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    Clinical Trial Results:
    A Phase 3 Randomized, Placebo-controlled Trial to Evaluate the Safety and Efficacy of Pembrolizumab (MK-3475) and Lenvatinib (E7080/MK-7902) Versus Pembrolizumab Alone as First-line Intervention in Participants with Advanced Melanoma (LEAP-003)

    Summary
    EudraCT number
    		 2018-002520-16
    Trial protocol
    		 SE   DE   ES   FR   GB   PL   IT  
    Global end of trial date
    01 Nov 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Oct 2025
    First version publication date
    23 Oct 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MK-7902-003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03820986
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 MSD: LEAP-003, Eisai Protocol Number: E7080-G000-312
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme LLC
    Sponsor organisation address
    126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ, United States, 07065
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@msd.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@msd.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Nov 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Jan 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Nov 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to assess the safety and efficacy of pembrolizumab (MK-3475) combined with lenvatinib (MK-7902/E7080) compared to pembrolizumab alone (with placebo for lenvatinib) as first-line treatment in adults with no prior systemic therapy for their advanced melanoma. The primary study hypotheses are that: 1) The combination of pembrolizumab and lenvatinib is superior to pembrolizumab and placebo as assessed by Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), and 2) The combination of pembrolizumab and lenvatinib is superior to pembrolizumab and placebo as assessed by Overall Survival (OS). For this study, RECIST 1.1 has been modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Mar 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Chile: 101
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    United States: 22
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Germany: 32
    Country: Number of subjects enrolled
    Italy: 78
    Country: Number of subjects enrolled
    Poland: 17
    Country: Number of subjects enrolled
    Spain: 113
    Country: Number of subjects enrolled
    Sweden: 16
    Country: Number of subjects enrolled
    France: 65
    Country: Number of subjects enrolled
    Switzerland: 7
    Country: Number of subjects enrolled
    Australia: 16
    Country: Number of subjects enrolled
    Brazil: 35
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    China: 62
    Country: Number of subjects enrolled
    Israel: 39
    Country: Number of subjects enrolled
    Korea, Republic of: 35
    Country: Number of subjects enrolled
    South Africa: 17
    Worldwide total number of subjects
    674
    EEA total number of subjects
    323
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    367
    From 65 to 84 years
    294
    85 years and over
    13

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Adult participants with advanced melanoma, who have not received prior systemic therapy were enrolled. 674 participants were randomly assigned in a 1:1 ratio to either combination therapy, Pembrolizumab+Lenvatinib, or Pembrolizumab+Placebo, to assess the safety and efficacy of combination therapy, Pembrolizumab+Lenvatinib.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pembrolizumab+Lenvatinib
    Arm description
    		 Participants received pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 administrations (up to approximately 2 years) PLUS lenvatinib 20 mg via oral capsule daily for up to at least 2 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    Other name
    MK-7902 E7080 LENVIMA®
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg via oral capsule daily for up to at least 2 years.

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475 KEYTRUDA®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 administrations (up to approximately 2 years)

    Arm title
    		 Pembrolizumab+Placebo
    Arm description
    		 Participants received pembrolizumab 200 mg via IV infusion on Day 1 of each 3-week cycle for up to 35 administrations (up to approximately 2 years) PLUS placebo for lenvatinib via oral capsule daily for up to at least 2 years.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo for Lenvatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo for Lenvatinib via oral capsule daily for up to at least 2 years.

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475 KEYTRUDA®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 administrations (up to approximately 2 years)

    Number of subjects in period 1
    		Pembrolizumab+Lenvatinib Pembrolizumab+Placebo
    Started
    334
    340
    Treated
    332
    338
    Completed
    0
    0
    Not completed
    334
    340
         Consent withdrawn by subject
    9
    4
         Physician decision
    1
    -
         Death
    201
    175
         Sponsor Decision
    122
    160
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pembrolizumab+Lenvatinib
    Reporting group description
    		 Participants received pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 administrations (up to approximately 2 years) PLUS lenvatinib 20 mg via oral capsule daily for up to at least 2 years.

    Reporting group title
    Pembrolizumab+Placebo
    Reporting group description
    		 Participants received pembrolizumab 200 mg via IV infusion on Day 1 of each 3-week cycle for up to 35 administrations (up to approximately 2 years) PLUS placebo for lenvatinib via oral capsule daily for up to at least 2 years.

