a CR may consider stopping pembrolizumab 
treatment. If a confirmed CR per RECIST 1.1 is attained, participants must 
receive pembrolizumab for at least 2 additional cycles after CR is first 
documented.
Participants with investigator-determined PD by RECIST 1.1 after first 
course treatment with pembrolizumab treatment has been completed (i.e., 
35 cycles) or stopped for confirmed CR may be eligible for up to 
17 additional cycles of pembrolizumab (approximately 1 year) in the 
Second Course Treatment phase upon experiencing PD (Section 8.10.3).
Note: As of Amendment 011-04, Second Course will no longer be 
offered. Any participant receiving Second Course treatment prior to 
initiation of Amendment 011-04 will be able to complete treatment as 
planned.
After the end of study intervention, each participant will be followed for 
safety and spontaneously reported pregnancy as described in Section 8.
Tumor imaging should be performed by site investigator/radiology 
assessment as per standard of care (SOC) for the disease and local 
guidelines. Imaging timing should follow calendar days and should not be 
adjusted for delays in cycle starts.
Note: As of Amendment 011-04, study participation will end after the final 
administration of pembrolizumab. Participants who either complete 
35 administrations of pembrolizumab or discontinue pembrolizumab will
discontinue from the study following the Safety Follow-up visit. AEs and 
spontaneously reported pregnancies will be reported and followed as 
described under Section 8.4. All participants in Efficacy Follow-up prior to 
initiation of Amendment 011-04 will stop efficacy assessments and be 
discontinued from the study. All participants in Survival Follow-up prior to 
initiation of Amendment 011-04 are considered to have completed the study
and should have a final survival contact. The overall study ends when the 
last participant completes the last study-related contact or visit, withdraws 
from the study, or is lost to follow-up (ie, the participant is unable to be 
contacted by the investigator).
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Additional study governance considerations are outlined in Appendix 1 (Section 10.1.4).
As of Amendment 011-03, Executive Oversight Committee and Data Monitoring 
Committee are no longer applicable.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document is in Appendix 10.
1.2
Schema
The original study design is shown in Figure 1 (Initial Treatment) and Figure 2 (Second 
Course). The revised study design as of Amendment 011-04 is depicted in Figure 3
(Initial Treatment) and Figure 4 (Second Course). Note: As of Amendment 011-04, 
Second Course will no longer be offered. Any participant currently receiving Second 
Course treatment will be able to complete treatment as planned.
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Figure 1
Initial Treatment (Original Study Design)
Abbreviations: 1L = first line; CPS = combined positive score; ECOG = Eastern Cooperative Oncology Group; 
IV = intravenously; PD = progressive disease; PD-L1 = programmed death ligand 1; PO = orally; 
PS = performance status; Q3W = every 3 weeks; QD = once daily; UC = urothelial carcinoma.
If pembrolizumab is discontinued because of toxicity, participants may continue receiving 
lenvatinib or placebo as long as they continue to show clinical benefit from the treatment. If 
lenvatinib or placebo is discontinued for any reason, pembrolizumab may be continued to 
complete the duration of 35 cycles of therapy unless there is a reason to discontinue 
pembrolizumab.
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Figure 2
Second Course (Original Study Design)
Abbreviations: CR = complete response; IV = intravenously; PD = progressive disease; PO = orally; PR = partial response; 
Q3W = every 3 weeks; QD = once daily; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1; SD = 
stable disease.
If pembrolizumab is discontinued because of toxicity, participants may continue receiving 
lenvatinib or placebo as long as they continue to show clinical benefit from the treatment. If 
lenvatinib or placebo is discontinued for any reason, pembrolizumab may be continued to 
complete the duration of 17 cycles of therapy unless there is a reason to discontinue 
pembrolizumab.
Figure 3
Initial Treatment (Amendment 011-04)
Abbreviations: IV = intravenously; Q3W = every 3 weeks; UC = urothelial carcinoma.
Figure 4
Second Course (Amendment 011-04)
Abbreviations: CR = complete response; IV = intravenously; PD = progressive disease; PR = partial response; Q3W = every 
3 weeks; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1; SD = stable disease.
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1.3
Schedule of Activities (SoA)
1.3.1
Initial Treatment
As of Amendment 011-04, study participation will end after the final administration of pembrolizumab. Participants who either 
complete 35 cycles of pembrolizumab or discontinue pembrolizumab will discontinue from the study following the Safety Follow-up 
visit. AEs and spontaneously reported pregnancies will be reported and followed as described under Section 8. All participants in 
Efficacy Follow-up prior to initiation of Amendment 011-04 will stop efficacy assessments and be discontinued from the study. All 
participants in Survival Follow-up prior to the initiation of Amendment 011-04 are considered to have completed the study and should 
have a final survival contact; these participants will no longer be contacted for survival information. The SoA has been amended to 
only show the required assessments.
Trial Period
Screening
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety FUa
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 35
At D/C
30 days
after last dose
All procedures performed before 
administration of study intervention unless 
otherwise indicated.
Cycle Day
1
1
1
1
1
1
Scheduling 
Window (days)
-28 to -1 
+3
±3
±3
±3
±3
±3
+7
Informed Consent
Informed consent
X
Signed before any protocol-specific screening 
procedures are performed.
Reconsent required at time of progression if 
study intervention is to be continued beyond 
progression.
Tumor Tissue Collection
Archived or newly 
obtained tumor 
tissue
X
Archived tissue sample, obtained before 
screening as part of SOC, may be used.
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Trial Period
Screening
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety FUa
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 35
At D/C
30 days
after last dose
All procedures performed before 
administration of study intervention unless 
otherwise indicated.
Cycle Day
1
1
1
1
1
1
Scheduling 
Window (days)
-28 to -1 
+3
±3
±3
±3
±3
±3
+7
Administrative and General Procedures
Inclusion/
exclusion criteria
X
Participant 
identification card
X
X*
*Update with randomization number from IRT.
Demographics and 
medical history
X
Prior/concomitant 
medications
X
X
Per SOC or as clinically indicated and required 
to be recorded when clinically relevant to an 
AEOSI, SAE or ECI.
Treatment 
randomization
X
First dose within 3 days of randomization.
Study Intervention Administration
Pembrolizumab 
administration IV 
Q3W
X
X
X
X
X
X
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Trial Period
Screening
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety FUa
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 35
At D/C
30 days
after last dose
All procedures performed before 
administration of study intervention unless 
otherwise indicated.
Cycle Day
1
1
1
1
1
1
Scheduling 
Window (days)
-28 to -1 
+3
±3
±3
±3
±3
±3
+7
Tumor Imaging
Chest imaging 
(CT) and response 
assessment
(Oral contrast is 
optional. IV 
contrast is 
required unless 
contraindicated.)
X
The same modality should be used for all scans.
Perform at screening (within 28 days of 
randomization); thereafter imaging is to be performed 
as per SOC for the disease and local guidelines.
Schedule should be followed regardless of treatment 
delays. If imaging was obtained within 4 weeks before 
EOT, a scan at EOT is not mandatory.
Abdomen/pelvis 
imaging 
(CT/MRI) and 
response 
assessment
(Oral contrast is 
optional. IV 
contrast is 
required unless 
contraindicated.)
X
Bone scan
X
Perform a baseline bone scan in all participants 
within 28 days prior to randomization. After 
randomization, if baseline scan is positive, 
perform bone scan as per SOC for the disease 
and local guidelines.
This schedule should be followed regardless of 
treatment delays. If imaging was obtained within 
4 weeks prior to EOT, a scan at EOT is not 
mandatory.
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Trial Period
Screening
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety FUa
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 35
At D/C
30 days
after last dose
All procedures performed before 
administration of study intervention unless 
otherwise indicated.
Cycle Day
1
1
1
1
1
1
Scheduling 
Window (days)
-28 to -1 
+3
±3
±3
±3
±3
±3
+7
Efficacy Procedures
Subsequent 
anticancer therapy 
status
X
X
FU information may be obtained at a clinic visit 
or by telephone, email, or from other sources.
Survival status
Clinical Procedures/Assessments
Directed physical 
examination
X
Per SOC or as clinically indicated.
Weight
X
X
Vital signs
X
X
Height
X
12-lead ECG with 
QTcF 
determination
X*
*After screening, per SOC or as clinically 
indicated.
MUGA scan or 
ECHO 
X*
*After screening, per SOC or as clinically 
indicated.
ECOG 
performance status
X
X
To be performed per SOC or as clinically 
indicated.
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Trial Period
Screening
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety FUa
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 35
At D/C
30 days
after last dose
All procedures performed before 
administration of study intervention unless 
otherwise indicated.
Cycle Day
1
1
1
1
1
1
Scheduling 
Window (days)
-28 to -1 
+3
±3
±3
±3
±3
±3
+7
AE/SAE review
X
Report NSAEs occurring within 30 days after the 
last dose of study intervention, regardless of 
initiation of new therapy.
Report SAEs occurring within 90 days after the 
last dose of study intervention, or within 30 days 
after the last dose of study intervention if new 
anticancer therapy is initiated, whichever is 
earlier.
Laboratory Procedures/Assessments (Local Laboratory)
Pregnancy test-
urine or serum 
β-HCG 
(WOCBP only)
X
X
Monthly pregnancy testing should be conducted 
as per local regulations where applicable.
Urine dipstick 
testing
X
Performed locally within 7 days before first 
dose. Thereafter, only required per SOC or if 
clinically indicated.
Urinalysis 
X
Performed locally within 7 days before first 
dose. Thereafter, only required per SOC or if 
clinically indicated.
Laboratory Procedures/Assessments (Local or Central Laboratory)
HIV, hepatitis B,
and hepatitis C
X
Only if mandated by local health authority.
Serum FSH 
(WONCBP only)
X
In the absence of 12 months of amenorrhea, 
confirmation with 2 FSH values in 
postmenopausal range is required.
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Trial Period
Screening
Treatment
Cycle = 21 days
EOT
Posttreatment
Notes
Safety FUa
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 35
At D/C
30 days
after last dose
All procedures performed before 
administration of study intervention unless 
otherwise indicated.
Cycle Day
1
1
1
1
1
1
Scheduling 
Window (days)
-28 to -1 
+3
±3
±3
±3
±3
±3
+7
CBC with 
differential
X
X
To be performed per SOC or as clinically 
indicated and required to be recorded when 
clinically relevant to an AEOSI, SAE or ECI.
Clinical chemistry
X
X
T3 or FT3, FT4, 
TSH
X
X
PT/INR and aPTT 
or PTT
X
Within 10 days of first dose
PTT is acceptable if aPTT cannot be determined.
Additional testing as clinically indicated for 
participants taking anticoagulants.
PK/Biomarkers (Central Laboratory)
Blood for genetic 
analysis
X
Predose. 
See Section 8.8 of the protocol for additional 
information.
Abbreviations: AE = adverse event; aPTT = activated partial thromboplastin time; BP = blood pressure; β-HCG; = β human chorionic gonadotropin; CBC = complete blood 
count; CR = complete response; CT = computed tomography; CXDY= Cycle X Day Y; D/C = discontinuation; DNA = deoxyribonucleic acid; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; ECHO = echocardiogram; EOT = end of treatment; FSH = follicle-stimulating hormone; FT3 = free triiodothyronine; FT4 = 
free thyroxine; FU = follow-up; HIV = human immunodeficiency virus; IEC = independent ethics committee; INR = international normalized ratio; IRB = institutional review 
board; IRT = interactive response technology; IV = intravenously; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; MUGA = multigated 
acquisition; NSAE = non-serious adverse event;  PD = progressive disease; PD-L1 = programmed death ligand 1; PO = orally; PT = prothrombin time; PTT = partial 
thromboplastin time; Q3W = every 3 weeks; Q9W = every 9 weeks; Q12W = every 12 weeks; Q18W = every 18 weeks; Q24W = every 24 weeks; QD = once daily; QTcF = 
QT interval corrected with Fridericia’s formula; RNA = ribonucleic acid; SAE = serious adverse event; SoA = schedule of activities; SOC = standard of care; 
T3 = triiodothyronine; TSH = thyroid-stimulating hormone; W = week; WOCBP = women of childbearing potential; WONCBP = women of non-childbearing potential.
a If the D/C visit takes place ≥30 days from the last dose of study intervention, a safety FU visit is not required.  In that event, all procedures required for both the D/C visit and 
the safety FU visit will be performed at the D/C visit. The D/C date is the date when the participant discontinues all study intervention.
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1.3.2
Second Course Treatment
Note: As of Amendment 011-04, Second Course will no longer be offered. Any participant currently receiving Second Course 
treatment will be able to complete treatment as planned. Participants who either complete 17 cycles of pembrolizumab or discontinue 
pembrolizumab will be discontinued from the study following the Safety Follow-up visit. AEs and spontaneously reported 
pregnancies will be reported and followed as described under Section 8. All participants in Efficacy Follow-up prior to initiation of 
Amendment 011-04 will stop efficacy assessments and be discontinued from the study. All participants in Survival Follow-up are 
considered to have completed the study and should have a final survival contact; these participants will no longer be contacted for 
survival information. The SoA has been amended to only show the required assessments.
Trial Period
Treatment
Cycle = 21 days
EOT
Post-treatment
Notes
Safety
FUa
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 17
At D/C
30 days after D/C 
(+ 7 days)
All procedures are to be performed before 
administration of study intervention unless 
otherwise indicated.
Scheduling Window (days)
±3
±3
±3
±3
±3
±3
+7
±7
Administrative and General Procedures
Second Course eligibility criteria
X
The SC eligibility criteria must be satisfied and all 
safety parameters listed in the inclusion criteria, 
and none listed in the exclusion criteria, are met.
Concomitant medications
X
Per SOC or as clinically indicated and required to 
be recorded when clinically relevant to an AEOSI, 
SAE or ECI.
Study Intervention Administration
Pembrolizumab 200 mg IV Q3W
X
X
X
X
X
X
Eligible participants may receive up to an
additional 17 cycles of pembrolizumab.
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Trial Period
Treatment
Cycle = 21 days
EOT
Post-treatment
Notes
Safety
FUa
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 17
At D/C
30 days after D/C 
(+ 7 days)
All procedures are to be performed before 
administration of study intervention unless 
otherwise indicated.
Scheduling Window (days)
±3
±3
±3
±3
±3
±3
+7
±7
Efficacy Procedures
Chest imaging (CT) and response 
assessment 
(Oral contrast is optional. IV contrast is 
required unless contraindicated.)
For SC, baseline imaging is CT scan showing PD 
that makes SC necessary. Baseline imaging within 
28 days before the first dose of treatment, in the 
Second Course. This may be the same day as the 
date of new PD.
Thereafter imaging is to be performed as per SOC.
This schedule should be followed regardless of 
treatment delays.
Abdomen/pelvis imaging (CT/MRI) and 
response assessment 
(Oral contrast is optional. IV contrast is 
required unless contraindicated.)
Bone scan
Perform baseline bone scan within 28 days before 
SC C1 only in the situation of an actively 
monitored bone scan in the Initial Treatment 
course or any evidence of symptomatic 
development of bone metastases. If the scan at SC 
C1 is positive, a bone scan is to be performed as 
per SOC for the disease and local guidelines. This 
schedule should be followed regardless of 
treatment delays.
Subsequent anticancer therapy status
X
X
FU information may be obtained at a clinic visit or 
by telephone, email, or from other sources.
Survival status
Upon Sponsor request, participants may be 
contacted for survival status at any time during 
the study.
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Trial Period
Treatment
Cycle = 21 days
EOT
Post-treatment
Notes
Safety
FUa
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 17
At D/C
30 days after D/C 
(+ 7 days)
All procedures are to be performed before 
administration of study intervention unless 
otherwise indicated.
Scheduling Window (days)
±3
±3
±3
±3
±3
±3
+7
±7
Clinical Procedures/Assessments
Full physical examination
X
X
Within 7 days before SC C1
Directed physical examination
X
Per SOC or as clinically indicated.
Vital signs; weight
X
ECOG performance status
X
12-lead ECG with QTcF determination
X
X
Perform only if clinically indicated.
AE/SAE review
Report NSAEs occurring within 30 days after the 
last dose of study intervention, regardless of 
initiation of new therapy.
Report SAEs occurring within 90 days after the 
last dose of study intervention, or within 30 days 
after the last dose of study intervention if a new 
anticancer therapy is initiated, whichever is 
earlier.
Laboratory Procedures/Assessments: (Local Laboratory)
Pregnancy test- urine or serum β-HCG
(WOCBP only)
X
Monthly pregnancy testing should be conducted 
as per local regulations where applicable.
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Trial Period
Treatment
Cycle = 21 days
EOT
Post-treatment
Notes
Safety
FUa
Visit Timing/
Cycle Number
1
2
3
4
5
6 to 17
At D/C
30 days after D/C 
(+ 7 days)
All procedures are to be performed before 
administration of study intervention unless 
otherwise indicated.
Scheduling Window (days)
±3
±3
±3
±3
±3
±3
+7
±7
Laboratory Procedures/Assessments (Local or Central Laboratory)
CBC with differential
X
To be performed Per SOC or as clinically 
indicated and required to be recorded when 
clinically relevant to an AEOSI, SAE or ECI.
Clinical chemistry
X
T3 or FT3, FT4, and TSH
X
PT/INR and aPTT/PTT
X
Additional testing as clinically indicated for 
participants taking anticoagulants
Abbreviations: AE = adverse event; aPTT = activated partial thromboplastin time; β-HCG = beta human chorionic gonadotropin; BP = blood pressure; CBC = complete blood 
count; CR = complete response; CT = computed tomography; C1 = cycle 1; CXDY = Cycle X Day Y; D/C = discontinuation; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; EOT = end of treatment; FT3 = free triiodothyronine; FT4 = free thyroxine; FU = follow-up; INR = international normalized ratio; IV = 
intravenous; MRI = magnetic resonance imaging; NSAE = nonserious adverse event; PD = progressive disease; PO = orally; PT = prothrombin time; PTT = partial 
thromboplastin time; QD =  every day; Q12W = every 12 weeks; Q24W = every 24 weeks; QTcF = QT interval corrected with Fridericia’s formula; SAE = serious adverse event; 
SC = second course; T3 = triiodothyronine; TSH = thyroid-stimulating hormone; WOCBP = women of childbearing potential.
aIf the D/C visit takes place ≥30 days from the last dose of study intervention, a safety FU visit is not required.  In that event, all procedures required for both the D/C visit and the 
safety FU visit will be performed at the D/C visit.  The D/C date is the date when the participant discontinues all study intervention.
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2
INTRODUCTION
2.1
Study Rationale
Urothelial carcinoma (UC), also referred to as transitional cell carcinoma, is a range of 
tumors that arise from the urothelial endothelium, including the bladder, renal pelvis, ureter, 
and urethra. The worldwide incidence of bladder cancer exceeds 300,000 cases annually
[Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D 2011]. UC is the predominant 
histologic type of bladder cancer in the United States and western Europe, where it accounts 
for approximately 90% of bladder cancers. 
UC disproportionately affects the elderly, who often have coexisting, impactful illnesses such 
as cardiovascular disease and impaired renal function. Such coexisting illnesses are important 
factors limiting treatment options for these patients [Bamias, A., et al 2007]. Many patients
with UC present with advanced disease [Siegel, R. L., et al 2016]. Inoperable, metastatic 
disease is typically incurable; prognosis is poor and treatment options are limited. Patients 
receive palliative chemotherapy or best supportive care as the only options.
For nearly 30 years, the first-line standard of care treatment for patients with locally 
advanced or metastatic UC has been cisplatin-containing combination chemotherapy, 
including either gemcitabine or methotrexate/vinblastine/doxorubicin [Sternberg, C. N., et al 
2006] [Logothetis, C. J., et al 1990] [von der Maase, H., et al 2000]. Median survival with 
cisplatin-based multi-agent chemotherapy is approximately 14 to 15 months [von der Maase, 
H., et al 2005]. While this result is superior to the estimated 6-month survival with metastatic 
disease before the development of modern chemotherapy regimens, the 5-year survival rate 
with contemporary regimens remains poor.
Chemotherapy, particularly with cisplatin, is toxic, and it has been estimated that only 
approximately 21% of patients are treated with cisplatin-based chemotherapy [Sonpavde, G., 
et al 2014]. Cisplatin ineligibility is commonly due to renal dysfunction (creatinine clearance 
[CrCl] <60 mL/min), ECOG performance status (PS) 2, or both. Hearing loss, Grade 2 
neuropathy, and heart failure may also confer cisplatin ineligibility [Galsky, M. D., et al 
2011] [Galsky, M. D., et al 2011] [Dash, A., et al 2006]. There is no standard of care 
chemotherapy for patients unable to tolerate cisplatin. Consensus guidelines, such as those of
the National Comprehensive Cancer Network (NCCN), recommend participation in clinical 
trials of new and more tolerable therapy for patients who cannot tolerate cisplatin-based 
chemotherapy. As an alternative chemotherapy to cisplatin and clinical trial participation, 
NCCN recommends gemcitabine/carboplatin on the basis of category 2 evidence 
(https://www.nccn.org/professionals/physician_gls/default.aspx). The NCCN 
recommendation for gemcitabine/carboplatin is based on the European Organisation for 
Research and Treatment of Cancer (EORTC) 30986 trial, one of the largest clinical trials 
evaluating carboplatin-based chemotherapy in the cisplatin-ineligible population [De Santis, 
M., et al 2012]. In this study, 238 cisplatin-ineligible participants with UC were randomized 
to receive either gemcitabine/carboplatin or methotrexate/carboplatin/vinblastine. Overall, 
chemotherapy was active; the ORR was 36.1%. However, median survival was poor (9.3 
months with gemcitabine/carboplatin, the more effective and less toxic of the 2 regimens 
studied) for the overall study population. Participants with baseline ECOG PS 2 and 
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glomerular filtration rate (GFR) <60 mL/min demonstrated a worse ORR of 26.5% and a 
median OS of 5.5 months (95% confidence interval [CI]: 4.1, 8.3). Participants with ECOG 
PS 2 and visceral metastatic disease (represented by Bajorin risk group 2 [below]) had an 
ORR of 26.5% and a median OS of 5.5 months (95% CI: 4.2, 7.3). The rate of severe acute 
toxicity, defined as death as a result of toxicity, renal toxicity (Grade 3 to 4), febrile 
neutropenia (Grade 3 to 4), hemorrhage/bleeding with thrombocytopenia (Grade 4), or 
mucositis (Grade 3 to 4) was 9.3% of the overall population in the gemcitabine/carboplatin 
arm of EORTC 30986. The rate of severe acute toxicity was 28% in participants with ECOG 
PS 2 and GFR <60 mL/min. Of the participants receiving gemcitabine/carboplatin, 72.9% 
required dose reduction and 21% discontinued therapy due to toxicities. In light of these 
results, the overall benefit derived from carboplatin is small.
Consistent with these recommendations, a risk categorization called the Bajorin risk model 
has been formulated and published [Bajorin, D. F., et al 1999]. The 2 risk factors in the 
Bajorin risk model are:

