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    Clinical Trial Results:
    A Phase III Study of Pembrolizumab (MK-3475) vs. Best Supportive Care as Second-Line Therapy in Subjects With Previously Systemically Treated Advanced Hepatocellular Carcinoma (KEYNOTE-240)

    Summary
    EudraCT number
    		 2015-004567-36
    Trial protocol
    		 IE   DE   DK   HU   FR   GB   PL   BE   IT  
    Global end of trial date
    22 Sep 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Sep 2022
    First version publication date
    15 Sep 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    3475-240
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02702401
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 JAPIC-CTI: 163456, Merck: KEYNOTE-240
    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@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC., ClinicalTrialsDisclosure@merck.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
    22 Sep 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Jan 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Sep 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a study of pembrolizumab (MK-3475) in participants with previously systemically treated advanced hepatocellular carcinoma (HCC). The primary objectives of this study are to determine 1) Progression-Free Survival (PFS) and 2) Overall Survival (OS) of pembrolizumab plus best supportive care (BSC) compared with placebo plus BSC. The primary hypotheses of this study are: 1) pembrolizumab plus BSC prolongs PFS per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, assessed by Blinded Independent Central Review compared to placebo plus BSC, and 2) pembrolizumab plus BSC improves OS compared with placebo plus BSC. Effective with Amendment 4: Upon study completion, participants are discontinued and may be enrolled in a pembrolizumab extension study, if available.
    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
    		 Background therapy will consist of best supportive care and will be administered to all arms in this study. Best supportive care will include pain management and management of other potential complications including ascites per local standards of care.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 May 2016
    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
    Argentina: 2
    Country: Number of subjects enrolled
    Australia: 11
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Chile: 8
    Country: Number of subjects enrolled
    Colombia: 3
    Country: Number of subjects enrolled
    Denmark: 5
    Country: Number of subjects enrolled
    France: 78
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Hong Kong: 14
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    Ireland: 3
    Country: Number of subjects enrolled
    Israel: 8
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Japan: 59
    Country: Number of subjects enrolled
    Korea, Republic of: 50
    Country: Number of subjects enrolled
    Mexico: 7
    Country: Number of subjects enrolled
    Norway: 6
    Country: Number of subjects enrolled
    Philippines: 2
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    Russian Federation: 17
    Country: Number of subjects enrolled
    Taiwan: 27
    Country: Number of subjects enrolled
    Thailand: 5
    Country: Number of subjects enrolled
    Turkey: 17
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    United States: 37
    Worldwide total number of subjects
    413
    EEA total number of subjects
    136
    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)
    173
    From 65 to 84 years
    233
    85 years and over
    7

    Subject disposition

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    Recruitment
    Recruitment details
    		 Although 278 participants were randomized to receive pembrolizumab and 135 to receive placebo, 1 participant in the placebo group received pembrolizumab in error. The efficacy population included all participants as randomized and the safety population was adjusted to account for actual treatment received (pembrolizumab = 279, placebo =134).

    Pre-assignment
    Screening details
    		 Per protocol, response/progression or adverse events during the second pembrolizumab course were not counted towards efficacy outcome measures or safety outcome measures.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pembrolizumab + Best Supportive Care
    Arm description
    		 Participants received pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS best supportive care (BSC). Participants who complete 35 administrations or achieve a complete response (CR) but progress after discontinuation can initiate a second course of pembrolizumab for up to 17 cycles (approximately 1 additional year).
    Arm type
    		 Experimental

    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 on Day 1 of each 3-week cycle.

    Arm title
    		 Placebo + Best Supportive Care
    Arm description
    		 Participants received placebo by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.90% w/v sodium chloride

    Number of subjects in period 1
    		Pembrolizumab + Best Supportive Care Placebo + Best Supportive Care
    Started
    278
    135
    Treated
    278
    135
    Received second course
    7
    0
    Completed
    0
    0
    Not completed
    278
    135
         Consent withdrawn by subject
    15
    5
         Physician decision
    1
    2
         Death
    242
    125
         Sponsor Decision
    19
    3
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pembrolizumab + Best Supportive Care
    Reporting group description
    		 Participants received pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS best supportive care (BSC). Participants who complete 35 administrations or achieve a complete response (CR) but progress after discontinuation can initiate a second course of pembrolizumab for up to 17 cycles (approximately 1 additional year).