    Reporting group values
    		 Pembrolizumab+Lenvatinib Pembrolizumab+Placebo Total
    Number of subjects
    		 334 340 674
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 180 187 367
        From 65-84 years
    		 145 149 294
        85 years and over
    		 9 4 13
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 61.8 ( 14.0 ) 62.0 ( 13.1 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 125 139 264
        Male
    		 209 201 410
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 55 43 98
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 1 3 4
        White
    		 243 261 504
        More than one race
    		 1 2 3
        Unknown or Not Reported
    		 34 31 65
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 70 79 149
        Not Hispanic or Latino
    		 224 225 449
        Unknown or Not Reported
    		 40 36 76
    Proto-oncogene B-Raf (BRAF) mutation positive
    Participants were stratified according to BRAF mutation status: BRAF mutation-positive, or BRAF wild-type or unknown.
    Units: Subjects
        No
    		 211 215 426
        Yes
    		 123 125 248

    End points

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    End points reporting groups
    Reporting group title
    Pembrolizumab+Lenvatinib
    Reporting group description
    		 Participants received pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 administrations (up to approximately 2 years) PLUS lenvatinib 20 mg via oral capsule daily for up to at least 2 years.

    Reporting group title
    Pembrolizumab+Placebo
    Reporting group description
    		 Participants received pembrolizumab 200 mg via IV infusion on Day 1 of each 3-week cycle for up to 35 administrations (up to approximately 2 years) PLUS placebo for lenvatinib via oral capsule daily for up to at least 2 years.

    Primary: Progression-free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR) per Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

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    End point title
    		 Progression-free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR) per Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    End point description
    PFS is defined as the time from date of randomization to the date of the first documentation of progressive disease (PD) or death from any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions is also considered PD. For this study, RECIST 1.1 has been modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The analysis population consisted of all randomized participants, included in the treatment group to which they were randomized. The final analysis for this end point is presented here.
    End point type
    Primary
    End point timeframe
    Up to approximately 34 months
    End point values
    		 Pembrolizumab+Lenvatinib Pembrolizumab+Placebo
    Number of subjects analysed
    334
    340
    Units: Months
        median (confidence interval 95%)
    9.1 (6.4 to 11.8)
    4.2 (3.1 to 6.3)
    Statistical analysis title
    		 Pembrolizumab+Lenvatinib vs Pembrolizumab+Placebo
    Comparison groups
    Pembrolizumab+Lenvatinib v Pembrolizumab+Placebo
    Number of subjects included in analysis
    674
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.0176 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 0.98
    Notes
    [1] - Based on Cox regression model with Efron’s method of tie handling with treatment as a covariate and stratified by BRAF mutation positive (Yes vs. No). Hazard Ratio (HR)=Pembrolizumab + Lenvatinib vs. Pembrolizumab + Placebo
    [2] - One-sided p-value based on log-rank test and stratified by BRAF mutation positive (Yes vs. No).

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS is defined as the time from date of randomization to date of death from any cause. The analysis population consisted of all randomized participants included in the treatment group to which they were randomized. The final analysis for this end point is presented here. A value of 9999 indicates that the upper limit was not reached.
    End point type
    Primary
    End point timeframe
    Up to approximately 46 months
    End point values
    		 Pembrolizumab+Lenvatinib Pembrolizumab+Placebo
    Number of subjects analysed
    334
    340
    Units: Months
        median (confidence interval 95%)
    25.8 (23.0 to 33.9)
    39.5 (26.6 to 9999)
    Statistical analysis title
    		 Pembrolizumab+Lenvatinib vs Pembrolizumab+Placebo
    Comparison groups
    Pembrolizumab+Lenvatinib v Pembrolizumab+Placebo
    Number of subjects included in analysis
    674
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.9521 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.97
         upper limit
    		 1.48
    Notes
    [3] - HR based on Cox regression model with Efron’s method of tie handling with treatment as a covariate and stratified by BRAF mutation positive (Yes vs. No). HR=Pembrolizumab + Lenvatinib vs. Pembrolizumab + Placebo
    [4] - One-sided p-value based on log-rank test and stratified by BRAF mutation positive (Yes vs. No).