Poor performance status (Karnofsky performance status <80%, equivalent to ECOG PS
≥2) 

Presence of visceral (lung, liver, or bone) metastasis 
Patients are placed in 3 prognostic groups (Bajorin risk groups 0, 1, or 2) depending on their 
number of adverse prognostic factors. Because of these findings, the NCCN warns that 
ECOG PS ≥2 and visceral metastatic disease or ECOG PS ≥2 and GFR <60 mL/min strongly 
predict a poor outcome of chemotherapy and suggests that such patients might be better 
served with best supportive care or participation in a clinical trial [National Comprehensive 
Cancer Network 2016]. The results of the EORTC 30986 clinical trial demonstrate that 
ECOG PS 2 plus an additional prognostic factor (GFR <60 mL/min or visceral metastases) 
are key characteristics that define chemotherapy unfitness [De Santis, M., et al 2012] and
suggested that alternative non-cisplatin-containing treatment regimens should be investigated 
for these patients.
Indeed, because of the frailty of this population with advanced UC and the toxicity associated 
with chemotherapy, it has been estimated that 48% of UC patients cannot be treated with any 
platinum chemotherapy at all. In addition, it has been shown that patients not treated with 
chemotherapy do worse than those who are able to tolerate it [Small, A. C., et al 2012] 
[Sonpavde, G., et al 2014] [Sonpavde, G., et al 2012]. The critical implication is that there 
are many patients who die not having received anticancer treatment. There are no clear 
guidelines or definitions of clinical characteristics for platinum-based chemotherapy 
ineligibility [Sonpavde, G., et al 2014]. Despite the absence of a precise definition, practicing 
clinical oncologists are adept at identifying patients who are good candidates for 
chemotherapy and do not offer chemotherapy to patients who are not good candidates for it. 
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The most frequently listed characteristics of patients deemed unfit for chemotherapy, and 
therefore of platinum ineligibility, are the following [Apolo, A. B., et al 2013]: 

ECOG PS 2 plus 1 of the following:

Visceral metastases

GFR 30 to 60 mL/min

Grade ≥2 audiometric hearing loss 

Grade ≥2 peripheral neuropathy

Other reason for the patient’s being unable to receive carboplatin safely
Recently, pembrolizumab has shown efficacy in first line (1L) and second line (2L) treatment 
of metastatic bladder cancer [Powles, T., et al 2014]. Pembrolizumab is indicated for the 
treatment of previously untreated patients with locally advanced or metastatic UC who are 
not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS 
≥10). In the US and some other regions, pembrolizumab is also indicated for patients who are 
not eligible for any platinum-containing chemotherapy, regardless of PD-L1 status. Data 
from KEYNOTE-052 [Balar, A. V., et al 2017], a large single-arm Phase 2 study 
investigating pembrolizumab for the first-line treatment of advanced UC in cisplatin-
ineligible participants, were the basis of approval for this indication. KEYNOTE-052
enrolled 370 participants who were cisplatin-ineligible (ECOG PS 2, CrCl ≥30 to 
<60 mL/min, Grade ≥2 neuropathy/hearing loss, New York Heart Association [NYHA] Class 
3 heart failure), had advanced UC, and had received no prior chemotherapy for metastatic 
disease. Participants received pembrolizumab 200 mg IV Q3W for up to 24 months. 
In KEYNOTE-052, 48% of participants (n = 179) were at least 75 years of age, and 10.8% 
(n = 40) were at least 85 years of age. Many participants had poor prognostic features at 
study entry: 41.9% (n = 155) had ECOG PS 2, 85.1% (n = 315) had visceral disease, and 
20.8% (n = 77) had liver metastases. In addition, 35% of participants (n = 130) had ECOG 
PS 2 and visceral metastatic disease and were considered ineligible for any 
platinum-containing chemotherapy. In summary, these participants represented the full 
spectrum of cisplatin-ineligible patients, including those who likely would not have been 
treated with any platinum chemotherapy at all had they not been enrolled into this study.  
The results of KEYNOTE-052 demonstrate compelling antitumor activity across the full 
spectrum of the cisplatin-ineligible population. Treatment resulted in a clinically meaningful 
ORR of 28.9% (95% CI: 24.3%, 33.8%). Responses were accompanied by unprecedented 
durability: median duration of response (DOR) was not reached, and DOR ranged from 1.4+ 
to 27.9+ months (+ denotes ongoing response). The median OS in the overall population was 
11.5 months (95% CI: 10.0, 13.3). In comparison to the overall population, median OS was 
longer in the PD-L1 CPS ≥10 subgroup (18.5 months [95% CI: 12.2, not reached]) and 
shorter in the PD-L1 CPS <10 subgroup (10.0 months [95% CI: 7.8, 11.6]). This included
participants considered cisplatin-ineligible as well as those who were ineligible for any 
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platinum-based combination chemotherapy. The median OS in the platinum-ineligible 
population was 8.3 months (95% CI: 5.2, 10.8). Due to the results of KEYNOTE-052, the 
NCCN recommends pembrolizumab as the standard of care for patients with 
cisplatin-ineligible UC and CPS ≥10 and for all platinum-ineligible patients.
Pembrolizumab is also indicated for use in patients with locally advanced or metastatic UC 
and disease progression during or after platinum-containing chemotherapy. KEYNOTE-045
was the basis of approval for this indication and was a multicenter, randomized, active-
controlled trial in which participants had previously received platinum-based chemotherapy 
and were randomized to receive either pembrolizumab 200 mg Q3W (n = 270) or the 
investigator’s choice of paclitaxel, docetaxel, or vinflunine (n = 272) [U.S. Prescribing 
Information. 2021].
In KEYNOTE-045 [Bellmunt, J., et al 2017], the median age of participants was 67 years in 
the pembrolizumab arm and 65 years in the chemotherapy arm. The majority of participants 
had ECOG PS 0 (44.1% for pembrolizumab and 39.0% for chemotherapy) or 1 (53.0% for 
pembrolizumab and 58.1% for chemotherapy). In addition, 89.2% of participants in the 
pembrolizumab arm and 86.0% of those in the chemotherapy arm had visceral metastases. 
The results of KEYNOTE-045 showed significantly superior overall survival (OS) with 
pembrolizumab (hazard ratio [HR] 0.73; 95% CI: 0.59, 0.91; p = 0.002) compared with 
chemotherapy. The median OS with pembrolizumab was 10.3 months (95% CI: 8.0, 11.8),
versus 7.4 months with chemotherapy (95% CI: 6.1, 8.3). KEYNOTE-045 also demonstrated 
higher response rates and longer response duration with pembrolizumab, compared with
chemotherapy. The results in the pembrolizumab arm have led to pembrolizumab’s becoming
a standard of care in this disease setting [Bellmunt, J., et al 2017].
Advanced/metastatic UC presents unique challenges and represents a clinical area in need of 
novel therapeutic approaches. The current study was originally designed to evaluate the 
safety and efficacy of combination therapy with pembrolizumab + lenvatinib versus 
pembrolizumab + placebo in cisplatin-ineligible participants whose tumors express PD-L1
(CPS ≥10) and participants ineligible for any platinum chemotherapy (eg, ineligible for 
cisplatin and carboplatin by virtue of comorbidities, advanced age, and clinical judgment), 
with pembrolizumab monotherapy as a treatment option.
2.2
Background
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) mAb with high specificity 
of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its interaction with 
PD-L1 and programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, 
pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an IV immunotherapy for advanced malignancies. Keytruda® is indicated for the treatment of 
patients across a number of indications, including locally advanced or metastatic UC. For 
more details on specific indications refer to the pembrolizumab Investigator’s Brochure (IB)
[IB Edition 21 2021].
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Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on pembrolizumab.
2.2.1
Pharmaceutical and Therapeutic Background
Pembrolizumab
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].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an 
immunoglobulin (Ig) superfamily member related to cluster of differentiation 28 (CD28) and 
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
[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 Ig-variable–type (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 CD3 zeta (CD3ζ), protein 
kinase C-theta (PKCθ), and zeta-chain-associated protein kinase (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 locally advanced or metastatic UC.
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Lenvatinib
NOTE: As of Amendment 011-03, this section is no longer applicable.
Angiogenesis, the formation of new blood vessels from a pre-existing vascular network, is 
essential for tumor growth and metastasis. VEGF and its family of receptors (VEGFRs 1-3) 
play a major role in tumor angiogenesis [Ferrara, N., et al 2003] [Ellis, L. M. and Hicklin, D. 
J. 2008] [Tammela, T. and Alitalo, K. 2010]. Accumulated evidence suggests that FGF and 
its receptor tyrosine kinase, FGFR, also play important roles 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.
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].
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 human umbilical vein endothelial cell 
(HUVEC) with IC50 values of 2.1 and 7.3 nmol/L, respectively. Analysis of the signal 
transduction molecules revealed that lenvatinib inhibited both the MAPK pathway and the 
mTOR-S6K-S6 pathway in HUVECs triggered by activated VEGFR and FGFR. 
Furthermore, lenvatinib (10, 30 mg/kg) significantly inhibited both VEGF- and FGF-driven 
angiogenesis in a murine in vivo model [Yamamoto, Y., et al 2014]. In vivo, lenvatinib 
exhibited antitumor activity against various human tumor xenografts in athymic mice 
including 5 types of thyroid carcinomas (differentiated [papillary and follicular], anaplastic, 
squamous, and medullary thyroid carcinomas), renal cell carcinoma (RCC), HCC, 
melanoma, gastric cancer, non-small cell lung cancer (NSCLC), ovarian cancer, Ewing’s 
sarcoma, and osteosarcoma. In addition, the antitumor activity of lenvatinib in combination 
with other anticancer agents in several xenograft models was greater than that of lenvatinib 
or the other agents alone.
In summary, lenvatinib inhibited VEGF-driven VEGFR2 phosphorylation and suppressed 
proliferation and tube formation in HUVEC models. Antitumor activity of lenvatinib in vivo 
has been shown in numerous xenograft animals. These results suggest that lenvatinib may be 
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a novel anticancer therapy through inhibition of angiogenesis and may be useful as either
monotherapy or in combination with other anticancer drugs.
Combination of Pembrolizumab With Lenvatinib
NOTE: As of Amendment 011-03, this section is no longer applicable.
Early studies have shown that lenvatinib has antitumor activity in many solid tumors. 
Lenvatinib is a kinase inhibitor indicated as a single agent for locally recurrent or metastatic, 
progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC), in 
combination with everolimus for advanced RCC following 1 prior anti-angiogenic therapy, 
and as a single agent for 1L treatment of unresectable hepatocellular carcinoma. In DTC and 
RCC, lenvatinib statistically significantly prolonged PFS [U.S. Prescribing Information 
2018]. In studies with lenvatinib monotherapy, the median duration of therapy was 13.8 
months for DTC and 7.3 months for hepatocellular carcinoma. In the RCC study, the median 
duration of therapy with lenvatinib in combination with everolimus was 7.6 months.
In preclinical models, lenvatinib decreased the tumor-associated macrophage (TAM) 
population, which is known as an immune regulator in the tumor microenvironment. By 
decreasing TAMs, expression levels of cytokines and immune-regulating receptors were 
changed to increase immune activation. The immune-modulating effect of lenvatinib may 
result in a potent combination effect with PD-1/PD-L1 signal inhibitors. The effect of 
combining lenvatinib with anti-PD-1/PD-L1 inhibitors has been investigated in the CT26 
colorectal cancer syngeneic model (anti-PD-L1 inhibitor) and the LL/2 lung cancer 
syngeneic model (anti-PD-1 monoclonal antibody [mAb]). Combination treatment with 
lenvatinib and either an anti-PD-1 or anti-PD-L1 inhibitor showed significant and superior 
antitumor effects compared with either compound alone in these 2 syngeneic models [Kato, 
Y., et al 2015].
For this reason, an open-label, Phase 1b/2 study (Study E7080-A001-111 [Study 111]) to 
assess the safety and preliminary antitumor activity of the combination of lenvatinib plus 
pembrolizumab in participants with selected solid tumors was initiated. Phase 1b of this 
study determined the maximum tolerated dose (MTD) and recommended Phase 2 dose 
(RP2D) of lenvatinib as 20 mg QD in combination with 200 mg of pembrolizumab IV Q3W. 
The safety and efficacy of the combination at the lenvatinib RP2D is being assessed in the 
Phase 2 portion of the study that includes 6 cohorts (i.e., NSCLC, RCC, endometrial cancer, 
UC, melanoma, and squamous cell carcinoma of the head and neck). Preliminary data show 
promising antitumor activity with the combination in many solid tumors. For participants
with endometrial cancer that progressed with approved therapy, the combination resulted in
an ORR of 48% in 23 participants [Makker, V., et al 2017]. Similarly, in 30 participants with 
RCC, an ORR of 63.3% was observed with combination therapy. The safety profile in 
participants with melanoma and RCC was consistent with the overall safety profile of the 
combination across tumor indications. In 20 participants with metastatic UC who received 
this combination the ORR at Week 24 was 25%, while an additional 45% had stable disease 
[Vogelzang, N., et al 2018].  
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2.2.2
Preclinical and Clinical Studies
NOTE: As of Amendment 011-3, information relative to lenvatinib is no longer 
applicable.
Completed Studies With Pembrolizumab and Lenvatinib
Refer to the respective IBs for pembrolizumab [IB Edition 21 2021] and lenvatinib [IB 
Edition 15-Eisai 2018] for additional preclinical and clinical study data for pembrolizumab 
and lenvatinib.
2.2.3
Ongoing Clinical Studies With Pembrolizumab and Lenvatinib
NOTE: As of Amendment 011-03, information relative to lenvatinib is no longer 
applicable.
Pembrolizumab is under evaluation in patients with metastatic UC as monotherapy and in 
combination with chemotherapy and targeted therapy. Lenvatinib is studied in patients with 
different types of solid tumors, including metastatic UC in combination with pembrolizumab 
(Study 111/KEYNOTE-146). Full lists of ongoing studies are in the respective IBs for 
pembrolizumab and lenvatinib. 
Study 111/KEYNOTE-146
Study 111/KEYNOTE-146 is a multicenter, open-label, Phase 1b/2 clinical trial being 
conducted to evaluate the efficacy and safety of lenvatinib in combination with 
pembrolizumab. The primary objective of the Phase 1b portion of the study is to determine 
the MTD in participants with unresectable solid tumors (NSCLC, RCC, endometrial cancer, 
UC, melanoma, and squamous cell carcinoma of the head and neck) that had progressed after 
treatment with approved therapies or for which no standard effective therapies were 
available. The MTD of lenvatinib in Study 111/KEYNOTE-146 was 20 mg/day + 
pembrolizumab 200 mg Q3W and was therefore the dose selected for this Phase 3 study.
The primary endpoint of the initial part of the Phase 2 portion of the study was ORR after 
24 weeks of treatment, with select secondary endpoints including ORR, DCR, PFS, and
DOR.
As of the data cutoff of 01-MAR-2018, 20 participants with confirmed metastatic UC and 
ECOG PS 0 or 1 were enrolled [Vogelzang, N. J., et al 2018] [Vogelzang, N., et al 2018]. Of 
the enrolled participants, 10 (50%) were PD-L1(+), 8 (40%) were PD-L1(-), and 2 (10%) 
were not tested; 4 (20%) were treatment-naïve and 11 (55%) and 5 (25%) had had 1 and 2
prior lines of prior anticancer therapies, respectively. The primary endpoint of ORR at 
Week 24 was 25% (95% CI: 8.7%, 49.1%) with an additional 45% having stable disease. A 
total of 18 participants (90%) experienced treatment-related AEs (TRAEs). Grade 3 and 
Grade 4 TRAEs occurred in 5 (25%) and 5 (25%) participants, respectively. There was 1 
fatal TRAE (gastrointestinal hemorrhage). The most common TRAEs of any grade were 
proteinuria (45%), diarrhea (40%), hypertension (35%), fatigue (30%), and hypothyroidism 
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(30%). The median PFS was 5.4 months (95% CI: 1.3, not estimable) based on investigator 
assessment per immune-related RECIST. The conclusion was that the combination of 
lenvatinib and pembrolizumab showed promising clinical activity with a manageable safety 
profile in previously treated participants with metastatic urothelial cancer who were not 
preselected for PD-L1 status, including those who had received more than 1 line of treatment.
2.3
Benefit/Risk Assessment
NOTE: As of Amendment 011-03, the risks for lenvatinib or for the combination of 
pembrolizumab and lenvatinib are no longer applicable.
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.
Pembrolizumab has been approved for first-line treatment of patients with locally advanced 
or metastatic bladder cancer who are not eligible for cisplatin-containing therapy and whose 
tumors express PD-L1 (combined positive score [CPS] ≥10), or in patients who are not 
eligible for any platinum-containing chemotherapy regardless of PD-L1 status. It is also 
approved for the treatment of patients with locally advanced or metastatic UC who have
disease progression during or following any platinum-containing chemotherapy, or within 
12 months of neoadjuvant or adjuvant treatment. There is an unmet medical need for safe and 
efficacious first-line therapy in patients with locally advanced or metastatic UC who are 
ineligible for any platinum-containing chemotherapy. As such, there is a continual need for 
novel therapies in this setting. 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.
Additional details regarding specific benefits and risks for participants in this study are in the 
accompanying IBs and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
The objectives and endpoints apply to a study population of male or female participants at 
least 18 years of age with a histologically confirmed diagnosis of advanced/unresectable or 
metastatic urothelial carcinoma (UC), who are cisplatin-ineligible and whose tumors express 
programmed death ligand 1 (PD-L1) (combined positive score [CPS] ≥10), or who are 
medically ineligible to receive any platinum-based chemotherapy.
This study will be considered to have met its primary objective if pembrolizumab +lenvatinib 
is superior to pembrolizumab + placebo for either primary endpoint.
Progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), 
and disease control rate (DCR) will be assessed per Response Evaluation Criteria in Solid 
Tumors Version 1.1 (RECIST 1.1) modified to follow a maximum of 10 target lesions and a 
maximum of 5 target lesions per organ.
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NOTE: As of Amendment 011-03, formal comparisons between study treatment arms will no 
longer be conducted. Imaging, ePROs, biomarkers, and PK/ADA samples are no longer 
being collected. Updated analyses are described in Section 9.
Primary Objectives
Primary Endpoints
To compare pembrolizumab + lenvatinib to 
pembrolizumab + placebo with respect to 
PFS per Response Evaluation Criteria in 
Solid Tumors Version 1.1 (RECIST 1.1) by 
blinded independent central review (BICR).
Hypothesis 1: Pembrolizumab + lenvatinib 
is superior to pembrolizumab + placebo with 
respect to PFS per RECIST 1.1 by BICR.
PFS, defined as the time from 
randomization to the first documented 
progressive disease (PD) or death from any 
cause, whichever occurs first.
To compare pembrolizumab + lenvatinib to 
pembrolizumab + placebo with respect to
overall survival (OS).
Hypothesis 2: Pembrolizumab + lenvatinib 
is superior to pembrolizumab + placebo with 
respect to OS.
OS, defined as the time from randomization
to the date of death from any cause.
Secondary Objectives
Secondary Endpoints
To compare pembrolizumab + lenvatinib to
pembrolizumab + placebo with respect to 
objective response rate (ORR) per RECIST 
1.1 by BICR.
Hypothesis 3: Pembrolizumab + lenvatinib 
is superior to pembrolizumab + placebo with 
respect to ORR per RECIST 1.1 by BICR.
Objective response (OR), defined as a 
confirmed complete response (CR) or 
partial response (PR).
To evaluate the safety and tolerability of 
treatment with pembrolizumab + lenvatinib 
versus pembrolizumab + placebo.
Adverse events (AEs) and discontinuations 
due to AEs.
To evaluate pembrolizumab + lenvatinib and
pembrolizumab + placebo with respect to 
duration of response (DOR) per RECIST 1.1
by BICR.
DOR, defined as the time from the first 
documented evidence of CR or PR to the 
earliest date of PD or death due to any 
cause, whichever comes first, for 
individuals with a confirmed CR or PR.
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To evaluate pembrolizumab + lenvatinib and
pembrolizumab + placebo with respect to 
disease control rate (DCR) per RECIST 1.1
by BICR.
Disease control, defined as a confirmed 
response of CR or PR or stable disease
(SD).
To evaluate changes in patient-reported 
outcomes (PROs) from baseline, and to 
evaluate time to deterioration (TTD) in 
European Organisation for Research and 
Treatment of Cancer (EORTC) Quality of 
Life Questionnaire Core 30 items (QLQ-
C30) global health status/quality of life 
(QoL).
EORTC QLQ-C30 global health status/QoL 
score.
TTD, defined as the time from baseline to 
the first onset of PRO deterioration in
EORTC QLQ-C30 global health status/QoL 
score.
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
To identify molecular (genomic, metabolic, 
or proteomic) biomarkers that may be 
indicative of clinical response/resistance, 
safety, and/or the mechanism of action of 
pembrolizumab and lenvatinib in all 
participants.
Molecular (genomic, metabolic, or
proteomic) determinants of response or 
resistance to treatments, using blood and/or 
tumor tissue.
To assess the pharmacokinetics (PK) of 
lenvatinib when co-administered with 
pembrolizumab.
Population PK parameters including 
clearance, volume of distribution, and 
absorption rate constant.
To compare pembrolizumab + lenvatinib to 
pembrolizumab + placebo with respect to 
PFS per iRECIST (RECIST 1.1 for immune-
based therapeutics) by investigator.
PFS, defined as the time from 
randomization to the first documented 
progressive disease (PD) or death from any 
cause, whichever occurs first.
To evaluate changes in PROs from baseline 
using the following instruments:

EORTC QLQ-C30
European Quality of Life Five 
Dimensional Five-Level Questionnaire 
(EuroQoL [EQ]-5D-5L).
Change in PROs from baseline in 

Scores for the multi-item and single-
item scales of the EORTC QLQ-C30

EQ-5D-5L visual analog scale (VAS) 
score.
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4
STUDY DESIGN
4.1
Overall Design
NOTE: As of Amendment 011-03, all text in this section relating to lenvatinib/placebo is 
no longer applicable.
This is a randomized, placebo-controlled, parallel-group, multi-site, double-blind study of 
pembrolizumab + lenvatinib in cisplatin-ineligible participants whose tumors express PD-L1 
(CPS ≥10), and in participants ineligible for any platinum-containing chemotherapy, with 
advanced/unresectable or metastatic UC. This Phase 3 study will be conducted in participants 
with measurable disease who provide tumor tissue (newly obtained or archival formalin-
fixed paraffin-embedded [FFPE] tumor biopsy) for determination of PD-L1 expression, as 
assessed with the diagnostic IHC 22C3 pharmDx at the central laboratory. Participants will 
be randomized 1:1 to Arm 1 (pembrolizumab + lenvatinib) or Arm 2 (pembrolizumab + 
placebo).
The original study design is shown in Figure 1 (Initial Treatment) and Figure 2 (Second 
Course). The current study design is shown in Figure 3 and Figure 4.
Approximately 694 participants will be enrolled. As of Amendment 011-03, approximately 
487 participants have been randomized and no additional participants will be randomized. 
Stratification factors for this study are:

Ineligible for any platinum-containing chemotherapy, PD-L1 CPS ≥10, ECOG PS 2

Ineligible for any platinum-containing chemotherapy, PD-L1 CPS <10, ECOG PS 2

Cisplatin-ineligible, PD-L1 CPS ≥10, ECOG PS 2

Cisplatin-ineligible, PD-L1 CPS ≥10, ECOG PS 0 or 1
Imaging assessments will include chest CT, abdomen, and pelvis CT/MRI and bone 
scintigraphy at baseline, repeated based on the initial result or symptoms. The timing of 
imaging assessments is given in the SoA (Sections 1.3.1 and 1.3.2) and in Section 8.2.1. 
Note: As of Amendment 011-04, participants who either completed pembrolizumab 
administration or discontinue pembrolizumab will discontinue from the study following 
the Safety Follow-up visit (Section 8.10.5). AEs and spontaneously reported pregnancies 
will be reported and followed as described under Section 8.4. All participants in Efficacy 
Follow-up prior to initiation of Amendment 011-04 will stop efficacy assessments and be 
discontinued from the study. All participants in Survival Follow-up prior to initiation of 
Amendment 011-04 are considered to have completed the study and should have a final 
survival contact; these participants will no longer be contacted for survival information.
During initial treatment, participants who have been receiving study intervention for 
≥24 weeks (8 cycles) and who attain a CR may consider stopping pembrolizumab treatment.
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If a confirmed CR per RECIST 1.1 is attained after at least 24 weeks, participants must 
receive pembrolizumab for at least 2 additional cycles after CR is first documented.
Adverse event monitoring will be ongoing throughout the study. AEs will be graded in 
severity according to the guidelines outlined in the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0.
Treatment with pembrolizumab will continue for up to 35 cycles, or until a discontinuation 
criterion (Section 7.1) is met.
Participants who stop pembrolizumab treatment after receiving 35 administrations of 
pembrolizumab, or participants who have been receiving study intervention for at least 
24 weeks, attain a confirmed CR, and stop study intervention may be eligible for up to 
17 additional cycles (approximately 1 year) of pembrolizumab upon experiencing PD. This 
retreatment is termed the Second Course Treatment phase and is only available if the study 
remains open, the participant meets the criteria in Section 8.10.3 and upon consultation with 
the Sponsor. Note: As of Amendment 011-04, Second Course will no longer be offered.
Any participant receiving Second Course treatment prior to the initiation of Amendment 011-
04 will be able to complete treatment as planned.
Pembrolizumab will be administered for a maximum of 35 cycles during initial treatment and 
17 cycles during the Second Course phase.
The study will be conducted in conformance with Good Clinical Practice (GCP).
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
NOTE: As of Amendment 011-03, all text in this section relating to lenvatinib/placebo is 
no longer applicable.
Patients with UC who are not eligible to receive cisplatin-based chemotherapy combinations 
have few options for 1L treatment of locally advanced or metastatic disease. The EORTC 
30986 study demonstrated a reasonable ORR with gemcitabine and carboplatin, but the 
median OS remained low at 5.5 months. In participants with ECOG PS 2 and either visceral 
metastases or CrCl <60 mL/min, the treatment was associated with significant toxicities and 
poor tolerance. The KEYNOTE-052 study demonstrated improved median OS with 
manageable safety in participants who were cisplatin-ineligible and had PD-L1 CPS ≥10, and 
in participants deemed too frail to receive any platinum-based combination therapy. 
Pembrolizumab monotherapy is considered a standard of care for this population.  
In addition, the use of a placebo control with the standard of care, pembrolizumab, will allow 
unbiased evaluation of the combination therapy. In Study 111, the adverse event profile of 
the combination of pembrolizumab with lenvatinib was not significantly greater than that of 
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either agent as monotherapy. This allows blinding to be an appropriate strategy for evaluation 
of the combined activity in this population with few options for treatment.
This Phase 3 study is being conducted to evaluate the efficacy and safety of pembrolizumab 
+ lenvatinib compared with pembrolizumab + placebo in locally advanced or metastatic UC,
to determine whether addition of lenvatinib will provide improvements to pembrolizumab 
monotherapy.
4.2.1
Rationale for Endpoints
Efficacy Endpoints
NOTE: As of Amendment 011-03, efficacy endpoints will be analyzed in a descriptive 
fashion, without conducting any formal comparison between treatment arms. Imaging
will no longer be assessed by BICR.
This study will use PFS per RECIST 1.1 assessed by BICR and OS as primary endpoints. 
ORR per RECIST 1.1 by BICR and DOR per RECIST 1.1 by BICR and DCR per RECIST 
1.1 by BICR will be used as 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 benefit/risk profile. The use of BICR and RECIST 1.1 to 
assess PFS is typically considered acceptable by regulatory authorities. Images will be read 
by an iCRO blinded to treatment assignment to minimize bias in response assessments. In 
addition, the final determination of radiologic progression will be based on the central 
assessment of progression, rather than on a local site assessment. The iCRO will verify 
progression by RECIST 1.1 in real time.
OS has been recognized as the gold standard for demonstration of superiority of a new 
antineoplastic therapy in randomized clinical studies.
ORR, DOR, and DCR per RECIST 1.1 by BICR are considered preliminary and supportive 
evidence of efficacy. As ancillary markers of efficacy, they are also chosen to be secondary 
endpoints in the study.  
4.2.1.1.1
Response Assessed by RECIST 1.1
As of Amendment 011-03, RECIST 1.1 will be used by the investigator when assessing 
images for efficacy measures and by the site when determining eligibility (Section 8.2.1.5). 
Although traditional RECIST 1.1 references a maximum of 5 target lesions in total and 2 per 
organ, this protocol has implemented a modification to RECIST 1.1 to allow a maximum of
10 target lesions in total and 5 per organ.
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4.2.1.1.2
iRECIST
NOTE: As of Amendment 011-03, all images will be locally assessed using RECIST 1.1 
and will no longer be submitted to the iCRO.
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
following treatment with pembrolizumab. Immunotherapeutic agents such as pembrolizumab 
may produce antitumor effects by potentiating endogenous cancer-specific immune 
responses. The response patterns seen with such an approach may extend beyond the typical 
time course of responses to cytotoxic agents, and patients treated with pembrolizumab may 
manifest a clinical response after an initial increase in tumor burden or even the appearance 
of new lesions. Thus, standard RECIST 1.1 may not provide an accurate response assessment 
of immunotherapeutic agents such as pembrolizumab. Based on an analysis of participants 
with melanoma enrolled in KEYNOTE-001, 7% of evaluable participants experienced 
delayed or early tumor pseudoprogression. Of note, participants with PD per RECIST 1.1 but 
not per immune-related response criteria [Wolchok, J. D., et al 2009] had longer OS than did 
participants with PD per both criteria [Hodi, F. S., et al 2014]. Additionally, the data suggest 
that RECIST 1.1 may underestimate the benefit of pembrolizumab in approximately 15% of 
patients. These findings support the need to apply a modification to RECIST 1.1 that takes 
into account the unique patterns of atypical responses to immunotherapy and enables 
treatment beyond initial radiographic progression, if the patient is clinically stable.
Modified RECIST 1.1 (iRECIST) has been developed and published by the RECIST 
Working Group with input from leading experts from industry and academia, along with 
participation from the US Food and Drug Administration and the EMA (European Medicines 
Agency) [Seymour, L., et al 2017]. Unidimensional measurement of target lesions, 
qualitative assessment of nontarget lesions, and response categories are identical to RECIST 
1.1, until progression occurs per RECIST 1.1. However, if a patient is clinically stable, 
additional imaging may be performed to confirm radiographic progression. iRECIST will be 
used by investigators to assess tumor response and progression and make treatment 
decisions.
Safety Endpoints
Safety parameters commonly used for evaluating investigational systemic anticancer 
treatments are included as safety endpoints, including but not limited to the incidence of, 
causality, and outcome of AEs/serious AEs (SAEs) and changes in vital signs and laboratory 
values. Adverse events will be assessed as defined by NCI CTCAE, Version 4.0.
Rationale for Patient-reported Outcomes
NOTE: As of Amendment 011-03, ePRO assessments will no longer be collected.
Symptomatic improvement is considered a clinical benefit and is accepted by health 
authorities. As part of the analyses for this study, participants will provide information 
regarding their health-related QoL via the EORTC QLQ-C30 and EQ-5D-5L questionnaires. 
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The EORTC QLQ-C30 and EQ-5D-5L PROs are not pure efficacy or safety endpoints 
because they are affected by both disease progression and treatment tolerability.
4.2.1.3.1
EORTC QLQ-30
The EORTC QLQ-C30 is a psychometrically and clinically validated instrument appropriate 
for assessing health-related QoL in oncology studies [Aaronson, N. K., et al 1993]. EORTC 
QLQ-C30 is the most widely used cancer-specific, health-related QoL instrument, which 
contains 30 items and measures 5 functional dimensions (physical, role, emotional, cognitive, 
and social), 3 symptom items (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, 
sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), and a global 
health status/QoL scale [Aaronson, N. K., et al 1993]. 
4.2.1.3.2
EQ-5D-5L
The EuroQoL 5-Dimensional 5-Level (EQ-5D-5L) is a standardized instrument for use as a 
measure of health outcome and will provide data for developing health utilities to be used in 
health economic analyses [Rabin, R. and de Charro, F. 2001]. The 5 health state dimensions 
in EQ-5D-5L are mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Each dimension is rated on a 5-point scale from 1 (no problem) to 5 
(unable to/extreme problems). EQ-5D-5L also includes a graded (0 to 100) vertical VAS on 
which the participant rates his or her general state of health at the time of the assessment. 
This instrument has been used extensively in cancer studies, and published results from these 
studies support its validity and reliability [Pickard, A. S., et al 2007].
Pharmacokinetic Endpoints
NOTE: As of Amendment 011-03, samples for PK and ADA assessments will no longer
be collected.
Based on PK data obtained in this study and from other studies, a population PK analysis of 
lenvatinib when co-administered with pembrolizumab will be performed to characterize PK 
parameters and support the proposed dosing regimen.
Standard PK parameters of clearance and volume of distribution at steady state are planned to 
be calculated for lenvatinib in this study, using the accepted mixed effects modeling 
approach. PK data from this study may be combined with data from other studies and 
analyzed using standard population PK techniques to further characterize basic PK 
parameters, explore the exposure/response relationship for lenvatinib antitumor activity, 
evaluate the effect of extrinsic and intrinsic factors in support of the proposed dosing 
regimen, and evaluate safety in the proposed participant population.
Pharmacodynamic Endpoints
No pharmacodynamic endpoints are planned for this study.
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Planned Exploratory Biomarker Research
As of Amendment 011-03, samples for exploratory biomarker research will no longer 
be collected.
Cancer immunotherapies represent an important and novel class of antitumor agents. 
However, the mechanism of action of these exciting new therapies, including novel 
combinations with antiangiogenesis therapy, is not completely understood and much remains 
to be learned regarding how best to leverage these new drugs in treating patients. Thus, to aid 
future patients, it is important to investigate the determinants of response or resistance to 
cancer immunotherapy and other treatments administered, as well as determinants of AEs in 
the course of our clinical studies. These efforts may identify novel predictive/PD biomarkers 
and generate information that may better guide single-agent and combination therapy with 
immuno-oncology drugs. To identify novel biomarkers, biospecimens (ie, blood components, 
tumor material) will be collected to support analyses of cellular components (eg, protein, 
DNA, RNA, metabolites) and other circulating molecules. Investigations may include but are 
not limited to:
Germline (blood) genetic analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing)
This research may evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
predict efficacy or AEs, the data might inform optimal use of therapies in the patient 
population. Furthermore, it is important to evaluate germline DNA variation across the 
genome in order to interpret tumor-specific DNA mutations.
Genetic (DNA) analyses from tumor
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (ie, mutations, methylation 
status, microsatellite instability) contributing towards the development/progression of cancer 
and/or driving response to therapy. Key molecular changes of interest to immuno-oncology 
drug development include the mutational burden of tumors and the clonality of T-cells in the 
tumor microenvironment. Increased mutational burden (sometimes referred to as a ‘hyper-
mutated’ state) may generate neo-antigen presentation in the tumor microenvironment. To 
conduct this type of research, it is important to identify tumor-specific mutations that occur 
across all genes in the tumor genome. Evaluation of molecular targets and signaling 
pathways including angiogenesis- or and growth factor related signaling pathways related to 
pembrolizumab and lenvatinib may also be explored. Thus, genome-wide approaches may be 
used for this effort. Note that in order to understand tumor-specific mutations, it is necessary 
to compare the tumor genome with the germline genome. Circulating tumor DNA and/or 
RNA may also be evaluated from blood samples.
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Tumor and blood RNA analyses
Both genome-wide and targeted messenger RNA (mRNA) expression profiling and 
sequencing in tumor tissue and in blood may be performed to define gene signatures that 
correlate to clinical response to treatment with pembrolizumab or other immunotherapies. 
Pembrolizumab induces a response in tumors that likely reflects an inflamed/immune 
phenotype. Specific immune-related gene sets (ie, those capturing interferon-gamma 
transcriptional pathways) may be evaluated and new signatures may be identified. Individual 
genes related to the immune system and growth factor signaling pathways (eg, VEGF and 
FGF) may also be evaluated. MicroRNA profiling may also be pursued as well as exosomal 
profiling.
Proteomics and immunohistochemistry (IHC) using blood or tumor
Tumor and blood samples from this study may undergo proteomic analyses (eg, PD-L1 IHC). 
PD-L1 protein level in tumor sections, assessed by IHC, has been shown to correlate with 
response to pembrolizumab in patients with NSCLC, and an in vitro diagnostic (IVD) device 
has been developed for use with pembrolizumab in NSCLC. Preliminary data indicates that 
this association may also be true in additional cancer types (ie, triple negative breast cancer, 
head and neck, and gastric). Additional tumor or blood-derived proteins may also correlate 
with response to pembrolizumab and lenvatinib combination therapy. Therefore, tumor tissue 
may be subjected to proteomic analyses using a variety of platforms that could include but 
are not limited to immunoassays and liquid chromatography/mass spectrometry. This 
approach could identify novel protein biomarkers that could aid in patient selection for 
pembrolizumab (MK-3475) and lenvatinib combination therapy.
Other blood-derived biomarkers
In addition to expression on the tumor tissue, PD-L1, circulating cytokines and angiogenic 
factors, and other tumor derived proteins can be shed from tumor and released into the blood. 
Assays such as enzyme-linked immunoassay (ELISA) measure such proteins in serum. 
Correlation of expression with response to pembrolizumab and lenvatinib combination 
therapy may identify new approaches for predictive biomarkers in blood, representing a 
major advance from today’s reliance on assessing tumor biomarkers. This research would 
serve to develop such assays for future clinical use.
Other molecular changes of interest include the subtype of T-cells in the tumor 
microenvironment. The T-cell repertoire from tumor tissue and blood components may be 
evaluated.
4.2.2
Rationale for the Use of Placebo
NOTE: As of Amendment 011-03, this section is no longer applicable.
The use of a placebo in combination with pembrolizumab will ensure the objectivity of the 
local investigators’ treatment decision and AE causality assessments.
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4.3
Justification for Dose
4.3.1
Lenvatinib
NOTE: As of Amendment 011-03, this section is no longer applicable.
The dosing regimen of lenvatinib was selected based on the results of the Phase 1b portion of 
Phase 1b/2 Study 111/KEYNOTE-146, the primary endpoint of which was to determine the 
MTD and RP2D for lenvatinib in combination with pembrolizumab 200 mg Q3W. Thirteen 
participants (lenvatinib 24 mg/day + pembrolizumab 200 mg IV Q3W: n=3; lenvatinib 
20 mg/day + pembrolizumab 200 mg: n=10) were enrolled 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 IV Q3W 
(1 participant had Grade 3 arthralgia, and another had Grade 3 fatigue); hence, this was 
defined as the toxic dose. No DLTs were reported in the next 10 participants (expansion 
part), all of whom received the lenvatinib 20 mg/day + pembrolizumab 200 mg Q3W dose.
Based on review of all of the clinical data from these 13 participants, the MTD and RP2D 
were determined to be 20 mg 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.The safety and efficacy of the combination of pembrolizumab and lenvatinib at the 
lenvatinib RP2D are being assessed in the Phase 2 portion of this study that includes 6 
cohorts (NSCLC, RCC, endometrial carcinoma, UC, melanoma, and squamous cell 
carcinoma of the head and neck). 
4.3.2
Pembrolizumab
The planned dose of pembrolizumab for this study is 200 mg Q3W. Based on the totality of 
data generated in the Keytruda development program, 200 mg Q3W is the appropriate dose 
of pembrolizumab for adults across all indications and regardless of tumor type. As outlined 
below, this dose was justified by:

Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W)

Clinical data showing meaningful improvement in benefit-risk including OS at 200 mg 
Q3W across multiple indications

Lack of clinically relevant effect of tumor burden or indication on distribution behavior 
of pembrolizumab, as assessed by the population pharmacokinetics (PopPK) model

Pharmacology data showing full target saturation in both systemic circulation (inferred 
from PK data) and tumor (inferred from physiologically-based PK analysis) at 200 mg 
Q3W
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Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and NSCLC, covering different disease settings (treatment-naïve, previously 
treated, PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and 
in combination with chemotherapy). Five studies compared 2 mg/kg Q3W versus 10 mg/kg 
Q3W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies 
compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and 
KN006). All of these studies demonstrated flat dose- and exposure-response relationships 
across the doses studied representing an approximate 5- to 7.5-fold difference in exposure. 
The 2 mg/kg (or 200 mg fixed dose) Q3W provided similar responses to the highest doses 
studied. Subsequently, flat dose-exposure-response relationships were also observed in other 
tumor types including head and neck cancer, UC, gastric cancer and classical Hodgkin 
lymphoma, confirming 200 mg Q3W as the appropriate dose independent of the tumor type. 
These findings are consistent with the mechanism of action of pembrolizumab, which acts by 
interaction with immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W. Second, a physiologically-based PK analysis was conducted to predict tumor PD-1 
saturation over a wide range of tumor penetration and PD-1 expression. This evaluation 
concluded that pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood 
and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that fixed dosing 
provides similar control of PK variability as weight-based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and the 2 mg/kg Q3W 
dose. Supported by these PK characteristics and given that a fixed dose has advantages of 
reduced dosing complexity and reduced potential for dosing errors, the 200 mg Q3W fixed 
dose was selected for evaluation across all pembrolizumab protocols.
Information on pembrolizumab dose modification is in Section 6.6.1.
4.3.3
Maximum Dose/Exposure for This Study
The maximum dose/exposure of pembrolizumab allowed in this study is 200 mg IV Q3W for 
up to 2 years (35 cycles) of initial treatment (Section 8.10.2), and for up to 1 year (17 cycles) 
of Second Course treatment (Section 8.10.3).
4.4
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
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Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study, if available.
4.4.1
Clinical Criteria for Early Study Termination
The study may be terminated early if the extent (incidence and/or severity) of emerging 
effects/clinical endpoints is such that the risk/benefit ratio 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.
Ample notification will be provided in the event of Sponsor decision to no longer supply 
pembrolizumab.
5
STUDY POPULATION
The study population includes cisplatin-ineligible participants whose tumors express PD-L1 
(CPS ≥10), and participants ineligible to receive any platinum-containing chemotherapy 
regimen, with advanced/unresectable or metastatic UC.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
To be eligible for inclusion in this study, the participant must:
1. Have a histologically or cytologically confirmed diagnosis of advanced/unresectable 
(inoperable) or metastatic urothelial carcinoma of the renal pelvis, ureter (upper urinary 
tract), bladder, or urethra. Both transitional cell and mixed transitional/nontransitional 
cell histology are allowed, but transitional cell carcinoma must be the predominant 
histology.
2. Have at least 1 measurable target lesion per RECIST 1.1 as assessed by the local site 
investigator/radiologist, per the following criteria: 1) lymph node (LN) lesion measuring 
≥15 mm in the short axis; 2) non-nodal lesion measuring ≥10 mm in the longest diameter; 
3) lesion suitable for repeat measurement with CT/MRI imaging. Lesions in a previously 
irradiated area are considered measurable if progression has been demonstrated in such 
lesions.
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3. Have provided an archival tumor tissue sample or newly obtained core or excisional 
biopsy of a tumor lesion not previously irradiated and adequate for PD-L1 evaluation. 
Formalin-fixed, paraffin-embedded tissue blocks are preferred to slides. Newly obtained 
biopsies are preferred to archived tissue. PD-L1 status (CPS ≥10 or CPS <10) must be 
obtained by the central laboratory during the screening period prior to enrollment.

Note: If submitting unstained cut slides, newly cut slides should be submitted to the 
testing laboratory within 14 days from the date they are cut (details pertaining to 
tumor submission are in the Procedures Manual).

Note: If PD-L1 is not evaluable (eg, not enough tissue is provided, or the tissue is of 
poor quality, such that assessment of PD-L1 status is not possible) the participant will 
be excluded.
4. Have received no prior systemic chemotherapy for advanced or metastatic UC with the
following exceptions:

Neoadjuvant platinum-based chemotherapy for treatment of muscle-invasive bladder 
cancer with recurrence >12 months from completion of the therapy is permitted.

Adjuvant platinum-based chemotherapy following radical cystectomy, with 
recurrence >12 months from completion of the therapy, is permitted.
Note: Low-dose chemotherapy (eg, low-dose cisplatin, cisplatin plus 5-FU, mitomycin 
plus 5-FU, or cisplatin plus paclitaxel), given concurrently with radiation to the primary 
tumor site for curative intent treatment of muscle-invasive bladder cancer, is not 
considered systemic therapy. In the clinical setting, chemotherapy is given with the sole 
purpose of sensitizing the tumor to local radiation and is not administered at doses with 
any systemic efficacy. Surgery is not considered 1L therapy following diagnosis of 
advanced/metastatic disease.
5. Meet criteria for either option a or option b (below): 
a.
Have a tumor(s) with PD-L1 CPS ≥10 and be considered ineligible to receive 
cisplatin-based combination therapy, based on 1 of the following:

ECOG PS 2 (Appendix 9) within 7 days prior to randomization

CrCl (calculated or measured using the institutional standard) ≥30 to ≤60 mL/min

NCI CTCAE Version 4.0 Grade ≥2 audiometric hearing loss 

NCI CTCAE Version 4.0 Grade ≥2 peripheral neuropathy 
OR
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b. In the opinion of the investigator, be considered ineligible to receive any platinum-
based chemotherapy (ie, ineligible for cisplatin and carboplatin) based on:

ECOG PS 2 within 7 days prior to randomization.
And at least 1 of the following: 

Documented visceral metastatic disease

CrCl ≥30 to ≤60 mL/min

NCI CTCAE Version 4.0 Grade ≥2 audiometric hearing loss

NCI CTCAE Version 4.0 Grade ≥2 peripheral neuropathy

Other reason, identified on the case report form (CRF), for the participant’s being 
unable to receive both cisplatin and carboplatin safely. Additional criteria for 
platinum ineligibility will be considered and allowed on a case-by-case basis, 
following consultation with the Sponsor.
Note: Participants considered ineligible for any platinum-based chemotherapy are 
eligible for this study regardless of their tumor PD-L1 status.
Note:  The reason(s) for ineligibility for cisplatin or any platinum-based chemotherapy 
must be documented in the participant’s medical record and on the electronic case report 
form (eCRF).
Demographics
6. Be male or female and ≥18 years of age and considered an adult per local regulations on 
the day of signing the informed consent.
7. Have ECOG PS 0, 1, or 2 within 7 days prior to randomization and a life expectancy of 
≥3 months.
Male Participants
8. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 30 days after the last dose of pembrolizumab or 
lenvatinib/placebo:  

Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
OR
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
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.
Please note that 30 days after lenvatinib/placebo is stopped, if the participant is on 
pembrolizumab only, no male contraception measures are needed.
Female Participants
9. A female participant is eligible to participate if she is not pregnant or breastfeeding and at 
least one of the following conditions applies:

Is not a WOCBP.
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year) with low user dependency or be abstinent from heterosexual 
intercourse as her preferred and usual lifestyle (abstinent on a long term and 
persistent basis), as described in Appendix 5 during the intervention period and for at 
least 120 days post pembrolizumab or 30 days post lenvatinib/placebo. The 
investigator should evaluate the potential for contraceptive method failure (ie, 
noncompliance, recently initiated) in relationship to the first dose of study 
intervention.

A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as 
required by local regulations) within 24 hours before the first dose of study 
intervention.

If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.

Additional requirements for pregnancy testing during and after study intervention are in 
Appendix 2.

The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk of including a woman with an early undetected 
pregnancy.
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Informed Consent
10. The participant (or legally acceptable representative if applicable) provides documented
informed consent for the study.
Medical History and Laboratory Values
11. Have adequately controlled BP with or without antihypertensive medications, defined as 
BP ≤150/90 mm Hg at screening and no change in antihypertensive medications within 
1 week prior to randomization.
12. Have adequate organ function as defined in Table 1.
Note: Specimens must be collected within 7 days before the start of study intervention.
Subjects may be enrolled based on local laboratory results pending central laboratory 
results.
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Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematologic
Absolute neutrophil count 
≥1500/µL
Platelets
≥100,000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/La
Renal
Creatinine or measured or calculatedb CrCl 
(GFR can be used in place of creatinine or 
CrCl)
≤1.5 × ULN OR ≥30 mL/min for participants with 
creatinine >1.5 × institutional ULN
Hepatic
Total bilirubin
≤1.5 × ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with liver 
metastases)
Coagulation
International normalized ratio (INR) or 
prothrombin time (PT)
Activated partial thromboplastin time 
(aPTT)
≤1.5 × ULN unless the participant is receiving 
anticoagulants, as long as PT or aPTT is within 
the therapeutic range for intended use of 
anticoagulants
Abbreviations: ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); 
AST (SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic transaminase); CrCl = creatinine 
clearance; GFR = glomerular filtration rate; ULN = upper limit of normal.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for administration of specific 
chemotherapies.
aThis criterion must be met without erythropoietin dependency and without packed red blood cell transfusion 
within the last 2 weeks.
bCrCl should be calculated per the institutional standard.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has disease that is suitable for local therapy administered with curative intent (eg, 
chemotherapy and radiation for Stage 3 disease). 
2. Has tumor with any neuroendocrine or small cell component.
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3. Has a history of a gastrointestinal condition or procedure (eg, gastric bypass, 
malabsorption) that, in the opinion of the investigator, may affect oral drug absorption.
4. Has had major surgery within 3 weeks prior to the first dose of study intervention.
Note: Adequate wound healing after major surgery must be assessed clinically, 
independent of time elapsed for eligibility.
5. Has a pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula.
6. Has radiographic evidence of major blood vessel invasion/infiltration or has had 
clinically significant hemoptysis (at least 0.5 teaspoon of bright red blood) or tumor 
bleeding within 2 weeks prior to the first dose of study intervention. The degree of tumor 
invasion/infiltration of major blood vessels should be considered because of the potential 
risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib 
therapy.
7. Has had significant cardiovascular impairment within 12 months of the first dose of study 
intervention, such as history of NYHA >Class II congestive heart failure, unstable 
angina, myocardial infarction or cerebrovascular accident (CVA)/stroke, cardiac 
revascularization procedure, or cardiac arrhythmia associated with hemodynamic 
instability.
8. Has known intolerance or severe hypersensitivity (Grade ≥3) to pembrolizumab or 
lenvatinib or any of their excipients.
9. Has received lenvatinib as monotherapy or in combination with a PD-1/PD-L1 inhibitor 
or has previously been enrolled in a clinical study evaluating lenvatinib for bladder 
cancer, regardless of the treatment received.
10. Is a WOCBP who has a positive urine pregnancy test within 24 hours before 
randomization (see Appendix 5). If the urine test is positive or cannot be confirmed as 
negative, a serum pregnancy test is required. In such cases, the participant must be 
excluded from participation if the serum pregnancy test result is positive. If >24 hours 
have elapsed between the screening pregnancy test and the first dose of study 
intervention, another pregnancy test (urine or serum) must be performed and must be 
negative for the participant to start receiving study intervention.
Prior/Concomitant Therapy
11. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 inhibitor, 
indoleamine-pyrrole 2,3 dioxygenase (IDO1) inhibitor, or agent directed to another 
stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137), or any other
antibody or drug targeting T-cell costimulatory pathways in the adjuvant or 
advanced/metastatic setting.
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12. Has received prior radiotherapy to a metastatic site without the use of chemotherapy 
radiosensitization within 3 weeks of the first dose of study intervention, with the 
exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 
weeks before the start of study intervention. Participants must have recovered from all 
radiation-related toxicities and must not require corticosteroids.  
13. Has received a live vaccine within 30 days prior to the first dose of study intervention
(see Appendix 7 for UK-specific study requirements). Examples of live vaccines include, 
but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken 
pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. 
Seasonal influenza vaccines for injection are generally killed virus vaccines and are 
allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated 
vaccines and are not allowed.
14. In the investigator’s judgment, has not recovered from toxicity or other complications 
from any major surgery prior to starting study intervention.
Prior/Concurrent Clinical Study Experience
15. Is currently participating in or has participated in a trial of an investigational agent or has 
used an investigational device within 4 weeks prior to the first dose of study intervention.
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
Diagnostic Assessments
16. Has an LVEF below the institutional normal range, as determined by MUGA or ECHO.
17. Has history or presence of an abnormal ECG that, in the investigator’s opinion, is 
clinically meaningful. Participants with QTcF >480 msec are excluded. If a single QTcF 
is >480 msec, the participant may be enrolled if the average QTcF for 3 ECGs is <480 
msec.
18. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (at a dose 
exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to randomization.
19. Has had an active malignancy (except locally advanced or metastatic UC) within the past 
36 months.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) who have 
undergone potentially curative therapy are not excluded. 
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
A history of prostate cancer (T2NXMX or lower with Gleason score ≤7) treated with 
definitive intent (surgically or with radiation therapy) at least 1 year prior to study 
entry is acceptable, provided that the participant is considered prostate cancer-free 
and the following criteria are met:

Participants who have undergone radical prostatectomy must have undetectable
prostate-specific antigen (PSA) for >1 year and at screening.

Participants who have had radiation must have a PSA doubling time >1 year 
(based on at least 3 values determined >1 month apart) and a total PSA value
which does not meet Phoenix criteria for biochemical recurrence (ie, <2.0 ng/mL
above nadir).

Participants with untreated low-risk prostate cancer (Gleason score ≤6) on active 
surveillance with PSA doubling time >1 year (based on at least 3 values determined 
>1 month apart) are also eligible.  
20. Has central nervous system (CNS) metastases, unless the participant has completed local 
therapy (eg, whole brain radiation therapy, surgery, or radiosurgery) and has discontinued 
use of corticosteroids for this indication for at least 4 weeks before starting treatment in 
this study. Any signs (eg, radiologic) or symptoms of CNS metastases must be stable for 
at least 4 weeks before starting study intervention.
21. Has an active autoimmune disease that has required systemic treatment in the past 2 years 
(ie, with disease-modifying agents, corticosteroids, or immunosuppressive drugs). 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment and is allowed.
22. Has a history of (non-infectious) pneumonitis that required systemic steroids, or current 
pneumonitis.
23. Has an active infection requiring systemic therapy.
24. Has a known history of human immunodeficiency virus (HIV) infection. Testing is not 
required unless mandated by the local health authority (see Appendix 7 for Germany- and 
UK-specific study requirements).
25. Has a known history of or is positive for active hepatitis B (hepatitis B surface antigen 
[HbsAg] reactive) or has active hepatitis C (HCV RNA). Testing is not required unless 
mandated by the local health authority (see Appendix 7 for Germany- and UK-specific 
study requirements).
26. Has active tuberculosis (see Appendix 7 for Germany-specific study requirements).
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27. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant’s participation 
for the full duration of the study, or is not in the best interest of the participant to 
participate, in the opinion of the treating investigator.
28. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
29. Is receiving hemodialysis.
30. A participant with >1+ proteinuria on urinalysis at screening will undergo 24-hour urine 
collection for quantitative assessment of proteinuria. A participant with urine protein 
≥1 g/24 h will be excluded.   
Other Exclusions
31. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 120 days after 
the last dose of pembrolizumab and lenvatinib/placebo.
32. Has had an allogeneic tissue/solid organ transplant.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention will not be replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (pembrolizumab) 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: As of Amendment 011-03, only pembrolizumab will be administered. Other 
study treatments (prior to this amendment) have been deleted. 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
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Treatment 
Period
Use
IMP/
NIMP
Sourcing
Arm 1
and 2
Experimental
Pembrolizumab
Biological/
Vaccine
Solution for 
Infusion
25 mg/mL
200 mg
IV Infusion
Q3W
Background 
Treatment
IMP
Central
Abbreviations: IV = intravenous; Q3W = every 3 weeks.
Definition of Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) is based on guidance issued by the European Commission. Regional 
and/or Country differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed.
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All supplies indicated in Table 2 will be provided per the “Sourcing” column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc.).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.1.1
Medical Devices
Not applicable.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
NOTE: As of Amendment 011-03, text in this section relating to dose modification of 
lenvatinib/placebo is no longer applicable and has been deleted.
Details of the preparation, storage, and administration of pembrolizumab are provided in the 
Pharmacy Manual. 
The rationale for selection of doses to be used in this study is in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
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
NOTE: As of Amendment 011-03, this section is no longer applicable and all 
participants will receive open-label pembrolizumab.
Intervention allocation/randomization will occur centrally using an interactive response 
technology (IRT) system. There are 2 study intervention arms. Participants will be assigned 
randomly in a 1:1 ratio to pembrolizumab + lenvatinib or to pembrolizumab + placebo, 
respectively.
6.3.2
Stratification
Stratification factors for this study are:

Ineligible for any platinum-containing chemotherapy, PD-L1 CPS ≥10, ECOG PS 2

Ineligible for any platinum-containing chemotherapy, PD-L1 CPS <10, ECOG PS 2

Cisplatin-ineligible, PD-L1 CPS ≥10, ECOG PS 2

Cisplatin-ineligible, PD-L1 CPS ≥10, ECOG PS 0 or 1.
6.3.3
Blinding
NOTE: As of Amendment 011-03, blinding is no longer applicable – all participants will 
receive open-label pembrolizumab monotherapy.
See Section 8.1.10 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
Lenvatinib/Placebo
NOTE: As of Amendment 011-03, this section is no longer applicable.
Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study, if available. A double-blinding technique with in-house 
blinding will be used. Lenvatinib and placebo will be packaged identically so that the blind is 
maintained. The participant, the investigator, and Sponsor personnel or delegate(s) who are 
involved in the study intervention administration or clinical evaluation of the participants are 
unaware of the intervention assignments.
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Pembrolizumab
Pembrolizumab will be administered open label; therefore, its identity will be known by the 
participant, the investigator, the Sponsor, and delegate(s) involved in study intervention 
administration or clinical evaluation of participants.
CPS Results
Investigators will be alerted to completion of a participant’s PD-L1 evaluation, as well as to 
instances where the tumor tissue sample is inadequate for PD-L1 evaluation (not evaluable). 
For cisplatin-ineligible participants, the investigator will be blinded to the central vendor’s 
PD-L1 CPS results.  However, the investigator will be informed of, and accordingly
unblinded to, the PD-L1 CPS category (ie, PD-L1 CPS ≥10 or <10). The inclusion criterion
for cisplatin-ineligible participants states a requirement for PD-L1 CPS ≥10.
Cisplatin-ineligible participants with PD-L1 CPS <10 will be excluded from the study.  Note: 
Participants with PD-L1 considered to be below detectable levels will be included in the CPS 
<10 category.  
For platinum-ineligible participants, the investigator will be blinded to the central vendor’s 
PD-L1 CPS results, in an attempt to reduce bias from treatment decisions. The Sponsor 
acknowledges that, due to the commercial availability of PD-L1 testing assays, it is possible 
that the investigator may know a participant’s CPS prior to screening. This risk is seen as 
acceptable, as the treatment interventions are hypothesized to provide benefit regardless of 
CPS.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment plan for >12 weeks for pembrolizumab
require consultation between the investigator and the Sponsor and written documentation of 
the collaborative decision on participant management.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the treatment period. If there is a clinical indication for any medication or vaccination 
that is specifically prohibited, please consult the Sponsor; discontinuation from study 
intervention may be required. 
Medication considered necessary for the participant’s health and not expected to interfere 
with the evaluation of or interact with the study medication may be continued during the 
study. Palliative and supportive care is permitted during the study for underlying medical 
conditions and symptom management. Surgery for tumor control is not permitted during the 
study. 
Palliative radiotherapy is permitted to a single lesion if considered medically necessary by 
the treating physician, as long as the lesion is NOT a RECIST 1.1-defined target lesion and 
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radiotherapy is NOT administered for tumor control. Study intervention should be withheld 
during the course of palliative radiotherapy and should be resumed no earlier than the next 
scheduled administration of study intervention. Specific details of the radiation therapy, 
including location, will be recorded. The investigator should discuss any questions regarding 
radiation therapy with the Sponsor. 
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
the participant’s primary physician. However, the decision to continue the participant’s 
receiving study intervention requires mutual agreement of the investigator, the Sponsor, and 
the participant.
All concomitant medications (including over-the-counter medications) administered to the 
participant during the course of the study will be reviewed. Concomitant medications 
administered throughout the Initial or Second Course phase and until study intervention 
discontinuation should be reviewed per SOC or as clinically indicated, and are required to be 
recorded on the appropriate CRF when an AE of special interest (AEOSI), SAE or event of 
clinical interest (ECI) occurs.
Additionally, all diagnostic, therapeutic, or surgical procedures relating to malignancy should 
be recorded. 
6.5.1
Allowed Concomitant Medications
Treatment of complications or AEs, or therapy to ameliorate symptoms (including blood 
products, blood transfusions, fluid transfusions, antibiotics, and antidiarrheal drugs), may be 
given at the discretion of the investigator, unless it is expected to interfere with the evaluation 
of (or to interact with) the study medication. Anti-emetic or any other prophylaxis should be 
considered in accordance with institutional guidelines.
The following concomitant medications are also allowed:

Hormone replacement therapy

Thyroid hormone suppressive therapy

Anticoagulants including low molecular weight heparin, warfarin, anti-Xa agents

Anti-inflammatory agents

Bisphosphonates or denosumab

Antihypertensive therapy (including additional antihypertensive treatment as appropriate 
if BP increases once the participant is enrolled)
Note: Any additional procedural or participant-specific particularities should be discussed 
with the investigator and the Sponsor.
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6.5.2
Prohibited Concomitant Medications
Participants are prohibited from receiving the following therapies during the screening and 
treatment periods of this study:

Concurrent anticancer therapies such as chemotherapy, targeted therapies, antitumor 
interventions (surgical resection, surgical tumor debulking, etc.), or cancer 
immunotherapy not specified in this protocol
-
Note: Topical anticancer agents to treat skin lesions (eg, in situ melanoma or 
squamous cell carcinoma) are allowed, excluding skin metastasis of melanoma.

Other concurrent investigational drugs.

Live vaccines within 30 days and while participating in the study (see Appendix 7 for 
UK-specific study requirements). Examples of live vaccines include, but are not limited 
to, measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) 
vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and 
are allowed. However, intranasal influenza vaccines (eg, FluMist®) are live attenuated 
vaccines, and are not allowed.
-
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, adenoviral 
vaccines, or inactivated vaccines. These vaccines will be treated just as any other 
concomitant therapy.
Investigational vaccines (i.e., those not licensed or approved for Emergency Use) are 
not allowed.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an AE 
that is suspected to have immunologic etiology. Physiologic doses of corticosteroids not 
exceeding 10 mg daily of prednisone equivalent may be used during the study. 
-
Note:  Inhaled steroids are allowed for management of asthma or seasonal allergies. 
See Section 6.5.4 for additional information. 

Radiotherapy for disease control.
-
Palliative radiotherapy is permitted to a single lesion if considered medically 
necessary by the treating physician, as long as the lesion is NOT a RECIST 1.1-
defined target lesion and radiotherapy is NOT administered for tumor control.
For participants who, in an assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management, continuation of the study medication 
and further participation in the study must be discussed and agreed upon with the Sponsor.
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If participants receive additional anticancer therapies, this will be judged to represent 
evidence of PD, 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.
6.5.3
Drug Interactions
As pembrolizumab is an IgG antibody that is administered parenterally and cleared by 
catabolism; food and drug-drug interactions (DDI) are not anticipated to influence exposure. 
No preclinical evaluations for DDI have been performed with pembrolizumab. Please refer to 
the labeling for SOC treatments.
6.5.4
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. 
For participants receiving pembrolizumab, suggested supportive care measures for the 
management of AEs with potential immunologic etiology are outlined, along with the dose 
modification guidelines in Table 3 in Section 6.6.1.1. Where appropriate, these guidelines 
include the use of oral or IV corticosteroids, as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids. Note that several courses of 
steroid tapering may be necessary, as symptoms may worsen when the steroid dose is 
decreased. For each disorder, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional supportive 
care. The treatment guidelines are intended to be applied when the investigator determines 
the events to be related to pembrolizumab.
Note: If, after the evaluation of an event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. 
Refer to Table 3 for guidelines regarding dose modification and supportive care.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of the evaluation of an event.
6.6
Dose Modification (Escalation/Titration/Other)
6.6.1
Pembrolizumab
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 (Section 6.4).
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Immune-related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related Adverse Events 
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 3.
Of note, any serious changes to the skin, including Stevens-Johnson syndrome or toxic 
epidermal necrolysis, require immediate discontinuation of pembrolizumab.
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Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated With 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if 
the irAEs are not controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 after 
corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants for signs and symptoms of 
pneumonitis
Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment
Add prophylactic antibiotics for opportunistic 
infections
Recurrent Grade 2 
or Grade 3 or 4 
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) and of bowel 
perforation (ie, peritoneal signs and ileus)
Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and
performing endoscopy to rule out colitis
Participants with diarrhea/colitis should be advised 
to drink liberal quantities of clear fluids. If 
sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST / ALT 
Elevation or 
Increased 
Bilirubin
Grade 2
Withhold
Administer corticosteroids 
(initial dose of 0.5-1 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor with liver function tests (consider weekly 
or more frequently until liver enzyme value 
returned to baseline or is stable)
Grade 3 or 4 
Permanently 
discontinue
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure
Withhold a
Initiate insulin replacement 
therapy for participants with 
T1DM
Administer anti-
hyperglycemic in participants 
with hyperglycemia
Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue a
Hyperthyroidism 
Grade 2
Continue
Treat with non-selective 
beta-blockers (eg, 
propranolol) or thionamides 
as appropriate
Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
Permanently 
discontinue a
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidism
Grade 2-4
Continue
Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care
Monitor for signs and symptoms of thyroid 
disorders
Nephritis and 
renal dysfunction
Grade 2
Withhold
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper
Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1 
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3, or 4
Permanently 
discontinue
All Other irAEs
Persistent Grade 2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold or 
discontinue b
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT=alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 
diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
b
Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically important irAEs 
(eg, vasculitis and sclerosing cholangitis).
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Dose Modification and Toxicity Management for Infusion Reactions 
Related to Pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion reactions, including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines for pembrolizumab-associated 
infusion reactions are provided in Table 4.
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Table 4
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the investigator.
None
Grade 2
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 h
Stop Infusion.
Additional appropriate medical therapy may include but is not limited to:
-
IV fluids
-
Antihistamines
-
NSAIDs
-
Acetaminophen
-
Narcotics
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping the drug infusion, the infusion 
may be restarted at 50% of the original rate (eg, from 100 mL/h to 50 mL/h). 
Otherwise, withhold dosing until symptoms resolve, and the participant should 
be premedicated for the next scheduled dose.
Participants who develop Grade 2 toxicity despite adequate premedication 
should be permanently discontinued from further study drug treatment.
The participant may be premedicated 
1.5 h (± 30 minutes) prior to infusion of 
pembrolizumab with:
-
Diphenhydramine 50 mg PO (or 
equivalent dose of antihistamine).
-
Acetaminophen 500 to 1000 mg PO 
(or equivalent dose of analgesic).
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NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (eg, 
renal impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy may include but is not limited to:
-
Epinephrine**
-
IV fluids
-
Antihistamines
-
NSAIDs
-
Acetaminophen
-
Narcotics
-
Oxygen
-
Pressors
-
Corticosteroids
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the investigator.
Hospitalization may be indicated.
**In case of anaphylaxis, epinephrine should be used immediately.
The participant is permanently discontinued from further study drug 
treatment.
No subsequent dosing
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous; NCI = National Cancer Institute; NSAIDs=nonsteroidal anti-inflammatory 
drugs; PO = orally.
Appropriate resuscitation equipment should be available at the bedside, and a physician should be readily available during drug administration.
For further information, please refer to CTCAE v4.0 at http://ctep.cancer.gov
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6.6.2
Other Allowed Dose Interruptions for Pembrolizumab
Pembrolizumab may be interrupted for situations other than treatment-related AEs, such as 
medical/surgical events or logistic reasons not related to study therapy. Participants should be 
returned to study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in the 
participant’s study record. Imaging should not be delayed for delays in treatment cycles. 
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
NOTE: As of Amendment 011-03, this section is no longer applicable.
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.10). In the 
event that the emergency unblinding call center is not available for a given site in this study, 
the central electronic intervention allocation/randomization system (IRT) should be used to 
unblind participants and to unmask study intervention identity. The Sponsor will not provide 
random code/disclosure envelopes or lists with the clinical supplies.
6.9
Standard Policies
NOTE: As of Amendment 011-03, all participants will receive open-label 
pembrolizumab monotherapy.
At the close of the study after unblinding, a letter is to be sent by the investigator to those 
participants who received placebo in the image of the competitor’s product to provide the 
following advice:
“You have participated in a study conducted by the Sponsor. This letter is to advise you that 
you were among those who received a look-alike capsule provided by the Sponsor to 
resemble the drug lenvatinib as much as possible. You did not receive the active drug 
lenvatinib as provided by MSD.”
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
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 
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who discontinue study intervention prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 1.3 and Section 
8.10.4.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:

The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.

ALT or AST elevation meeting the following criteria:
o
ALT or AST > 5 × ULN for more than 2 weeks
o
ALT or AST > 3 × ULN and (TBL > 2 X ULN or INR > 1.5)
o
ALT or AST > 3 × ULN with appearance of fatigue, nausea, vomiting, RUQ 
pain/tenderness, fever, rash, and/or eosinophilia (>5%)

The participant interrupts study drug administration for >12 weeks for pembrolizumab, 
except if agreed to by the Sponsor.

The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, places the participant at unnecessary risk from continued 
administration of study intervention.

The participant has a confirmed positive serum pregnancy test.

Disease progression is radiographically documented per RECIST 1.1.
Note: If a participant has unconfirmed PD and is clinically stable*, the assigned study 
intervention per protocol may be continued at the investigator’s discretion until PD is 
confirmed at least 28 days from the date of imaging suggesting PD. If subsequent 
imaging does not confirm PD, the participant should continue to receive study 
intervention and imaging to monitor disease status should continue as per SOC.
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*Clinical stability is defined as:
-
Absence of symptoms and signs (including worsening of laboratory values) 
indicating clinically significant disease progression
-
No decline in ECOG performance status
-
Absence of disease progression or progressive tumor at critical anatomic sites (eg, 
cord compression) requiring urgent alternative medical intervention

The participant has intercurrent illness preventing further administration of study 
intervention.

The participant has any progression or recurrence of any malignancy, or any occurrence 
of another malignancy that requires active treatment. Exceptions to secondary 
malignancy include basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, new nonulcerated primary melanoma <1 mm in depth with no nodal involvement, 
or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone 
potentially curative therapy. Exceptions should be discussed with the Sponsor before 
continuing therapy or follow-up.

The participant has unacceptable toxicities (Section 6.6).

The investigator decides to discontinue study intervention.

The participant has recurrent Grade 2 pneumonitis.
The participants must be discontinued from pembrolizumab treatment after completing 
35 cycles of Initial Treatment (approximately 2 years) with pembrolizumab, and, if 
applicable, after 17 cycles (approximately 1 year) of Second Course treatment with 
pembrolizumab (Section 4.3.3).
Discontinuation of pembrolizumab may be considered for participants who have attained 
a confirmed CR and have been treated for at least 8 cycles (at least 24 weeks), receiving 
at least 2 doses of pembrolizumab beyond the date when the initial CR was declared.
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.  
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The investigator or qualified designee should clarify whether a participant is withdrawing 
from study intervention, follow-up visits, and/or contact. Given the importance of OS in this 
study, efforts should be made to clarify if participants are willing to be followed for survival. 
For participants unwilling to be followed for survival, a review of public records is required 
by the investigative site.
7.3
Lost to Follow-up
Note: As of Amendment 011-04, this section is no longer applicable. 
There will be no additional efforts to contact participants who are lost to follow-up.
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of maintaining 
the protocol-specified visit schedule.
The investigator or designee must make every effort to regain contact with the participant at 
each missed visit (eg, telephone calls and/or a certified letter to the participant’s last known 
mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
The investigator is responsible for ensuring that procedures are conducted by appropriately 
qualified (by education, training, and experience) staff. Delegation of study site personnel 
responsibilities will be documented in the Investigator Trial File Binder (or equivalent).
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
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Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline purposes 
provided the procedure met the protocol-specified criteria and were performed within the 
time frame defined in the SoA.
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing may 
be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations may 
require that additional informed consent be obtained from the participant. In these cases, such 
evaluations/testing will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the study 
will be provided in the Laboratory Manual. Repeat or unscheduled samples may be collected 
for safety reasons or because of technical issues with the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant or each participant’s legally 
acceptable representative prior to participating in a 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 consent is in place.
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the Institutional Review Board/Independent Ethics Committee’s 
(IRB/IEC’s) approval/favorable opinion in advance of use. The participant or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available that may be relevant to the participant’s willingness to continue participation in the 
study. The communication of this information will be provided and documented via a revised 
consent form or addendum to the original consent form that captures the participant’s dated 
signature or by the participant’s legally acceptable representative’s dated signature.
The participant or his/her legally acceptable representative will be asked to sign consent at 
the point of initial radiographic disease progression.
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Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
allocation/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
8.1.5
Prior and Concomitant Medications Review
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 30 days before the first dose of study intervention.
Concomitant Medications
The investigator or qualified designee will review all medications, if any, taken by the 
participant during the study. Concomitant medications administered throughout the Initial or 
Second Course phase and until study intervention discontinuation should be reviewed per 
SOC or as clinically indicated, and are required to be recorded on the appropriate CRF when 
an AEOSI, SAE or ECI occurs.
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8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details of screening/rescreening visit 
requirements are provided in Section 8.10.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be allocated by random assignment and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Pembrolizumab: Administration of pembrolizumab will be witnessed by the investigator 
and/or study staff and or qualified designee per institutional guidelines and procedures.
Timing of Dose Administration
Pembrolizumab: Pembrolizumab will be administered as a 30-minute IV infusion on Day 1 
of each 21-day cycle. Sites should make every effort to target the infusion time to be as close 
to 30 minutes as possible. However, given the variability of infusion pumps from site to site, 
a window of -5 minutes to +10 minutes is permitted (ie, infusion time is 30 minutes
[-5 min/+10 min]).
After Cycle 1 Day 1, pembrolizumab may be administered up to 3 days before or after the 
scheduled Day 1 of each subsequent cycle due to administrative reasons.
Compliance
Pembrolizumab: Administration of pembrolizumab will be witnessed by the investigator 
and/or qualified designee. The total volume of study intervention infused will be compared 
with the total volume prepared to determine compliance with each dose administered.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits.
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When a participant withdraws from participation in the study, all applicable activities 
scheduled for the final study visit should be performed (at the time of withdrawal). Any AEs
that are present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
8.1.10
Participant Blinding/Unblinding
NOTE: As of Amendment 011-03, blinding is no longer applicable – all participants will 
receive open-label pembrolizumab alone.
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY, FOR THE WELFARE OF THE PARTICIPANT.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity/toxicity grade of the AEs observed, the relation to study intervention, the reason 
thereof, etc., in the medical chart. If it is not possible to record this assessment in the chart 
prior to the unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
Once an emergency unblinding or a nonemergency unblinding that is part of the study design 
has taken place, the principal investigator, site personnel, and Sponsor personnel may be 
unblinded so that the appropriate follow-up medical care can be provided to the participant.
The IRT system should be used for emergency unblinding in the event that this is required 
for participant safety.
At the end of the study, random code/disclosure envelopes or lists and unblinding logs are to 
be returned to the Sponsor or designee.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
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8.1.12
Demographics
Participant demographic information will be collected at the screening visit. Demographic 
information includes date of birth (or age), sex, and race/ethnicity.
8.1.13
Subsequent Antineoplastic Treatment
The investigator or qualified designee will review all new antineoplastic treatment initiated 
after the last dose of study intervention as outlined in the SoA (Section 1.3).
8.2
Efficacy Assessments
8.2.1
Tumor Imaging and Assessment of Disease
In addition to survival, efficacy will be assessed based on imaging evaluation of changes in 
tumor burden over time, until the participant is discontinued from the study or enters survival 
follow-up. The process for image collection and transmission to the iCRO is in the Site 
Imaging Manual. CT using IV contrast (unless contraindicated) with the use of oral contrast 
as optional is strongly preferred for tumor imaging; the use of oral contrast is optional. For 
the abdomen and pelvis, contrast-enhanced MRI may be used when CT with iodinated 
contrast is contraindicated, or when mandated by local practice. MRI is the strongly preferred 
modality for imaging of the brain. The same imaging technique should be used for a 
participant throughout the study to optimize reproducibility of assessment of existing and 
new tumor burden, and to improve the accuracy of the response assessment based on 
imaging. Note: for the purposes of assessing tumor imaging, the term “investigator” refers to 
the local investigator at the site and/or the radiologic reviewer at the site or at an offsite 
facility.
NOTE: As of Amendment 011-03, images for all participants should no longer be 
submitted to the iCRO.
Treatment and imaging should continue until PD by RECIST 1.1 per investigator assessment.
Initial Tumor Imaging
Initial tumor imaging at screening must be performed within 28 days prior to the date of 
randomization. Any imaging obtained after Cycle 1 Day 1 cannot be included in the 
screening assessment. The site study team must review screening images to confirm that the 
participant has measurable disease per RECIST 1.1.
Tumor imaging performed as part of routine clinical management is acceptable as screening 
imaging if it is of diagnostic quality and performed within 28 days prior to the date of 
randomization and can be assessed by the iCRO.  
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Tumor imaging at baseline includes the following:

CT or MRI of the abdomen and pelvis

CT of the chest

Bone scan 
Bone scans must be performed to confirm CR if positive at baseline.
If brain imaging is performed to document the stability of existing metastases, MRI should 
be used if possible. If MRI is medically contraindicated, CT with contrast is an acceptable 
alternative. Note: for participants with stable brain metastases at randomization, repeat brain 
imaging must be performed to document CR.
Tumor Imaging During the Study
NOTE: As of Amendment 011-03, central review of images and iRECIST are no longer
applicable. Imaging will be performed as per local SOC guidelines; however, the data 
will not be collected. This section has been updated accordingly.
The first on-study imaging assessment should be performed at 6 weeks (42 days +7 days) 
from the date of randomization. Subsequent tumor imaging should be performed by site 
investigator/radiology assessment as per SOC for the disease and local guidelines. Imaging 
timing should follow calendar days and not be adjusted for delays in cycle starts. Imaging 
should continue to be performed until any of these conditions are met: disease progression is 
identified by the investigator, pregnancy, the start of new anticancer treatment, withdrawal of 
consent, or death.
8.2.1.2.1
Bone Imaging During the Study
A bone scan at screening will be performed in all participants within 28 days prior to 
randomization. As of Amendment 011-03, if the baseline scan is positive, subsequent scans 
will be performed by site investigator/radiology assessment as per SOC for the disease and 
local guidelines. This schedule should be followed regardless of treatment delays. If a bone 
scan was obtained within 4 weeks prior to end of treatment (EOT), a scan at EOT is not 
mandatory.  
End of Treatment and Follow-up Tumor Imaging
If previous imaging was obtained within 4 weeks prior to the date of discontinuation, 
imaging at intervention discontinuation is not mandatory. For participants who discontinue 
study intervention due to documented disease progression, this is the final required tumor 
imaging.
For participants who discontinue study intervention without documented disease progression, 
every effort should be made to obtain a final image at the end of treatment visit.
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Second Course Treatment Tumor Imaging
Note: As of Amendment 011-04, Second Course will no longer be offered. Any 
participant receiving Second Course prior to the initiation of Amendment 011-04 will be able 
to complete treatment as planned and should continue with tumor imaging as outlined in the 
SoA (Section 1.3.2).
Imaging scan showing PD in Initial Treatment phase will be considered the baseline scan for 
Second Course Treatment as long as it is performed within 28 days of beginning the Second 
Course C1D1. If imaging was conducted outside of the 28-day window, the scans should be 
repeated. Local reading (investigator assessment with site radiology reading) will be used to 
determine eligibility and response.
Subsequent tumor imaging should be performed by site investigator/radiology assessment as 
per SOC for the disease and local guidelines.
Imaging should continue until disease progression, the start of new anticancer treatment, 
withdrawal of consent, death, or notification by the Sponsor, whichever occurs first.
If previous imaging was obtained within 4 weeks prior to the date of discontinuation, 
imaging at intervention discontinuation is not mandatory. For participants who discontinue 
study intervention due to documented disease progression, this is the final required tumor 
imaging.
For participants who discontinue Second Course study treatment without documented disease 
progression, every effort should be made to continue monitoring disease status by tumor 
imaging per SOC until the start of new anticancer treatment, disease progression, death, 
withdrawal of consent, or the end of the study, whichever occurs first.
8.2.1.4.1
Bone Imaging During Second Course
Note: As of Amendment 011-04, Second Course will no longer be offered. Any 
participant receiving Second Course prior to the initiation of Amendment 011-04 will be able 
to complete treatment as planned and should continue with bone imaging (if indicated) as 
outlined in the SoA (Section 1.3.2).
A bone scan will be performed within 28 days before restarting study intervention only in 
those participants for whom bone scans were being acquired due to a positive bone scan 
during the Initial Treatment phase, and for all participants with new clinical symptoms prior 
to beginning Second Course phase. As of Amendment 011-03, subsequent scans will be 
performed by site investigator/radiology assessment as per SOC for the disease and local 
guidelines.
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RECIST 1.1 Assessment of Disease
NOTE: As of Amendment 011-03, all images will be locally assessed using RECIST 1.1 
and will no longer be submitted to iCRO.
RECIST 1.1 will be used as the primary measure of tumor response and date of disease 
progression, and as a basis for all protocol guidelines related to disease status (eg, 
discontinuation of study intervention). Although RECIST 1.1 references a maximum of 
5 target lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions 
in total and 5 per organ, if clinically relevant, to enable a broader sampling of tumor burden.
Initial tumor imaging showing site-assessed PD per RECIST 1.1 should be submitted as soon 
as possible, but within 72 hours of acquisition, when feasible, for BICR verification of PD. 
The site and Sponsor will be notified whether the BICR verifies PD using RECIST 1.1. 
Figure 5 illustrates the imaging flow for verification of PD for clinically stable participants.
iRECIST Assessment of Disease
NOTE: As of Amendment 011-03, iRECIST is no longer applicable.
iRECIST is based on RECIST 1.1 but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor 
response and progression and make treatment decisions. When clinically stable, participants 
should not be discontinued until progression is confirmed by the investigator working with 
the local radiology department, according to the rules outlined in Appendix 8. This allowance 
to continue treatment despite initial radiologic PD takes into account the observation that 
some participants can have a transient tumor flare in the first few months after the start of 
immunotherapy and then experience disease response. These data will be captured in the 
clinical database.
Clinical stability is defined as the following: 

Absence of symptoms and signs (including worsening of laboratory values) indicating 
clinically significant progression of disease

Absence of rapid progression of disease or of progressive tumor at critical anatomic sites 
(eg, cord compression) requiring urgent alternative medical intervention

No decline in ECOG performance status 

No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care
Any participant deemed clinically unstable should be discontinued from study intervention at 
central verification of site-assessed first radiologic evidence of PD and is not required to have 
repeat tumor imaging for confirmation of PD by iRECIST.
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If the investigator decides to continue study intervention, the participant may continue to 
receive study intervention, and tumor assessment should be repeated 4 to 8 weeks later to 
confirm PD by iRECIST per investigator assessment. Images should continue to be sent to 
the iCRO for potential retrospective BICR in the Initial Treatment course only. 
If repeat imaging does not confirm PD per iRECIST as assessed by the investigator, and the 
participant continues to be clinically stable, study intervention may continue with the regular 
imaging schedule. If PD is confirmed, participants will be discontinued from study treatment.
If a participant has confirmed radiographic progression (iCPD) as defined in Appendix 8, 
study intervention should be discontinued. However, if the participant is achieving clinically 
meaningful benefit, an exception to continue study intervention may be considered following 
consultation with the Sponsor. In this case, if study intervention is continued, tumor imaging
should continue at the intervals outlined in Section 1.3, and images should be submitted to 
the iCRO. 
A description of the adaptations and iRECIST process is in Appendix 8, with additional 
details in the iRECIST publication [Seymour, L., et al 2017]. A summary of imaging and 
treatment requirements after first radiologic evidence of progression is provided in Table 5
and illustrated as a flow chart in Figure 5.
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Table 5
Imaging and Treatment After First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD 
per RECIST 1.1 
by investigator 
assessment
Submit imaging for 
verification by 
BICR
Repeat imaging in 
4 to 8 weeks to 
confirm PD
May continue 
study intervention 
at investigator 
assessment and 
after participant’s 
consent
Submit imaging for 
verification by 
BICR
Repeat imaging in 4 
to 8 weeks to 
confirm PD per 
investigator’s 
discretion only
Discontinue study 
intervention
First radiologic 
evidence of PD 
per RECIST 1.1
verified by 
BICR
Repeat imaging in 
4 to 8 weeks to 
confirm PD
May continue 
study intervention 
at investigator’s 
discretion while 
awaiting 
confirmatory 
imaging by site 
per iRECIST
Repeat imaging in 4 
to 8 weeks to 
confirm PD per 
investigator’s 
discretion only
Discontinue study 
intervention
Repeat imaging 
confirms PD 
(iCPD) per 
iRECIST by 
investigator 
assessment
No additional 
imaging required
Discontinue study 
intervention 
(exception 
possible upon 
consultation with 
Sponsor)
No additional 
imaging required
Not applicable
Repeat imaging 
shows iUPD per 
iRECIST by 
investigator 
assessment
Repeat imaging in 
4 to 8 weeks to 
confirm PD
May take place at 
next regularly 
scheduled imaging 
visit
Continue study 
intervention at 
investigator’s
discretion
Repeat imaging in 4 
to 8 weeks to 
confirm PD per 
investigator’s 
discretion only
Discontinue study 
intervention
Repeat imaging 
shows iSD, iPR, 
or iCR per 
iRECIST by 
investigator 
assessment
Continue regularly 
scheduled imaging 
assessments
Continue study 
intervention at 
investigator’s 
discretion
Continue regularly 
scheduled imaging 
assessments
May restart study 
intervention if 
participant’s condition 
has improved and/or 
participant is clinically
stable per 
investigator’s 
discretion. The next 
imaging should take 
place per the regular 
imaging schedule.
Abbreviations: BICR = blinded independent central review; iCPD = iRECIST confirmed progressive disease; iCR = 
iRECIST complete response; iPR = iRECIST partial response; iRECIST = modified Response Evaluation Criteria in 
Solid Tumors Version 1.1 for immune-based therapeutics; iSD = iRECIST stable disease; iUPD = iRECIST unconfirmed 
progressive disease; PD = progressive disease; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1; 
VOP = verification of progression.
Note: If progression has been centrally verified, further management is by the site, based on iRECIST. Any further 
imaging should still be submitted to the iCRO, but there will be no rapid review. If RECIST 1.1 disease progression has 
not been centrally verified, the site should continue study intervention. Whether or not study intervention continues, 
images should be collected and submitted to the iCRO with a request for VOP, until RECIST 1.1 progression is verified 
by BICR.
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Figure 5
Imaging and Treatment for Clinically Stable Participants Treated with 
Pembrolizumab After First Radiologic Evidence of Progressive Disease Assessed by the 
Investigator
Abbreviations: iCRO = imaging contract research organization; iRECIST = Response Evaluation Criteria in 
Solid Tumors Version 1.1 for immune-based therapeutics; PD = progressive disease; RECIST 1.1 = Response 
Evaluation Criteria in Solid Tumors version 1.1.\
8.2.2
Patient-reported Outcomes
NOTE: As of Amendment 011-03, PRO questionnaires will no longer be administered 
to participants.
The EORTC QLQ-C30 and EQ-5D-5L questionnaires will be administered by trained site 
personnel and completed electronically by participants; EORTC QLQ-C30 should be 
administered before EQ-5D-5L. The questionnaires should be administered on Day 1 prior to 
dosing:

In Cycle 1 to Cycle 7

In Cycle 9

In every 3 subsequent cycles through Cycle 18 (Cycles12, 15, and 18)
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
Then in every 4 cycles until the end of study intervention (Cycles 22, 26, 30, and 34)

At the EOT visit
It is best practice and strongly recommended that electronic patient-reported outcomes 
(ePROs) be determined for allocated participants before study intervention administration, 
AE evaluation, and disease status notification. If a participant does not complete the ePRO 
instruments at a scheduled time point, the MISS_MODE form must be completed to capture 
the reason that this assessment was not performed.
8.3
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
The total amount of blood to be drawn over the course of the study (from prestudy to 
poststudy visits), including approximate blood volumes drawn by visit, can be found in the 
laboratory manual.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per the institutional standard. Physical 
examinations (comprehensive or symptom-directed) will be performed at screening and EOT 
as specified in the SoA (Section 1.3). A comprehensive physical examination will include 
evaluations of the head, eyes, ears, nose, throat, neck, chest (including heart and lungs), 
abdomen, limbs, and skin, and a complete neurologic examination. Documentation of the 
physical examination will be included in the source documentation at the investigational site. 
Significant findings prior to participant 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 and weight will also be measured and recorded.
A brief directed physical examination will be conducted per SOC or as clinically indicated. A 
directed physical examination is also required to be performed when an AEOSI, SAE, or ECI 
occurs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
Vital sign measurements (ie, systolic and diastolic BP [mm Hg], pulse [beats per minute], 
respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) will be 
obtained as per SOC or as clinically indicated as designated in the SoA (Section 1.3). Vital 
sign measurements are also required to be performed when an AEOSI, SAE, or ECI occurs.

BP and pulse will be measured after the participant has been resting for 5 minutes. All BP 
measurements should be performed on the same arm, preferably by the same person.
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8.3.3
Electrocardiograms
Electrocardiograms (ECGs) will be obtained as designated in the SoA (Section 1.3). 
Complete, standardized, 12-lead ECG recordings that permit all 12 leads to be displayed on a 
single page with an accompanying lead II rhythm strip below the customary 3 × 4 lead 
format are to be used. In addition to a rhythm strip, a minimum of 3 full complexes should be 
recorded from each lead simultaneously. Participants must be in the recumbent position for a 
period of 5 minutes prior to the ECG. The Fridericia correction method for calculating QTc 
will be used. 
An ECG abnormality may meet the criteria of an AE as described in this protocol (see 
Appendix 3) and the CRF Completion Guidelines. In these instances, the AE corresponding 
to the ECG abnormality will be recorded on the appropriate CRF. 
8.3.4
Echocardiograms or Multiple Gated Acquisition Scans
A MUGA scan (using a technetium-based tracer) or an echocardiogram will be performed to 
assess LVEF as designated in the SoA (Section 1.3.1). MUGA or echocardiogram scans 
should be performed locally in accordance with the institution’s standard practice. MUGA 
scans are the preferred modality. However, whichever modality is used for an individual 
participant at baseline should be repeated for all subsequent LVEF assessments for that 
participant. LVEFs as assessed by the institution will be entered on the CRF. Investigator 
assessment will be based on institutional reports.
8.3.5
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
The investigator or medically qualified designee (consistent with local requirements) must 
review the laboratory report, document this review, and record any clinically relevant 
changes occurring during the study in the AE section of the CRF. The laboratory reports 
must be filed with the source documents. Clinically significant abnormal laboratory findings 
are those which are not associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the Laboratory Manual and the SoA.
If laboratory values from nonprotocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose modification), 
then the results must be recorded in the appropriate CRF (eg, SLAB).
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For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
Hematology and Clinical Chemistry
Hematology and clinical chemistry assessments will be performed within 7 days prior to 
administration of the first dose of study intervention. Thereafter, hematology and clinical 
chemistry are to be performed per SOC or as clinically indicated as designated in the SoA 
(Section 1.3). When laboratory tests are clinically relevant (ie, inform diagnosis or 
management) for an AEOSI, SAE, or ECI then the laboratory test results should be entered 
into the eCRF.
Urine Dipstick Testing/Urinalysis
Urine dipstick testing will be performed locally within 7 days prior to the start of study 
intervention. Thereafter, urinalysis is only required per SOC or if clinically indicated.
Urinalysis will be performed locally within 7 days prior to the start of study intervention. 
Thereafter, urinalysis is only required per SOC or if clinically indicated.
Thyroid Function Testing
The screening blood sample for thyroid function testing should be obtained within 14 days 
before the first dose of study intervention. Thereafter, thyroid function testing will be 
performed per SOC or as clinically indicated. When thyroid function tests are clinically 
relevant (ie, inform diagnosis or management) for an AEOSI, SAE, or ECI then the test 
results should be entered into the eCRF.
8.3.6
Eastern Cooperative Oncology Group Performance Status
The investigator or qualified designee will assess ECOG performance status at screening. 
Thereafter, ECOG performance status will be assessed per SOC or when clinically indicated
(Section 1.3). When ECOG assessments are clinically relevant (ie, inform diagnosis or 
management) for an AEOSI, SAE, or ECI then the assessment should be entered into the 
eCRF.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
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).
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The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed 
but before intervention allocation/randomization must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event cause the 
participant to be excluded from the study, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, or a procedure.
All AEs from the time of intervention allocation/randomization through 30 days following 
cessation of study intervention must be reported by the investigator.
All AEs meeting serious criteria, from the time of intervention allocation/randomization 
through 90 days following cessation of study intervention or 30 days following cessation of 
study intervention if the participant initiates new anticancer therapy, whichever is earlier, 
must be reported by the investigator (see Appendix 7 for Germany-specific study 
requirements).
All pregnancies and exposure during breastfeeding, from the time of intervention 
allocation/randomization through 120 days following pembrolizumab, or 30 days following 
cessation of lenvatinib/placebo, whichever occurs last, must be reported by the investigator. 
If the participant initiates new anticancer therapy following discontinuation of study 
intervention, the time period for reporting pregnancies and exposure during breastfeeding is 
reduced to 30 days following cessation of study intervention.  
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified above must be reported immediately to the Sponsor if the event is 
considered drug-related.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 6.
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See Appendix 7 for Germany-specific study requirements.
Table 6
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified 
Follow-up 
Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
Nonserious Adverse 
Event (NSAE) 
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse 
Event (SAE) 
including Cancer 
and Overdose
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 hours 
of learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- due to 
intervention
- causes 
exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 hours 
of learning of 
event
Event of Clinical 
Interest (require 
regulatory reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- potential drug-
induced liver 
injury (DILI)
- require 
regulatory 
reporting
Not required
Within 24 hours 
of learning of 
event
Event of Clinical 
Interest (do not 
require regulatory 
reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 
calendar days of 
learning of event
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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, nonleading verbal questioning of the participant is the 
preferred method of inquiring about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events 
including pregnancy and exposure during breastfeeding, events of clinical interest (ECIs), 
cancer, and overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occur during the study are reportable to the Sponsor. 
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
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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. 2021].
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor.  
Specifically, the suspected/actual events covered in this exception include any event that is 
PD of the cancer under study.
The Sponsor will monitor aggregated efficacy endpoint events and safety data to ensure the 
safety of the participants in the study. Any suspected endpoint that, upon review, is not 
progression of the cancer under study will be forwarded to Global Pharmacovigilance as an 
SAE within 24 hours of determination that the event is not progression of the cancer under 
study.
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor. 
Events of clinical interest for this study include: 

An overdose of Sponsor’s product, as defined in Section 8.5, that is not associated with 
clinical symptoms or abnormal laboratory results.