    Reporting group title
    Placebo + Best Supportive Care
    Reporting group description
    		 Participants received placebo by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC.

    Reporting group values
    		 Pembrolizumab + Best Supportive Care Placebo + Best Supportive Care Total
    Number of subjects
    		 278 135 413
    Age categorical
    Units: Participants
        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)
    		 109 64 173
        From 65-84 years
    		 164 69 233
        85 years and over
    		 5 2 7
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 65.6 ( 11.1 ) 64.4 ( 10.3 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 52 23 75
        Male
    		 226 112 338
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 5 1 6
        Asian
    		 113 52 165
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Black or African American
    		 13 6 19
        White
    		 143 70 213
        More than one race
    		 3 5 8
        Unknown or Not Reported
    		 0 1 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 22 13 35
        Not Hispanic or Latino
    		 233 113 346
        Unknown or Not Reported
    		 23 9 32
    Region of enrollment
    Units: Subjects
        Asia without Japan
    		 67 31 98
        European Union
    		 96 43 139
        Japan
    		 40 19 59
        United States
    		 21 16 37
        Others
    		 54 26 80
    Macrovascular invasion
    The presence or absence of macrovascular invasion was obtained from case report forms.
    Units: Subjects
        Yes (Present)
    		 36 16 52
        No (Absent)
    		 242 119 361
    Alpha-fetoprotein level
    Alpha-fetoprotein levels were measured using an enzyme-linked immunosorbent assay (ELISA) and participants were categorized by those having alpha-fetoprotein levels of <200 ng/mL and those having levels of ≥200 ng/mL.
    Units: Subjects
        <200 ng/mL
    		 149 77 226
        ≥200 ng/mL
    		 129 58 187

    End points

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    End points reporting groups
    Reporting group title
    Pembrolizumab + Best Supportive Care
    Reporting group description
    		 Participants received pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS best supportive care (BSC). Participants who complete 35 administrations or achieve a complete response (CR) but progress after discontinuation can initiate a second course of pembrolizumab for up to 17 cycles (approximately 1 additional year).

    Reporting group title
    Placebo + Best Supportive Care
    Reporting group description
    		 Participants received placebo by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC.

    Subject analysis set title
    Pembrolizumab + Best Supportive Care
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received pembrolizumab 200 mg by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC. Participants who complete 35 administrations or achieve a complete response (CR) but progress after discontinuation can initiate a second course of pembrolizumab for up to 17 cycles (approximately 1 additional year).

    Subject analysis set title
    Placebo + Best Supportive Care
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received placebo by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC.

    Primary: Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

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    End point title
    		 Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    End point description
    PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first, per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR). PD was defined as ≥20% increase in the sum of diameters of target lesions and an absolute increase of ≥5 mm. The appearance of ≥1 new lesion was also considered PD. If there was no disease progression or death, participants were censored at the date of their last disease assessment. The PFS was analyzed using the product-limit (Kaplan-Meier) method for censored data. Final analyses for PFS was performed for the first pembrolizumab course at protocol specified cut off of 26-Mar-2018. The analysis population included all randomized participants. Participants were included in the treatment group to which they were randomized.
    End point type
    Primary
    End point timeframe
    Through database cutoff date of 26-Mar-2018 (Up to approximately 21 months)
    End point values
    		 Pembrolizumab + Best Supportive Care Placebo + Best Supportive Care
    Number of subjects analysed
    278
    135
    Units: Months
        median (confidence interval 95%)
    3.0 (2.8 to 4.1)
    2.8 (2.5 to 4.1)
    Statistical analysis title
    		 PFS Hazard Ratio
    Statistical analysis description
    Cox regression model with Efron’s method (treatment as covariate) stratified by geographic region, macrovascular invasion and alfa-fetoprotein level
    Comparison groups
    Pembrolizumab + Best Supportive Care v Placebo + Best Supportive Care
    Number of subjects included in analysis
    413
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0186 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.775
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.609
         upper limit
    		 0.987
    Notes
    [1] - One-sided p-value stratified by geographic region, macrovascular invasion and alfa-fetoprotein level.