    Secondary: Number of Participants with Adverse Events (AEs)

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    End point title
    		 Number of Participants with Adverse Events (AEs)
    End point description
    An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The analysis population consisted of all randomized participants who received at least one dose of study intervention. The final analysis for this end point is presented here.
    End point type
    Secondary
    End point timeframe
    Up to approximately 67 months
    End point values
    		 Pembrolizumab+Lenvatinib Pembrolizumab+Placebo
    Number of subjects analysed
    332 [5]
    338 [6]
    Units: Participants
    331
    330
    Notes
    [5] - Number of subjects analyzed is all randomized participants who got ≥1 dose of study treatment.
    [6] - Number of subjects analyzed is all randomized participants who got ≥1 dose of study treatment.
    No statistical analyses for this end point

    Secondary: Number of Participants Who Discontinue Study Treatment Due to Adverse Events (AEs)

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    End point title
    		 Number of Participants Who Discontinue Study Treatment Due to Adverse Events (AEs)
    End point description
    An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who discontinued any study treatment due to an AE is presented. The analysis population consisted of all randomized participants who received at least one dose of study intervention. The final analysis for this end point is presented here.
    End point type
    Secondary
    End point timeframe
    Up to approximately 63 months
    End point values
    		 Pembrolizumab+Lenvatinib Pembrolizumab+Placebo
    Number of subjects analysed
    332 [7]
    338 [8]
    Units: Participants
    104
    68
    Notes
    [7] - Number of subjects analyzed is all randomized participants who got ≥1 dose of study treatment.
    [8] - Number of subjects analyzed is all randomized participants who got ≥1 dose of study treatment.
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) as Assessed by BICR per RECIST 1.1

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    End point title
    		 Duration of Response (DOR) as Assessed by BICR per RECIST 1.1
    End point description
    For participants who demonstrated CR (disappearance of all target lesions) or PR (at least a 30% decrease in sum of diameters of target lesions), DOR is defined as the date of the first documented evidence of CR or PR until disease progression or death from any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. RECIST 1.1 has been modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Analysis population is randomized participants with a confirmed complete or partial response included in the treatment group to which they were randomized. The final analysis for this end point is presented here. 9999 indicates value not reached at time of data cut-off due to insufficient number of participants with an event.
    End point type
    Secondary
    End point timeframe
    Up to approximately 46 months
    End point values
    		 Pembrolizumab+Lenvatinib Pembrolizumab+Placebo
    Number of subjects analysed
    145 [9]
    121 [10]
    Units: Months
        median (full range (min-max))
    26.9 (3.4 to 9999)
    9999 (9999 to 9999)
    Notes
    [9] - Number of subjects analyzed is randomized participants with confirmed complete or partial response
    [10] - Number of subjects analyzed is randomized participants with confirmed complete or partial response
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR) as Assessed by BICR per RECIST 1.1

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    End point title
    		 Objective Response Rate (ORR) as Assessed by BICR per RECIST 1.1
    End point description
    ORR is defined as the percentage of participants in the analysis population who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. For this study, RECIST 1.1 has been modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The analysis population consisted of all randomized participants, included in the treatment group to which they were randomized. The final analysis for this end point is presented here.
    End point type
    Secondary
    End point timeframe
    Up to approximately 46 months
    End point values
    		 Pembrolizumab+Lenvatinib Pembrolizumab+Placebo
    Number of subjects analysed
    334
    340
    Units: Percentage of participants
        number (confidence interval 95%)
    43.4 (38.0 to 48.9)
    35.6 (30.5 to 40.9)
    No statistical analyses for this end point

    Secondary: Change from Baseline in European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire-Core 30 [QLQ-C30] Global Health Status (GHS)/Quality of Life (QoL) Score

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    End point title
    		 Change from Baseline in European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire-Core 30 [QLQ-C30] Global Health Status (GHS)/Quality of Life (QoL) Score
    End point description
    The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. The GHS/QoL combined score consists of participant responses to the questions "How would you rate your overall health during the past week?" and "How would you rate your overall quality of life during the past week?" GHS/QoL responses range in score from 0 to 100, with a higher score indicating a better outcome. The analysis population consisted of all randomized participants who had at least 1 assessment available for the EORTC QLQ-C30 GHS/QoL score and had received at least 1 dose of study intervention. The final analysis for this end point is presented here.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 21
    End point values
    		 Pembrolizumab+Lenvatinib Pembrolizumab+Placebo
    Number of subjects analysed
    325 [11]
    334 [12]
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    -6.38 (-8.91 to -3.84)
    -2.69 (-5.30 to -0.08)
    Notes
    [11] - Subjects analyzed is randomized participants who got ≥1 dose of study drug & had ≥1 GHS/QoL Score
    [12] - Subjects analyzed is randomized participants who got ≥1 dose of study drug & had ≥1 GHS/QoL Score
    Statistical analysis title
    		 Pembrolizumab+Lenvatinib vs Pembrolizumab+Placebo
    Statistical analysis description
    Based on a constrained longitudinal data analysis (cLDA) model with GHS/QoL as the response variable, with covariates for treatment by time interaction, stratification factor BRAF mutation status as covariate. No formal hypothesis testing was conducted. P-value is nominal. Difference in Least Squared (LS) means= Pembrolizumab + Lenvatinib vs. Pembrolizumab + Placebo
    Comparison groups
    Pembrolizumab+Lenvatinib v Pembrolizumab+Placebo
    Number of subjects included in analysis
    659
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0345 [13]
    Method
    		 cLDA model
    Parameter type
    		 Difference in LS means
    Point estimate
    -3.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.1
         upper limit
    		 -0.27
    Notes
    [13] - No formal hypothesis testing was conducted. P-value is nominal.