An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose exceeding the prescribed 
dose for pembrolizumab of ≥5 times the protocol-specified dose.
No specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, pembrolizumab should be withheld and the participant should be observed 
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closely for signs of toxicity. Appropriate supportive treatment should be provided if 
clinically indicated.
If an AE(s) is associated with (“results from”) the overdose of pembrolizumab, the AE(s) is 
reported as an SAE, even if no other seriousness criteria are met. An overdose associated 
with lenvatinib should be reported as a nonserious event of clinical interest, unless the AE 
itself meets criteria for an SAE.
If a dose of study drug meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
nonserious ECI, using the terminology “accidental or intentional overdose without adverse 
effect.”
All reports of overdose with and without an AE must be reported by the investigator within 
24 hours to the Sponsor either by electronic media or paper.
8.6
Pharmacokinetics
NOTE: As of Amendment 011-03, this section is no longer applicable.
Blood samples will be collected from participants as specified in the SoA for initial treatment 
(Section 1.3.1). Study sites must have appropriately trained staff and adequate equipment for 
procuring and processing specimens. Instructions for collection, handling, and shipping of 
PK samples will be provided in the Laboratory Manual.
If at some point during enrollment prospective PK/ADA blood sample collection is no longer 
required, the sites will be notified.
8.6.1
Blood Collection for Serum Pembrolizumab
To evaluate pembrolizumab immunogenicity and exposure during treatment with lenvatinib 
+ pembrolizumab, sample collections for analysis of ADA and PK are currently planned as 
shown in the SoA for initial treatment (Section 1.3.1). Blood samples will be obtained to 
measure PK and ADA for serum pembrolizumab. These samples may be stored, and analysis
may be performed if required. If ongoing ADA and/or PK results are deemed unnecessary by 
the Sponsor, it may be decided to discontinue or reduce further sample collection in this 
study. Should this occur, it will be communicated by an administrative memo. If PK and/or 
ADA analyses are performed, the results of these analyses will be reported separately.
8.6.2
Blood Collection for Plasma Lenvatinib
Plasma concentrations of lenvatinib co-administered with pembrolizumab will be measured. 
Lenvatinib data will be analyzed using a population PK approach. Lenvatinib will be 
quantified by validated tandem high-performance liquid chromatography/mass spectroscopy.  
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8.7
Pharmacodynamics
Not applicable
8.8
Biomarkers
As of Amendment 011-03, samples for exploratory biomarker research will no longer 
be collected.
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 serum biomarker analyses
Blood for genetic analysis
Blood for RNA analysis
Blood for circulating tumor nucleic acids 
Blood for plasma biomarker analyses
Archived or newly obtained tumor tissue
Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be provided in the Laboratory Manual.
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes.
8.9
Medical Resource Utilization and Health Economics
NOTE: As of Amendment 011-03, this section is no longer applicable.
Medical resource utilization and health economics data associated with medical encounters 
will be collected in the CRF by the investigator and study site personnel for all participants 
throughout the study.
Protocol-mandated procedures, tests, and encounters are excluded.
The data collected may be used to conduct exploratory economic analyses. All-cause 
hospitalizations and emergency department visits must be reported on the eCRF from the 
time of allocation through 90 days following cessation of study intervention, or 30 days 
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following cessation of study intervention if the participant initiates new anticancer therapy, 
whichever is earlier.
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8. Unscheduled visits are permitted at any time during the study.
8.10.1
Screening
NOTE: As of Amendment 011-03, this section is no longer applicable.
Twenty-eight days prior to allocation, potential participants will be evaluated to determine 
that they fulfill the entry requirements as provided in Section 5. Note:  Screening procedures 
may be repeated after consultation with the Sponsor.
Written consent must be obtained prior to performing any protocol-specific procedures. 
Results of a test performed prior to the participant’s 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 prior to the first dose of 
study intervention except for the following:

Laboratory tests are to be performed within 7 days prior to the first dose of study 
intervention. An exception is hepatitis and HIV testing, which may be done up to 28 days 
prior to the first dose of study intervention. Repeated laboratory evaluation to establish 
eligibility is not allowed unless discussed and agreed upon with the Sponsor.

Baseline imaging is to be performed within 28 days of randomization.

ECOG performance status is to be evaluated within 7 days before randomization.

Full physical examination is to be performed within 7 days prior to the start of study 
intervention.

For WOCBP, a urine or serum pregnancy test will be performed within 24 hours prior to 
the first dose of study intervention. If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test will be required.
Rescreening
NOTE: As of Amendment 011-03, this section is no longer applicable.
Participants may be rescreened after initially failing to meet inclusion/exclusion criteria.  
Results of assessments during the original screening period are acceptable in lieu of repeat
screening tests if obtained within the specified time frame and the corresponding criteria are 
met.  Rescreened participants will retain their original screening numbers
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8.10.2
Initial Treatment
Visit requirements are outlined in the SoA (Section 1.3). Assessments/procedures are to be 
performed prior to administration of study intervention.
Telephone Contact or Visit
NOTE: As of Amendment 011-03, this section is no longer applicable.
A telephone contact or visit will be conducted on Cycle 1 Day 8 to assess participants for 
development of early toxicity, as outlined in the SoA (Section 1.3.1).
8.10.3
Second Course Treatment
Note: As of Amendment 011-04, Second Course will no longer be offered. Any 
participant receiving Second Course treatment prior to the initiation of Amendment 011-04 
will be able to complete treatment as planned.
All participants who have completed the first course may be eligible for up to an additional 
17 cycles of pembrolizumab if there is investigator-determined progressive disease by 
RECIST 1.1 after initial treatment or first course has been completed or stopped for 
confirmed CR. This retreatment is the Second Course of this study.
Participants may enter the Second Course if all of the following criteria are met:
1. The participant received pembrolizumab, determined on unblinding if applicable
2. No new anticancer treatment was administered after the last dose of study intervention
3. The participant meets all of the inclusion criteria and none of the exclusion criteria
4. The study is ongoing
Treatment may continue until a discontinuation criterion is met (Section 7.1).
Second Course visit requirements are outlined in the SoA (Section 1.3.2). Specific 
procedure-related details are provided in Sections 8.1 and 8.2.
An objective response or disease progression occurring during the Second Course phase will 
not be counted as an event for the primary analysis of either endpoint in this study.
8.10.4
Discontinued Participants Continuing to be Monitored in the Study
The discontinuation visit should take place at the time study intervention is discontinued for 
any reason. If the discontinuation visit takes place 30 days from the last dose of study 
intervention, at the time of the mandatory safety follow-up visit, the safety visit is not 
required. All procedures required at the discontinuation visit and at the 30-day safety follow-
up visit should be performed.
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8.10.5
Post-treatment Visits
Safety Follow-up Visit
The mandatory safety follow-up visit should take place approximately 30 days after the last 
dose of study intervention or before initiation of new anticancer treatment, whichever comes 
first.  
Participants who are eligible for Second Course Treatment may have up to 2 safety follow up 
visits, 1 after initial treatment and 1 after Second Course treatment.
Efficacy Follow-up Visits
Note: As of Amendment 011-04, this section is no longer applicable. Participants in 
Efficacy Follow-up prior to the initiation of Amendment 011-04 will stop efficacy 
assessments and be discontinued from the study. AEs and spontaneously reported 
pregnancies will be reported and followed as described under Section 8.4.
Participants who discontinue study intervention for a reason other than PD will move into the 
follow-up phase and should be assessed as outlined in the SoA (Section 1.3) to monitor 
disease status. Every effort should be made to collect information regarding disease status 
until the start of new anticancer therapy, PD, death, end of study, or the participant begins 
retreatment as detailed in Section 8.10.3. Information regarding poststudy anticancer 
treatment will be collected if new treatment is initiated.
Participants who are eligible for retreatment according to the criteria in Section 8.10.3 may 
move from follow-up to the Second Course phase if they experience PD. Details are provided 
in the SoA (Section 1.3.2).
8.10.6
Survival Follow-up
Note: As of Amendment 011-04, this section is no longer applicable. Participants in 
Survival Follow-up prior to initiation of Amendment 011-04 are considered to have 
completed the study and should have a final survival contact; these participants will no 
longer be contacted for survival information. AEs and spontaneously reported 
pregnancies will be reported and followed as described under Section 8.4.
Participants who experience confirmed disease progression or start a new anticancer therapy, 
will move into the Survival Follow-up phase and should be contacted approximately every 
12 weeks to assess for survival status until death, withdrawal of consent, or the end of the 
study, whichever occurs first.
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8.10.7
Survival Status
Note: As of Amendment 011-04, this section is no longer applicable. Survival data is no 
longer being collected.
To ensure that current and complete survival data are available at the time of database locks, 
updated survival data may be requested during the study by the Sponsor. For example, 
updated survival data may be requested prior to, but not limited to, an external DMC review 
or an interim or final analysis.  Upon Sponsor notification, all participants who do not or will 
not have a scheduled study visit or study contact during the Sponsor-defined period will be 
contacted for their survival status.
9
STATISTICAL ANALYSIS PLAN
NOTE: Efficacy data and non-binding futility boundaries were provided to the eDMC, 
in addition to safety analyses, to evaluate the benefit/risk ratio of the experimental arm 
relative to the control arm for LEAP-011 (data cutoff: 26-APR-2021). The interim 
efficacy data indicated that although the study did not meet non-binding futility 
boundaries for any of the analyzed endpoints, improvements of outcomes in favor of the 
combination are unlikely to be as high as initially hypothesized. Based upon these data 
and the recommendation of the eDMC, Amendment 011-03 was implemented to 
unblind the study and remove lenvatinib and matching placebo from the treatment 
arms. The prespecified interim and final analyses of the study described in the 
statistical analysis plan (SAP) will not be performed. Selected analyses of safety 
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. If, after the 
study has begun, but before any unblinding/final database lock, changes are made to primary 
and/or key secondary hypotheses, or the statistical methods related to those hypotheses, then 
the protocol will be amended (consistent with ICH Guideline E9). Changes to exploratory or 
other nonconfirmatory analyses made after the protocol has been finalized, but before 
unblinding/final database lock, will be documented in a supplemental statistical analysis plan 
(sSAP) and referenced in the clinical study report (CSR) for the study. Post hoc exploratory 
analyses will be clearly identified in the CSR. Other planned analyses (ie, those specific to 
PK/ADA data and PROs) will be documented in separate analysis plans.
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9.1
Statistical Analysis Plan Summary
Key elements of the SAP are summarized below. The comprehensive plan is provided in 
Sections 9.2 through 9.12.
Study Design 
Overview
A Phase 3, Randomized, Double-blind Study to Compare the Efficacy and Safety 
of Pembrolizumab (MK-3475) in Combination with Lenvatinib (E7080/MK-
7902) Versus Pembrolizumab and Placebo as First Line Treatment for Locally 
Advanced or Metastatic Urothelial Carcinoma in Cisplatin-ineligible Participants 
Whose Tumors Express PD-L1, and in Participants Ineligible for Any Platinum-
containing Chemotherapy Regardless of PD-L1 Expression (LEAP-011)
Treatment Assignment
Approximately 694 participants will be randomized in a 1:1 ratio between 
2 treatment arms: (1) pembrolizumab + lenvatinib and (2) pembrolizumab + 
placebo.
As of Amendment 011-03, approximately 487 participants have been randomized 
and no additional participants will be randomized. Stratification factors are as 
follows:

Ineligible for any platinum-containing chemotherapy, PD-L1 CPS ≥10, 
ECOG PS 2

Ineligible for any platinum-containing chemotherapy, PD-L1 CPS <10, 
ECOG PS 2

Cisplatin-ineligible, PD-L1 CPS ≥10, ECOG PS 2

Cisplatin-ineligible, PD-L1 CPS ≥10, ECOG PS 0 or 1.
Analysis Populations
Efficacy: Intention to Treat (ITT)
Safety: All Participants as Treated (APaT)
Primary Endpoints

PFS per RECIST 1.1 by BICR

OS
Key Secondary 
Endpoint

ORR per RECIST 1.1 by BICR
Statistical Methods for
Key Efficacy Analyses
PFS and OS 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.
Statistical Methods for
Key Safety Analyses
Point estimates (count and percentage) by treatment group will be provided for
safety endpoints.
Interim Analyses
There is no efficacy interim analyses. During the course of the study, DMC 
performed 6 quarterly safety reviews, including 4 futility analyses. The final 
analysis will be performed at when approximately 487 participants are 
randomized.
Multiplicity
There is no multiplicity adjustment.
Sample Size and 
Power
The total sample size is 487 participants.
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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 will be conducted as a double-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics Department will generate the randomized allocation schedule(s) for 
study intervention assignment.
Blinding issues related to the planned interim analyses are described in Section 9.7.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below, followed by descriptions of the derivations of selected 
endpoints. 
9.4.1
Efficacy Endpoints
Primary

Progression-free Survival (PFS): PFS is defined as the time from randomization to the 
first documented disease progression (PD) per RECIST 1.1 by BICR, or death due to any 
cause, whichever occurs first. See Section 9.6.1.1 for the definition of censoring.

Overall Survival (OS): OS is defined as the time from randomization to death due to 
any cause.
Secondary

Objective Response Rate (ORR): ORR is the percentage of participants with a 
confirmed CR or PR per RECIST 1.1 by BICR.

Duration of Response (DOR): DOR is defined as the time from the first documented 
evidence of CR or PR to PD per RECIST 1.1 by BICR or death due to any cause, 
whichever occurs first.

Disease Control Rate (DCR): DCR is defined as the percentage of participants with a 
confirmed response of CR, PR, or SD per RECIST 1.1 by BICR. Stable disease must 
be achieved at ≥6 weeks after randomization to be considered a best overall response.
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9.4.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, SAEs, fatal AEs, laboratory tests, and vital signs. Furthermore, specific events will be 
collected and designated as ECIs as described in Section 8.4.7.
9.4.3
Patient-Reported Outcome Endpoints
As of Amendment 011-03, ePRO endpoints will not be analyzed.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The analyses of the primary efficacy endpoints are based on the intention-to-treat (ITT) 
population. All randomized participants will be included in this population. Participants will 
be analyzed in the treatment group to which they are randomized. Details of the approach to 
handling missing data are provided in Section 9.6.
9.5.2
Safety Analysis Populations
Safety analyses will be conducted in the All Participants as Treated (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 
receive incorrect study intervention for the entire treatment period; such participants will be 
included in the treatment group corresponding to the study intervention actually received. 
Any participant who receives the incorrect study intervention for one cycle but receives the 
randomized study intervention for all other cycles, will be analyzed according to the 
randomized treatment group, and a narrative will be provided for any events that occur 
during the cycle for which the participant is incorrectly dosed.
At least one laboratory, vital sign, or ECG 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.
9.6
Statistical Methods
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary efficacy 
objectives. Methods related to exploratory objectives will be described in the sSAP. Nominal 
p-values will be computed for other efficacy analyses but should be interpreted with caution 
because of potential issues of multiplicity.
An OR PD that occurs during Second Course treatment will not be counted as an event for 
the primary analyses of either endpoint in this study.
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Progression-free Survival
The nonparametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment arm. A stratified Cox proportional hazard model with Efron’s method of tie 
handling will be used to estimate the magnitude of the treatment comparison (ie, HR) 
between the treatment arms. The HR and its 95% CI from the stratified Cox model with a 
single treatment covariate will be reported.
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. For the primary analysis, for the participants who have PD, the true date of 
disease progression will be approximated by the date of the first assessment at which PD is 
objectively documented per RECIST 1.1 by BICR, regardless of discontinuation of study 
drug. 
For the primary analysis, if the events (PD or death) are after more than 1 missed disease 
assessment, the data are censored at the last disease assessment before missing visits. Also,
data after new anticancer therapy are censored at the last disease assessment before the 
initiation of new anticancer therapy. If a participant meets multiple criteria for censoring, the 
censoring criterion that occurs earliest will be applied. The censoring rules are summarized in
Table 7.
Table 7
Censoring Rules for Primary Analyses of Progression-free Survival
Situation
Primary Analysis
No PD and no death; new anticancer treatment is not 
initiated
Censored at last disease assessment
No PD and no death; new anticancer treatment is 
initiated
Censored at last disease assessment before new 
anticancer treatment
PD or death documented after ≤1 missed disease 
assessment and before new anticancer treatment
Progressed at date of documented PD or death
PD or death documented immediately after ≥2 
consecutive missed disease assessments or after new 
anticancer treatment
Censored at last disease assessment prior to the 
earlier date of ≥ 2 consecutive missed disease 
assessments and new anticancer treatment
Abbreviation: PD = progressive disease.
Overall Survival
The nonparametric Kaplan-Meier method will be used to estimate the OS curve in each 
treatment arm. A stratified Cox proportional hazard model with Efron’s method of tie 
handling will be used to estimate the magnitude of the treatment comparison (ie, HR) 
between the treatment arms. The HR and its 95% CI 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 of last known contact. Analysis using the Restricted 
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Mean Survival Time method may be conducted for OS to account for the possible non-
proportional hazards effect.
Objective Response Rate
ORR will be estimated by treatment group. 95% CI for ORR will be provided using the
Clopper-Pearson (exact) method.
Analysis Strategy for Key Efficacy Endpoints
A summary of the primary analysis strategy for the key efficacy endpoints is provided in
Table 8.
Table 8
Analysis Methods for Key Efficacy Endpoints
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Analyses
PFS per RECIST 1.1
by BICR
Estimation: Stratified Cox 
model with Efron’s tie 
handling method 
ITT
Censored according to rules in 
Table 7
OS
Estimation: Stratified Cox 
model with Efron’s tie 
handling method
ITT
Censored at last known alive date
Key Secondary Analyses
ORR per RECIST 
1.1 by BICR
Estimation: Clopper-Pearson 
(exact) method
ITT
Participants with missing data are 
considered nonresponders
Abbreviations: BICR = blinded independent central review; ITT = intent-to-treat; ORR = objective response
rate; OS = overall survival; PFS = progression-free survival; RECIST 1.1 = Response Evaluation Criteria in 
Solid Tumors.
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, vital signs, and ECG measurements.
Individual events and the broad AE categories consisting of the proportion of participants 
with any AE, a drug-related AE, a serious AE, an AE which is both drug-related and serious, 
a Grade 3-5 AE, a drug-related Grade 3-5 AE, a fatal AE, dose interruption due to an AE, 
discontinuation due to an AE, adverse event of special interest (AEOSI), clinically significant 
adverse event (CSAE) will be summarized by counts and percentages by treatment group
(Table 9).
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Table 9
Analysis Strategy for Safety Parameters
Safety Endpoint
Descriptive Statistics
Any AE 
X
Any drug-related AE
X
Any Grade 3-5 AE 
X
Any drug-related Grade 3-5 AE
X
Any serious AE
X
Any serious drug-related AE
X
Treatment interruption due to AE
X
Treatment discontinuation due to AE
X
Death
X
Any AEOSI
X
Any CSAE
X
Any Grade 3-5 AEOSI
X
Any Grade 3-5 CSAE
X
Any serious Grade 3-5 AEOSI
X
Any serious Grade 3-5 CSAE
X
Change from baseline results (laboratory test toxicity grade)
X
Abbreviations: AE=adverse event; AEOSI=adverse event of special interest; CSAE=clinically significant adverse event.
9.6.3
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed using tables and/or graphs. No statistical hypothesis tests will 
be performed on these characteristics. The number and percentage of participants 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.
9.7
Interim Analyses
NOTE: As of Amendment 03, there will be no interim efficacy analysis.
9.8
Multiplicity
NOTE: As of Amendment 03, no hypothesis testing will be performed in this study.
Therefore, no multiplicity adjustment is needed.
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9.9
Sample Size and Power Calculations
Note: As of Amendment 011-03, the study randomized 487 participants in a 1:1 ratio 
into the pembrolizumab + lenvatinib and pembrolizumab + placebo arms. Because no 
statistical testing will be performed, the power calculations are not applicable.
The study will randomize 694 participants in a 1:1 ratio into the pembrolizumab + lenvatinib 
and pembrolizumab + placebo arms. PFS and OS are primary endpoints for the study, with 
ORR as the key secondary endpoint.
Based on the 694 participants with at least 7 months of follow-up, the power of the ORR
testing at the allocated α=0.025 is approximately 99.6% to detect a 17-percentage point 
difference between an underlying 30% response rate in the control arm and a 47% response 
rate in the experimental arm.
For the PFS endpoint, based on a target number of 558 events and 1 interim analyses at 
approximately 95% of the target number of events, the study has approximately 95% power 
to detect an HR of 0.7 at an overall α level of 0.005 (1-sided), and 99% power at an α level of 
0.025 (1-sided).
For the OS endpoint, based on a target number of 552 events and 2 interim analyses at 
approximately 70% and 85% of the target number of events, the study has approximately 
90% power to detect an HR of 0.75 at an overall α level of 0.02 (1-sided), and 91.5% power 
at an α level of 0.025 (1-sided).
Based on KEYNOTE-052 and KEYNOTE-361 data, the above sample size and power 
calculations for PFS and OS assume the following:

PFS follows an exponential distribution with a median of 3.2 months for the control 
group.

OS follows an exponential distribution with a median of 10.0 months for the control 
group.

Enrollment period of 17 months.

An annual dropout rate of 12% and 5% for PFS and OS, respectively.