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was determined for all participants and was defined as the time from randomization to death due to any cause. Participants were censored at the date of their last follow-up. The OS was analyzed using the product-limit (Kaplan-Meier) method for censored data. Final analyses for OS was performed for the first pembrolizumab course at protocol specified cut off of 02-Jan-2019. The analysis population included all randomized participants. Participants were included in the treatment group to which they were randomized.
    End point type
    Primary
    End point timeframe
    Through database cutoff date of 02-Jan-2019 (Up to approximately 30 months)
    End point values
    		 Pembrolizumab + Best Supportive Care Placebo + Best Supportive Care
    Number of subjects analysed
    278
    135
    Units: Months
        median (confidence interval 95%)
    13.9 (11.6 to 16.0)
    10.6 (8.3 to 13.5)
    Statistical analysis title
    		 OS Hazard Ratio
    Statistical analysis description
    Cox regression model with Efron’s method (treatment as covariate) stratified by geographic region, macrovascular invasion and alfa-fetoprotein level
    Comparison groups
    Pembrolizumab + Best Supportive Care v Placebo + Best Supportive Care
    Number of subjects included in analysis
    413
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0238 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.781
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.611
         upper limit
    		 0.998
    Notes
    [2] - One-sided p-value stratified by geographic region, macrovascular invasion and alfa-fetoprotein level.

    Secondary: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

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    End point title
    		 Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    End point description
    ORR was determined in all participants and was defined as the percentage of participants who had a confirmed 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 as assessed by Blinded Independent Central Review (BICR). Participants with missing data were considered non-responders. The ORR was analyzed using the Miettinen & Nurminen method. The percentage of participants who experienced a CR or PR per RECIST 1.1 is presented. Final analyses for ORR was performed for the first pembrolizumab course at protocol specified cut off of 02-Jan-2019. The analysis population included all randomized participants. Participants were included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Through database cutoff date of 02-Jan-2019 (Up to approximately 30 months)
    End point values
    		 Pembrolizumab + Best Supportive Care Placebo + Best Supportive Care
    Number of subjects analysed
    278
    135
    Units: Percentage of participants
        number (confidence interval 95%)
    18.3 (14.0 to 23.4)
    4.4 (1.6 to 9.4)
    Statistical analysis title
    		 ORR Difference in Percent
    Statistical analysis description
    Miettinen & Nurminen method stratified by geographic region, macrovascular invasion and alfa-fetoprotein level
    Comparison groups
    Pembrolizumab + Best Supportive Care v Placebo + Best Supportive Care
    Number of subjects included in analysis
    413
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percent
    Point estimate
    13.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.7
         upper limit
    		 19.5

    Secondary: Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

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    End point title
    		 Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    End point description
    DCR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions), Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters), or Stable Disease (SD) per RECIST 1.1 after ≥6 weeks as assessed by Blinded Independent Central Review (BICR). The DCR was analyzed using the Miettinen & Nurminen method. The percentage of participants who experienced a CR, PR, or SD is presented. Final analyses for DCR was performed for the first pembrolizumab course at protocol specified cut off of 02-Jan-2019. The analysis population included all randomized participants. Participants were included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Through database cutoff date of 02-Jan-2019 (Up to approximately 30 months)
    End point values
    		 Pembrolizumab + Best Supportive Care Placebo + Best Supportive Care
    Number of subjects analysed
    278
    135
    Units: Percentage of participants
        number (confidence interval 95%)
    62.2 (56.2 to 68.0)
    53.3 (44.6 to 62.0)
    No statistical analyses for this end point

    Secondary: Time to Progression (TTP) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