    Secondary: Change from Baseline in European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire-Core 30 [QLQ-C30] Physical Function (PF) Score

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    End point title
    		 Change from Baseline in European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire-Core 30 [QLQ-C30] Physical Function (PF) Score
    End point description
    The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. The PF Score consists of participant responses to questions regarding PF (5 questions about daily activities [strenuous activities, long walks, short walks, bed/chair rest and needing help with eating, dressing, washing themselves or using the toilet]). For PF, responses range in score from 0 to 100, with a higher score indicating a better outcome. The analysis population consisted of all randomized participants who had at least 1 assessment available for the EORTC QLQ-C30 PF score and had received at least 1 dose of study intervention. The final analysis for this end point is presented here.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 21
    End point values
    		 Pembrolizumab+Lenvatinib Pembrolizumab+Placebo
    Number of subjects analysed
    325 [14]
    334 [15]
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    -9.50 (-11.66 to -7.34)
    -4.02 (-6.23 to -1.80)
    Notes
    [14] - Subjects analyzed is randomized participants who got ≥1 dose of study drug & had ≥1 PF Score
    [15] - Subjects analyzed is randomized participants who got ≥1 dose of study drug & had ≥1 PF Score
    Statistical analysis title
    		 Pembrolizumab+Lenvatinib vs Pembrolizumab+Placebo
    Statistical analysis description
    Based on a cLDA model with PF as the response variable, with covariates for treatment by time interaction, stratification factor BRAF mutation status as covariate. No formal hypothesis testing was conducted. P-value is nominal. Difference in Least Squared (LS) means= Pembrolizumab + Lenvatinib vs. Pembrolizumab + Placebo
    Comparison groups
    Pembrolizumab+Lenvatinib v Pembrolizumab+Placebo
    Number of subjects included in analysis
    659
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    P-value
    		 = 0.0004
    Method
    		 cLDA model
    Parameter type
    		 Difference in LS means
    Point estimate
    -5.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.53
         upper limit
    		 -2.45
    Notes
    [16] - No formal hypothesis testing was conducted. P-value is nominal.

    Secondary: Time to True Deterioration (TTD) Based on Change from Baseline in EORTC QLQ-C30 GHS/QoL score

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    End point title
    		 Time to True Deterioration (TTD) Based on Change from Baseline in EORTC QLQ-C30 GHS/QoL score
    End point description
    TTD is defined as the time from Baseline to 1st onset of a ≥10-point negative change (decrease) in EORTC-QLQ-C30 GHS Score. The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. The GHS/QoL Score consists of participant responses to the questions "How would you rate your overall health during the past week?" and "How would you rate your overall quality of life during the past week?" GHS/QoL responses range in score from 0 to 100, with a higher score indicating a better outcome. A longer TTD indicates a better outcome. The analysis population consisted of all randomized participants who have at least one assessment available for EORTC QLQ-C30 and have received at least one dose of the study intervention; and had data available for this TTD change from baseline in GHS/QoL outcome using EORTC QLQ-C30. The final analysis for this end point is presented here. 9999 indicates upper limit not reached.
    End point type
    Secondary
    End point timeframe
    Up to approximately 30 months
    End point values
    		 Pembrolizumab+Lenvatinib Pembrolizumab+Placebo
    Number of subjects analysed
    305 [17]
    323 [18]
    Units: Months
        median (confidence interval 95%)
    5.62 (4.34 to 9.69)
    24.58 (11.04 to 9999)
    Notes
    [17] - Subjects analyzed is randomized participants who got ≥1 dose of study drug & had TTD GHS/QoL Score
    [18] - Subjects analyzed is randomized participants who got ≥1 dose of study drug & had TTD GHS/QoL Score
    Statistical analysis title
    		 Pembrolizumab+Lenvatinib vs Pembrolizumab+Placebo
    Statistical analysis description
    Based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by BRAF mutation status (positive vs wild type or unknown). No formal hypothesis testing was conducted. P-value is nominal. HR=Lenvatinib + Pembrolizumab vs. Placebo + Pembrolizumab
    Comparison groups
    Pembrolizumab+Lenvatinib v Pembrolizumab+Placebo
    Number of subjects included in analysis
    628
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0001 [19]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.25
         upper limit
    		 2
    Notes
    [19] - No formal hypothesis testing was conducted. P-value is nominal.