A follow-up period of 6 and 22 months for PFS and OS, respectively, after the last 
participant enrolls.
The sample size and power calculations were performed using R (“gsDesign” package) and 
EAST 6.4.
9.10
Subgroup Analyses
Note: As of Amendment 011-03, this section is no longer applicable.
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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 in which the 
participant receives the study intervention. Summary statistics will be provided for the extent 
of exposure in the APaT population.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (eg, contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, 
efficacy, and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. 
Alternatively, MSD may conduct outcomes research trials, trials to assess or validate various endpoint 
measures, or trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of 
Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data 
are verified versus source documentation according to standard operating procedures. Per MSD policies and 
procedures, if fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
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are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing, in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have 
access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
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B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
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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.
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
Scientific Advisory Committee
This study was developed in collaboration with a Scientific Advisory Committee (SAC). The 
SAC includes 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.
Executive Oversight Committee
NOTE: As of Amendment 011-03, this section is no longer applicable.
The Executive Oversight Committee (EOC) will receive and decide upon any 
recommendations made by the DMC regarding the study. Additional details regarding the 
EOC are in the DMC charter.
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External Data Monitoring Committee
NOTE: As of Amendment 011-03, this section is no longer applicable.
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), and 
recommend to the EOC whether the study should continue in accordance with the protocol.
Specific details of composition, responsibilities, and governance, including the roles and 
responsibilities of the various committee members and the 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.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
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disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of GCP); and all applicable federal, state and local laws, rules and 
regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
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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 signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
10.1.9
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.
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10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
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10.2
Appendix 2: Clinical Laboratory Tests
The tests detailed in Table 10 will be performed by either the local or central laboratory 
except for pregnancy, urine dipstick testing, and urinalysis ,which will be performed by the 
local laboratory.
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1 and 5.2.
Prior to study treatment administration, the protocol-mandated safety laboratory tests (ie,
complete blood count with differential, clinical chemistry, coagulation, and thyroid function 
tests, as applicable to each treatment cycle) should be performed locally per standard of care
to ensure subject’s safety prior to treatment. 

Treatment decisions may be made based on local laboratory results. 

Additionally, if the local laboratory results significantly disagree with those results 
obtained from the central laboratory and that a patient management decision was made 
based on local laboratory value(s), then the value(s) supporting the patient management 
decision are required to be entered in the relevant eCRF, as applicable. 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable Safety Events 
must be reported per instructions detailed in Section 8.4 and Appendix 3.
Additional tests may be performed at any time during the study as determined necessary by 
the investigator or required by local regulations.

Pregnancy testing

Pregnancy testing requirements for study inclusion are described in Section 5.1.

Pregnancy testing (urine or serum) should be performed as required by local 
regulations during study treatment.

Pregnancy testing (urine or serum) should be performed as required by local 
regulations at the end of relevant systemic exposure and correspond with the time 
frame for female participant contraception in Section 5.1.

Additional urine or serum pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulations, to establish the absence 
of pregnancy at any time during the participant’s participation in the study.
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Table 10
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet count 
RBC indices:
MCVc
MCHc
% reticulocytesc
WBC count with 
differentiala:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC count
Hemoglobin
Hematocrit
Chemistry
Blood urea 
nitrogenb
Potassium
Aspartate 
aminotransferase/ serum 
glutamic-oxaloacetic 
transaminase 
Total bilirubin 
(and direct 
bilirubin, if total 
bilirubin is 
elevated above the 
upper limit of 
normal)
Albumin
Bicarbonatec
Chloridec
Phosphorusc
Creatinined
Sodium
Alanine 
aminotransferase/ serum 
glutamic-pyruvic 
transaminase 
Total Proteinc
Glucose 
Calcium
Alkaline phosphatase
Magnesium
Thyroid-stimulating 
hormone
Free thyroxinef
Lactate dehydrogenasec
Amylase
Lipasee
Cholesterolc
Triglyceridesc
CPKg
Pregnancy test
Triiodothyronine 
(total T3)f
Routine 
Urinalysish
Specific gravity
pH, glucose, proteini, hemoglobin or blood, ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Other Screening 
Tests
PT/INR and aPTT/PTTj
Serology (HIV RNA, HbsAg, and hepatitis C virus antibody) (if required by local health 
authority)
Serum or urine β human chorionic gonadotropin (β-HCG) pregnancy test (as needed for 
WOCBP)
FSH as needed for WONCBP
aPTT=activated partial thromboplastin time; BUN=blood urea nitrogen; CPK=creatine phosphokinase; FSH=follicle-
stimulating hormone; GFR=glomerular filtration rate; HbsAg=hepatitis B surface antigen hCG=human chorionic 
gonadotropin; HIV=human immunodeficiency virus; INR=international normalized ratio; MCH=mean corpuscular 
hemoglobin; MCV=mean corpuscular volume; PT=prothrombin time; RBC=red blood cell; TSH=thyroid stimulating 
hormone; ULN=upper limit of normal; UPCR=urine protein/creatinine ratio; WBC=white blood cell WOCBP=women of 
childbearing potential; WONCBP=women of nonchildbearing potential.
a Absolute or % acceptable per institutional standard.
b Urea is acceptable if BUN is not available as per institutional standard.
c Performed only if considered local standard of care.
d GFR (measured or calculated) or creatinine clearance can be used in place of creatinine.
e    After Cycle 1, retrospective review of lipase results is allowed when the results are not available during 
dosing.
f Free T4, total T3, and TSH levels will be determined during screening and then repeated on Day 1 of every 
cycle (starting Cycle 2), at the time of discontinuation (End of Treatment), and at the safety follow-up 
visits. Free T3 is acceptable where total T3 cannot be determined. There may be instances when sites are 
unable to obtain thyroid function testing results prior to the scheduled dosing. After C1, review of thyroid 
function test results after dosing is acceptable. 
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Laboratory 
Assessments
Parameters
g CPK isoenzymes (CK-MM and CK-MB) should be evaluated if CPK is greater than 3 × ULN.
h If urine dipstick testing suggests a urinary tract infection, or if clinically indicated, urine microscopy, 
culture, and sensitivity should be performed at the institution’s laboratory.
i 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/creatinine ratio (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.
j Performed as part of the screening assessment and as clinically indicated for participants taking 
anticoagulants.
The investigator (or medically qualified designee) must document his or her review of each 
laboratory safety report.
For platinum-ineligible participants, the investigator will be blinded to the central vendor’s 
PD-L1 CPS results, in an attempt to reduce bias from treatment decisions. The Sponsor 
acknowledges that, due to the commercial availability of PD-L1 testing assays, it is possible 
that the investigator may know a participant’s CPS prior to screening. This risk is seen as 
acceptable, as the treatment interventions are hypothesized to provide benefit regardless of 
CPS.
For cisplatin-ineligible participants, the investigator will be blinded to the central vendor’s 
PD-L1 CPS results. However, the investigator will be unblinded to the PD-L1 CPS category 
(ie, PD-L1 CPS ≥10 or <10). The inclusion criterion for cisplatin-ineligible participants 
includes a requirement for PD-L1 CPS ≥10.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the study 
intervention.
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of a study intervention.
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic agent, 
or protocol specified procedure whether investigational or marketed (including placebo, 
active comparator product, or run-in intervention), manufactured by, licensed by, provided 
by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECG, radiological scans, vital signs measurements), including those 
that worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the investigator.
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.
New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study.
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication.
For all reports of overdose (whether accidental or intentional) with an associated AE, the AE 
term should reflect the clinical symptoms or abnormal test result. An overdose without any 
associated clinical symptoms or abnormal laboratory results is reported using the 
terminology “accidental or intentional overdose without adverse effect.”
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Events NOT meeting the AE definition
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE.
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital).
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE). A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
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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.
10.3.3
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
Is a new cancer (that is not a condition of the study)
Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to the 
event.
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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 4.0. Any AE that changes 
CTCAE grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
-
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
-
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental 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?
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
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.

The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc), expected pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with IMP)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the 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.)
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-
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.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.

Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?

The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.

Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
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
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.

The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.

For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
Follow-up of AE and SAE
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation 
with other health care professionals.
New or updated information will be recorded in the CRF.
The investigator will submit any updated SAE data to the Sponsor within 24 hours of receipt 
of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
If the electronic system is unavailable for more than 24 hours, then the site will use the paper 
AE Reporting form.
Reference Section 8.4.1 for reporting time requirements.
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The site will enter the SAE data into the electronic system as soon as it becomes available.
After the study is completed at a given site, the EDC tool will be taken off-line to prevent the 
entry of new data or changes to existing data.
If a site receives a report of a new SAE from a study participant or receives updated data on a 
previously reported SAE after the EDC tool has been taken off-line, then the site can report 
this information on a paper SAE form or by telephone (see next section).
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE paper 
CRF is the preferred method to transmit this information to the Sponsor.
In rare circumstances and in the absence of facsimile equipment, notification by telephone is 
acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service.
Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames.
Contacts and instructions for SAE reporting and paper reporting procedures can be found in 
the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:

Premenarchal

Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.

Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high 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 non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.

Progestogen-only subdermal contraceptive implantc

IUSd

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 for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview. 
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.

Combined (estrogen- and progestogen- containing) hormonal contraceptionc
-
Oral
-
Intravaginal
-
Transdermal
-
Injectable

Progestogen-only hormonal contraceptionc
-
Oral
-
Injectable
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
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and 
correctly).
c
If locally required, in accordance with CTFG guidelines, acceptable hormonal contraceptives are limited 
to those which inhibit ovulation.
d IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
- Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and 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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10.5.3
Pregnancy Testing

Pregnancy testing requirements for study inclusion are described in Section 5.1.

Pregnancy testing ([urine or serum] as required by local regulations) should be conducted
as indicated in Section 1.3 during the treatment period and at least every 30 days during 
intervention.

Pregnancy testing ([urine or serum] as required by local regulations) should be conducted 
at the end of relevant systemic exposure.

Additional serum or urine pregnancy tests may be performed, as determined necessary by 
the investigator or required by local regulation, to establish the absence of pregnancy at 
any time during the subject's participation in the study.
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
Not applicable
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Germany-specific Requirements
1. Section 5.2 - Exclusion criterion 24: HIV testing is mandatory.
2. Section 5.2 - Exclusion criterion 25: Hepatitis B and C testing is mandatory.
3. Section 5.2 - Exclusion criterion 26: Tuberculosis testing is mandatory.    
4. Section 8.4.1 (Time Period and Frequency for Collecting AE, SAE and Other Reportable 
Safety Event Information): All AEs meeting serious criteria are to be collected for 120 
days after the last dose of study intervention.
10.7.2
UK-specific Requirements
1. Section 5.2 - Exclusion criterion 24: HIV testing is mandatory.
2. Section 5.2 - Exclusion criterion 25: Hepatitis B and C testing is mandatory.
3. Section 6.5.2 (Prohibited Concomitant Medications): Live vaccines must not be 
administered for 90 days after the last dose of study intervention.
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10.8
Appendix 8: Description of the iRECIST Process for Assessment of Disease 
Progression
NOTE: As of Amendment 011-03, iRECIST is no longer applicable.
Assessment at Screening and Prior to RECIST 1.1 Progression
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment.
Assessment and Decision at RECIST 1.1 Progression
For participants with evidence of radiologic PD by RECIST 1.1 as determined by the 
investigator, the investigator will decide whether to continue study intervention until repeat 
imaging 4 to 8 weeks later is obtained (using iRECIST for participant management [Table 5
and Figure 5]). This decision by the investigator should be based on the participant’s overall 
clinical condition.
Clinical stability is defined as the following: 

Absence of symptoms and signs indicating clinically significant progression of disease

No decline in ECOG performance status 

No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care

Any participant deemed clinically unstable should be discontinued from study treatment 
at site-assessed first radiologic evidence of PD and is not required to have repeat tumor 
imaging for confirmation of PD by iRECIST.

If the investigator decides to continue study intervention, the participant may continue to 
receive study intervention, and tumor assessment should be repeated 4 to 8 weeks later to 
confirm PD per iRECIST by per investigator assessment. Images should continue to be 
sent to the iCRO for potential retrospective BICR, in the Initial Treatment course only.

Tumor flare may manifest as any factor causing radiographic progression per RECIST 
1.1, including:

Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir
Note: “sum of diameters” will be used in this protocol, consistent with the original 
RECIST 1.1 terminology.

Unequivocal progression of nontarget lesion(s) identified at baseline

Development of new lesion(s)
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iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, 
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression.
At this visit, target and nontarget lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or nonmeasurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target. 
The sum of diameters of these lesions will be calculated and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively 
as New Lesions – Nontarget.
Assessment at the Confirmatory Imaging
At confirmatory imaging, the participant will be classified as progression confirmed (with an 
overall response of iCPD), as showing persistent unconfirmed progression (with an overall 
response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:

Any of the factors that were the basis for the iUPD at the previous visit show worsening

For target lesions, worsening is a further increase in the sum of diameters of ≥5 mm, 
compared to any prior iUPD time point.

For nontarget lesions, worsening is any significant growth in lesions overall
compared to a prior iUPD time point; this does not have to meet the “unequivocal” 
standard of RECIST 1.1.

For new lesions, worsening is any of these:

An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD time 
point 

Visible growth of new nontarget lesions 

Appearance of additional new lesions
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
Any new factor appears that would have triggered PD by RECIST 1.1.
Persistent iUPD

Progression is considered not confirmed, and the overall response remains iUPD, if:

None of the progression-confirming factors identified above occurs AND

The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)

Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging 
on which iUPD is seen. This may correspond to the next visit in the original visit 
schedule. The assessment of the subsequent confirmation imaging proceeds in an 
identical manner, with possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:

None of the progression-confirming factors identified above occurs, AND

The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold. 
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudoprogression, and the level of 
suspicion for progression is “reset”. This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST as assessed by the investigator, and the 
participant continues to be clinically stable, study intervention may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
intervention.
Note: If a participant has confirmed radiographic progression (iCPD) as defined above 
but is achieving a clinically meaningful benefit, an exception to continue study 
intervention may be considered following consultation with the Sponsor. In this case, if 
study intervention is continued, tumor imaging should continue to be performed at the 
intervals outlined in Section 1.3 and submitted to the iCRO.
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Detection of Progression at Visits After Pseudoprogression Resolves
After resolution of pseudoprogression (ie, achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events:

Target lesions

The sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from 
nadir) either for the first time or after resolution of previous pseudoprogression. The 
nadir is always the smallest sum of diameters seen during the entire trial, either before 
or after an instance of pseudoprogression.

Nontarget lesions

If nontarget lesions have never shown unequivocal progression, their doing so for the 
first-time results in iUPD.

If nontarget lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
nontarget lesions, taken as a whole.

New lesions

New lesions appear for the first time.

Additional new lesions appear.

Previously identified new target lesions show an increase of ≥5 mm in the new lesion 
sum of diameters, from the nadir value of that sum.

Previously identified nontarget lesions show any significant growth.
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception:  if new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve 
to iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication [Seymour, L., et 
al 2017].
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10.9
Appendix 9: Eastern Cooperative Oncology Group (ECOG) Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry out all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry out any self-care. 
Totally confined to bed or chair.
5
Dead.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity And
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5;649-55. The 
Eastern Cooperative Oncology Group, Robert Comis MD, Group Chair.
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10.10 Appendix 10: Abbreviations
Abbreviation
Expanded Term
5-FU
5-fluorouracil
ADA
antidrug antibodies
ADR
adverse drug reaction
AE
adverse event 
AEOSI
adverse event of special interest
ALK
anaplastic lymphoma kinase gene
ALT
alanine aminotransferase
APaT
all participants as treated
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
ATP
adenosine triphosphate
BCG
Bacillus Calmette-Guérin
β-HCG
β human chorionic gonadotropin
BICR
blinded independent central review
BMI
body mass index
BP
blood pressure
bpm
beats per minute
CBC
complete blood count
CD3ζ
CD3 zeta
CD28
cluster of differentiation 28
CI
confidence interval
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
CPK
creatine phosphokinase
CPS
combined positive score
CrCl
creatinine clearance
CR
complete response
CRF
case report form 
CRP
C-reactive protein
CSAE
clinically significant adverse event
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTFG
Clinical Trial Facilitation Group
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
CVA
cerebrovascular accident
CXDY
Cycle X Day Y
CYP
cytochrome P450
D/C
discontinuation
DCR
disease control rate
DILI
drug-induced liver injury
DLT
dose-limiting toxicities
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
DOR
duration of response
DTC
Differentiated thyroid cancer
EC
endometrial cancer
ECG
electrocardiogram 
ECOG
Eastern Cooperative Oncology Group
ECHO
echocardiogram
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Abbreviation
Expanded Term
ECI
event of clinical interest
eCRF
electronic case report form
EDC
electronic data collection
EGFR
epithelial growth factor receptor
ELISA
enzyme-linked immunoassay
EMA
European Medicines Agency
EOC
Executive Oversight Committee
EORTC
European Organisation for the Research and Treatment of Cancer
EOT
end of treatment
ePRO
electronic patient-reported outcome
EQ-5D-5L
EuroQoL 5-Dimensional 5-Level Questionnaire
FA
final analysis
FAS
full analysis set
FDAAA
Food and Drug Administration Amendments Act
FGF
fibroblast growth factor
FGFR
fibroblast growth factor receptor
FSH
follicle-stimulating hormone 
FT3
free triiodothyronine
FT4
free thyroxine
FU
follow-up
GCP
Good Clinical Practice 
GFR
glomerular filtration rate
HbsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
hazard ratio
HRT
hormone replacement therapy
IA
interim analysis
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
iCPD
iRECIST confirmed progressive disease
iCR
iRECIST complete response
iCRO
imaging contract research organization
IDO1
indoleamine-pyrrole 2,3 dioxygenase inhibitor
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgV
immunoglobulin-variable
IHC
immunohistochemistry
ILD
interstitial lung disease
IMP
investigational medicinal product
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
iUPD
iRECIST unconfirmed progressive disease
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Abbreviation
Expanded Term
IUS
intrauterine hormone-releasing system
IV
intravenous(ly)
1L
first-line
2L
second-line
LAM
lactational amenorrhea method
LEAP
Lenvatinib And Pembrolizumab
LFTs
liver function tests
LVEF
left ventricular ejection fraction
mAb
monoclonal antibody
MCH
mean corpuscular hemoglobin
MCV
mean corpuscular volume
MRI
magnetic resonance imaging
MTD
maximum tolerated dose 
MUGA
multigated acquisition
NaF PET
18F sodium fluoride positron emission tomography
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NIMP
non-investigational medicinal product
NSAE
non-serious adverse event
NSAIDS
nonsteroidal anti-inflammatory drugs
NSCLC
non-small cell lung cancer
NYHA
New York Heart Association
OR
objective response
ORR
objective response rate
OS
overall survival
PD
progressive disease
PD-1
programmed cell death 1
PDGF
platelet-derived growth factor
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PFS
progression-free survival
P-gp
P-glycoprotein
PK
pharmacokinetic(s)
PKCθ
protein kinase C-theta
PO
oral(ly)
PopPK
population PK
PR
partial response
PRES
posterior reversible encephalopathy syndrome
PRO
patient-reported outcome
PS
performance status
PSA
prostate-specific antigen
PT
prothrombin time
PTT
partial thromboplastin time
Q3W
every 3 weeks
Q9W
every 9 weeks
Q12W
every 12 weeks
Q24W
every 24 weeks
QD
once daily
QLQ-C30
Quality of Life Questionnaire Core 30 items
QoL
quality of life
QTcF
QT interval corrected with Fridericia’s formula
RBC
red blood cell
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Abbreviation
Expanded Term
RCC
renal cell carcinoma
RECIST 1.1
Response Evaluation Criteria in Solid Tumors Version 1.1
RNA
ribonucleic acid
ROS1
c-ros oncogene 1
RP2D
recommended Phase 2 dose
RPLS
reversible posterior leukoencephalopathy syndrome
RTK
receptor tyrosine kinase
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SC 
second course
SD
stable disease
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SoA
schedule of activities
SOC
standard of care
SP-D
surfactant protein D
SpO2
peripheral capillary oxygen saturation
sSAP
supplemental Statistical Analysis Plan
T1DM
type 1 diabetes mellitus
T3
triiodothyronine
TAM
tumor-associated macrophage
TEAE
treatment-emergent adverse event
TMDD
target-mediated drug disposition
TRAE
treatment-related adverse event(s)
TSH
thyroid-stimulating hormone
TTD
time to deterioration
UC
urothelial carcinoma
ULN
upper limit of normal
UPCR
urine protein/creatinine ratio
USA
United States of America
VAS
visual analog scale
VEGF
vascular endothelial growth factor
VEGFR
vascular endothelial growth factor receptor
VOP
verification of progression
WBC
white blood cell
WOCBP
woman/women of childbearing potential 
WONCBP
woman/women of non-childbearing potential
ZAP70
zeta-chain-associated protein kinase
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