    Secondary: Time to True Deterioration (TTD) Based on Change from Baseline in EORTC QLQ-C30 in Physical Function (PF) Score

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    End point title
    		 Time to True Deterioration (TTD) Based on Change from Baseline in EORTC QLQ-C30 in Physical Function (PF) Score
    End point description
    TTD is defined as the time from Baseline to 1st onset of a ≥10-point negative change (decrease) in EORTC-QLQ-C30 PF Score. The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. The PF Score consists of participant responses to questions regarding PF (5 questions about daily activities [strenuous activities, long walks, short walks, bed/chair rest & needing help with eating, dressing, washing themselves or using the toilet]. For PF, responses range in score from 0 to 100, with a higher score indicating a better outcome. The protocol-specified final analysis is presented. The analysis population consisted of all randomized participants who have at least one assessment available for EORTC QLQ-C30 and have received at least one dose of the study intervention; and had data available for this TTD change from baseline in PF Score outcome using EORTC QLQ-C30. The final analysis for this end point is presented here. 9999 indicates value not reached.
    End point type
    Secondary
    End point timeframe
    Up to approximately 30 months
    End point values
    		 Pembrolizumab+Lenvatinib Pembrolizumab+Placebo
    Number of subjects analysed
    305 [20]
    323 [21]
    Units: Months
        median (confidence interval 95%)
    5.55 (4.40 to 9.69)
    9999 (9999 to 9999)
    Notes
    [20] - Subjects analyzed is randomized participants who got ≥1 dose of study drug & had TTD PF Score
    [21] - Subjects analyzed is randomized participants who got ≥1 dose of study drug & had TTD PF Score
    Statistical analysis title
    		 Pembrolizumab+Lenvatinib vs Pembrolizumab+Placebo
    Statistical analysis description
    Based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by BRAF mutation status (positive vs wild type or unknown). No formal hypothesis testing was conducted. P-value is nominal. HR=Lenvatinib + Pembrolizumab vs. Placebo + Pembrolizumab
    Comparison groups
    Pembrolizumab+Lenvatinib v Pembrolizumab+Placebo
    Number of subjects included in analysis
    628
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0001 [22]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.52
         upper limit
    		 2.5
    Notes
    [22] - No formal hypothesis testing was conducted. P-value is nominal.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 67 months
    Adverse event reporting additional description
    All Cause Mortality: all randomized participants included in the treatment group to which they were randomized. AEs: all randomized participants who got ≥1 dose of study intervention. Per protocol, MedDRA preferred terms “Neoplasm progression (NP), Malignant NP and Disease progression” not related to study drug are omitted as AEs.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.1
    Reporting groups
    Reporting group title
    Lenvatinib + Pembrolizumab
    Reporting group description
    		 -

    Reporting group title
    Placebo + Pembrolizumab
    Reporting group description
    		 -

    Serious adverse events
    		 Lenvatinib + Pembrolizumab Placebo + Pembrolizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    124 / 332 (37.35%)
    96 / 338 (28.40%)
         number of deaths (all causes)
    206
    176
         number of deaths resulting from adverse events
    14
    13
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    3 / 332 (0.90%)
    2 / 338 (0.59%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer recurrent
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lentigo maligna
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm skin
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraneoplastic syndrome
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    2 / 332 (0.60%)
    2 / 338 (0.59%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 332 (0.30%)
    3 / 338 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour ulceration
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma stage I
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesothelioma
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 338 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    3 / 332 (0.90%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Ectopic pregnancy
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Fatigue
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 338 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    4 / 332 (1.20%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Haemophagocytic lymphohistiocytosis
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Immune-mediated lung disease
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Interstitial lung disease
         subjects affected / exposed
    2 / 332 (0.60%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 332 (0.30%)
    3 / 338 (0.89%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pneumothorax
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    5 / 332 (1.51%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    4 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Amylase increased
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    2 / 332 (0.60%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin T increased
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest injury
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic fracture
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular access site inflammation
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shoulder fracture
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Tracheo-oesophageal fistula
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    4 / 332 (1.20%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amnesia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 332 (0.60%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis autoimmune
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hemiparesis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated encephalitis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myasthenic syndrome
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 332 (0.60%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Uveitis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    4 / 332 (1.20%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune colitis
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic gastritis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    3 / 332 (0.90%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    6 / 332 (1.81%)
    4 / 338 (1.18%)
         occurrences causally related to treatment / all
    6 / 7
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 332 (0.30%)
    2 / 338 (0.59%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated enterocolitis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 332 (0.60%)
    2 / 338 (0.59%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic disorder
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic fistula
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 332 (0.30%)
    3 / 338 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    3 / 332 (0.90%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 338 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    3 / 332 (0.90%)
    2 / 338 (0.59%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis bullous
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug eruption
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephritis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    4 / 332 (1.20%)
    3 / 338 (0.89%)
         occurrences causally related to treatment / all
    1 / 4
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune nephritis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Addison's disease
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    3 / 332 (0.90%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocytic hypophysitis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Axillary mass
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertrophic osteoarthropathy
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoporotic fracture
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Enteritis infectious
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal abscess
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal sepsis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    2 / 332 (0.60%)
    5 / 338 (1.48%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    COVID-19 pneumonia
         subjects affected / exposed
    3 / 332 (0.90%)
    6 / 338 (1.78%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Cellulitis
         subjects affected / exposed
    2 / 332 (0.60%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    3 / 332 (0.90%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Rectal abscess
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma infection
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemophilus infection
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster oticus
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal candidiasis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 332 (1.51%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 332 (0.60%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Skin candida
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tick-borne fever
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitamin B1 deficiency
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Lenvatinib + Pembrolizumab Placebo + Pembrolizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    326 / 332 (98.19%)
    319 / 338 (94.38%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    203 / 332 (61.14%)
    75 / 338 (22.19%)
         occurrences all number
    378
    119
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    95 / 332 (28.61%)
    82 / 338 (24.26%)
         occurrences all number
    164
    122
    Fatigue
         subjects affected / exposed
    92 / 332 (27.71%)
    86 / 338 (25.44%)
         occurrences all number
    130
    109
    Mucosal inflammation
         subjects affected / exposed
    39 / 332 (11.75%)
    10 / 338 (2.96%)
         occurrences all number
    54
    12
    Oedema peripheral
         subjects affected / exposed
    39 / 332 (11.75%)
    34 / 338 (10.06%)
         occurrences all number
    43
    43
    Pyrexia
         subjects affected / exposed
    40 / 332 (12.05%)
    42 / 338 (12.43%)
         occurrences all number
    50
    60
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    43 / 332 (12.95%)
    41 / 338 (12.13%)
         occurrences all number
    51
    54
    Dysphonia
         subjects affected / exposed
    54 / 332 (16.27%)
    3 / 338 (0.89%)
         occurrences all number
    61
    3
    Dyspnoea
         subjects affected / exposed
    25 / 332 (7.53%)
    25 / 338 (7.40%)
         occurrences all number
    30
    27
    Epistaxis
         subjects affected / exposed
    19 / 332 (5.72%)
    3 / 338 (0.89%)
         occurrences all number
    20
    3
    Oropharyngeal pain
         subjects affected / exposed
    18 / 332 (5.42%)
    4 / 338 (1.18%)
         occurrences all number
    22
    4
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    25 / 332 (7.53%)
    29 / 338 (8.58%)
         occurrences all number
    29
    30
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    75 / 332 (22.59%)
    55 / 338 (16.27%)
         occurrences all number
    118
    89
    Amylase increased
         subjects affected / exposed
    47 / 332 (14.16%)
    37 / 338 (10.95%)
         occurrences all number
    73
    72
    Aspartate aminotransferase increased
         subjects affected / exposed
    82 / 332 (24.70%)
    47 / 338 (13.91%)
         occurrences all number
    130
    67
    Blood alkaline phosphatase increased
         subjects affected / exposed
    34 / 332 (10.24%)
    24 / 338 (7.10%)
         occurrences all number
    52
    30
    Blood bilirubin increased
         subjects affected / exposed
    40 / 332 (12.05%)
    19 / 338 (5.62%)
         occurrences all number
    81
    34
    Blood cholesterol increased
         subjects affected / exposed
    36 / 332 (10.84%)
    13 / 338 (3.85%)
         occurrences all number
    77
    27
    Blood creatine phosphokinase increased
         subjects affected / exposed
    49 / 332 (14.76%)
    41 / 338 (12.13%)
         occurrences all number
    77
    73
    Blood creatinine increased
         subjects affected / exposed
    42 / 332 (12.65%)
    26 / 338 (7.69%)
         occurrences all number
    73
    48
    Blood glucose increased
         subjects affected / exposed
    18 / 332 (5.42%)
    16 / 338 (4.73%)
         occurrences all number
    40
    28
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    33 / 332 (9.94%)
    21 / 338 (6.21%)
         occurrences all number
    63
    28
    Blood sodium decreased
         subjects affected / exposed
    21 / 332 (6.33%)
    10 / 338 (2.96%)
         occurrences all number
    46
    19
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    56 / 332 (16.87%)
    18 / 338 (5.33%)
         occurrences all number
    79
    36
    Blood triglycerides increased
         subjects affected / exposed
    31 / 332 (9.34%)
    22 / 338 (6.51%)
         occurrences all number
    67
    43
    Blood urea increased
         subjects affected / exposed
    21 / 332 (6.33%)
    14 / 338 (4.14%)
         occurrences all number
    38
    43
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    36 / 332 (10.84%)
    23 / 338 (6.80%)
         occurrences all number
    49
    30
    Lipase increased
         subjects affected / exposed
    85 / 332 (25.60%)
    61 / 338 (18.05%)
         occurrences all number
    171
    115
    Platelet count decreased
         subjects affected / exposed
    26 / 332 (7.83%)
    3 / 338 (0.89%)
         occurrences all number
    42
    3
    Weight decreased
         subjects affected / exposed
    91 / 332 (27.41%)
    30 / 338 (8.88%)
         occurrences all number
    111
    36
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    40 / 332 (12.05%)
    27 / 338 (7.99%)
         occurrences all number
    54
    29
    Dysgeusia
         subjects affected / exposed
    23 / 332 (6.93%)
    5 / 338 (1.48%)
         occurrences all number
    32
    6
    Headache
         subjects affected / exposed
    76 / 332 (22.89%)
    51 / 338 (15.09%)
         occurrences all number
    131
    59
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    40 / 332 (12.05%)
    53 / 338 (15.68%)
         occurrences all number
    58
    70
    Thrombocytopenia
         subjects affected / exposed
    21 / 332 (6.33%)
    6 / 338 (1.78%)
         occurrences all number
    32
    6
    Neutropenia
         subjects affected / exposed
    25 / 332 (7.53%)
    8 / 338 (2.37%)
         occurrences all number
    43
    16
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    58 / 332 (17.47%)
    40 / 338 (11.83%)
         occurrences all number
    96
    45
    Abdominal pain upper
         subjects affected / exposed
    47 / 332 (14.16%)
    19 / 338 (5.62%)
         occurrences all number
    58
    22
    Constipation
         subjects affected / exposed
    59 / 332 (17.77%)
    50 / 338 (14.79%)
         occurrences all number
    90
    60
    Diarrhoea
         subjects affected / exposed
    171 / 332 (51.51%)
    84 / 338 (24.85%)
         occurrences all number
    454
    141
    Dry mouth
         subjects affected / exposed
    36 / 332 (10.84%)
    23 / 338 (6.80%)
         occurrences all number
    39
    26
    Dyspepsia
         subjects affected / exposed
    31 / 332 (9.34%)
    12 / 338 (3.55%)
         occurrences all number
    39
    13
    Nausea
         subjects affected / exposed
    111 / 332 (33.43%)
    61 / 338 (18.05%)
         occurrences all number
    204
    85
    Stomatitis
         subjects affected / exposed
    30 / 332 (9.04%)
    4 / 338 (1.18%)
         occurrences all number
    43
    4
    Vomiting
         subjects affected / exposed
    75 / 332 (22.59%)
    38 / 338 (11.24%)
         occurrences all number
    134
    51
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    21 / 332 (6.33%)
    12 / 338 (3.55%)
         occurrences all number
    23
    12
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    52 / 332 (15.66%)
    4 / 338 (1.18%)
         occurrences all number
    71
    4
    Pruritus
         subjects affected / exposed
    68 / 332 (20.48%)
    78 / 338 (23.08%)
         occurrences all number
    81
    114
    Rash
         subjects affected / exposed
    62 / 332 (18.67%)
    57 / 338 (16.86%)
         occurrences all number
    89
    75
    Vitiligo
         subjects affected / exposed
    21 / 332 (6.33%)
    41 / 338 (12.13%)
         occurrences all number
    23
    41
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    100 / 332 (30.12%)
    35 / 338 (10.36%)
         occurrences all number
    177
    61
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    44 / 332 (13.25%)
    17 / 338 (5.03%)
         occurrences all number
    48
    18
    Hypothyroidism
         subjects affected / exposed
    157 / 332 (47.29%)
    44 / 338 (13.02%)
         occurrences all number
    198
    50
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    100 / 332 (30.12%)
    69 / 338 (20.41%)
         occurrences all number
    162
    100
    Back pain
         subjects affected / exposed
    64 / 332 (19.28%)
    42 / 338 (12.43%)
         occurrences all number
    78
    56
    Myalgia
         subjects affected / exposed
    63 / 332 (18.98%)
    42 / 338 (12.43%)
         occurrences all number
    76
    52
    Pain in extremity
         subjects affected / exposed
    31 / 332 (9.34%)
    32 / 338 (9.47%)
         occurrences all number
    37
    38
    Infections and infestations
    COVID-19
         subjects affected / exposed
    21 / 332 (6.33%)
    28 / 338 (8.28%)
         occurrences all number
    21
    33
    Urinary tract infection
         subjects affected / exposed
    28 / 332 (8.43%)
    35 / 338 (10.36%)
         occurrences all number
    39
    44
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    113 / 332 (34.04%)
    54 / 338 (15.98%)
         occurrences all number
    166
    58
    Hypercholesterolaemia
         subjects affected / exposed
    35 / 332 (10.54%)
    18 / 338 (5.33%)
         occurrences all number
    64
    27
    Hyperglycaemia
         subjects affected / exposed
    52 / 332 (15.66%)
    39 / 338 (11.54%)
         occurrences all number
    92
    62
    Hypertriglyceridaemia
         subjects affected / exposed
    59 / 332 (17.77%)
    28 / 338 (8.28%)
         occurrences all number
    118
    49
    Hyperuricaemia
         subjects affected / exposed
    17 / 332 (5.12%)
    9 / 338 (2.66%)
         occurrences all number
    29
    16
    Hypoalbuminaemia
         subjects affected / exposed
    21 / 332 (6.33%)
    8 / 338 (2.37%)
         occurrences all number
    33
    9
    Hypokalaemia
         subjects affected / exposed
    37 / 332 (11.14%)
    16 / 338 (4.73%)
         occurrences all number
    51
    23
    Hyponatraemia
         subjects affected / exposed
    37 / 332 (11.14%)
    20 / 338 (5.92%)
         occurrences all number
    57
    26
    Hypomagnesaemia
         subjects affected / exposed
    20 / 332 (6.02%)
    9 / 338 (2.66%)
         occurrences all number
    27
    13

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Mar 2019
    Amendment 01: To address feedback from regulatory authority and add MK-7902 program level updates.
    24 Apr 2020
    Amendment 02: To clarify AE safety follow-up timelines, to clarify allowed concomitant medications, and to add MK-7902 program level updates.
    01 Jul 2021
    Amendment 03: To update the Dose Modification and Toxicity Management Guidelines for irAEs and table for alignment with the USPI as requested by the FDA.
    16 Sep 2021
    Amendment 04: Due to slower than expected Overall Survival event rate, a third IA for Overall Survival was added. IA strategies were adjusted to achieve optimal timing for IAs.
    03 Oct 2022
    Amendment 06: 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.
    31 Jul 2023
    Amendment 07: Protocol amended consistent with recommendations of the eDMC after an interim review of the data; specifically, to discontinue the study due to lack of efficacy.
    11 Dec 2023
    Amendment 08: This change was made to address incorrect standard text that was inadvertently changed in Amendment 07. The language was reverted to text provided in Amendment 06 to maintain consistency within the study.
    07 Apr 2024
    Amendment 09: The changes in this amendment are related to study extension. The changes allow additional data collection and longer follow-up for all participants enrolled in China.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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