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    End point title
    		 Time to Progression (TTP) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    End point description
    TTP was defined as the time from randomization to the first documented disease progression per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR). PD was defined as ≥20% increase in the sum of diameters of target lesions and an absolute increase of ≥5 mm. The appearance of ≥1 new lesion was also considered PD. If there was no documented disease progression, TTP was censored at last tumor assessment date. The TTP was analyzed using the product-limit (Kaplan-Meier) method for censored data. TTP per RECIST 1.1 is presented for all participants. Final analyses for TTP was performed for the first pembrolizumab course at protocol specified cut off of 02-Jan-2019. The analysis population included all randomized participants. Participants were included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Through database cutoff date of 02-Jan-2019 (Up to approximately 30 months)
    End point values
    		 Pembrolizumab + Best Supportive Care Placebo + Best Supportive Care
    Number of subjects analysed
    278
    135
    Units: Months
        median (confidence interval 95%)
    3.8 (2.8 to 4.4)
    2.8 (1.6 to 2.9)
    Statistical analysis title
    		 TTP Hazard Ratio
    Statistical analysis description
    Cox regression model with Efron’s method (treatment as covariate) stratified by geographic region, macrovascular invasion and alfa-fetoprotein level
    Comparison groups
    Pembrolizumab + Best Supportive Care v Placebo + Best Supportive Care
    Number of subjects included in analysis
    413
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0011 [3]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.688
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 0.877
    Notes
    [3] - One-sided p-value stratified by geographic region, macrovascular invasion and alfa-fetoprotein level.

    Secondary: Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

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    End point title
    		 Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    End point description
    In participants with a Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in sum of diameters of target lesions) per RECIST 1.1 by BICR, DOR was the time from first CR/PR until progressive disease (PD: ≥20% increase in the sum of diameters and an absolute increase of ≥5 mm; appearance of ≥1 new lesion is also PD) or death. Participants who did not progress or die at time of analysis were censored at last tumor assessment. Final analysis for DOR was done for the first pembrolizumab course at protocol specified cut off of 02-Jan-2019. The analysis population was all randomized participants who demonstrated at least a partial response. Participants were included in the treatment group to which they were randomized. "9999" indicates median and upper limit were not reached according to the prespecified methodology in the protocol.
    End point type
    Secondary
    End point timeframe
    From time of first documented evidence of CR or PR through database cutoff date of 02-Jan-2019 (Up to approximately 30 months)
    End point values
    		 Pembrolizumab + Best Supportive Care Placebo + Best Supportive Care
    Number of subjects analysed
    51
    6
    Units: Months
        median (confidence interval 95%)
    13.8 (6.9 to 9999)
    9999 (2.8 to 9999)
    No statistical analyses for this end point

    Secondary: Number of Participants Who Experienced At Least One Adverse Event (AE)

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    End point title
    		 Number of Participants Who Experienced At Least One Adverse Event (AE)
    End point description
    An AE was defined as any untoward medical occurrence in a participant given a study treatment and not necessarily have to have a causal relationship with this treatment. An AE can thus be any unfavorable, unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Also worsening of a pre-existing condition temporally associated with the use of study treatment, was an AE. The number of participants who experienced at least one AE is presented. Final analyses for AE was performed for the first pembrolizumab course at protocol specified cut off of 02-Jan-2019. The analysis population included participants who received ≥1 dose of study treatment. Participants were grouped by actual treatment received.
    End point type
    Secondary
    End point timeframe
    Through database cutoff date of 02-Jan-2019 (Up to approximately 30 months)
    End point values
    		 Pembrolizumab + Best Supportive Care Placebo + Best Supportive Care
    Number of subjects analysed
    279
    134
    Units: Participants
    269
    121
    No statistical analyses for this end point

    Secondary: Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)

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    End point title
    		 Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
    End point description
    An AE was defined as any untoward medical occurrence in a participant given a study treatment and not necessarily have to have a causal relationship with this treatment. An AE can thus be any unfavorable, unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Also worsening of a pre-existing condition temporally associated with the use of study treatment, was an AE. The number of participants who discontinued study treatment due to an AE is presented. Final analyses for AE was performed for the first pembrolizumab course at protocol specified cut off of 02-Jan-2019. The analysis population included participants who received ≥1 dose of study treatment. Participants were grouped by actual treatment received.
    End point type
    Secondary
    End point timeframe
    From Day 1 through end of treatment (Up to approximately 24 months)
    End point values
    		 Pembrolizumab + Best Supportive Care Placebo + Best Supportive Care
    Number of subjects analysed
    279
    134
    Units: Participants
    48
    12
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Through database cutoff date of 22-Sep-2021 (Up to approximately 59.3 months).
    Adverse event reporting additional description
    All participants who received ≥1 dose of study treatment. Per protocol, MedDRA terms "Neoplasm progression (NP)", "Malignant NP" & "Disease progression" unrelated to study drug are excluded as AEs. Due to a dosing error, the population for all-cause mortality and AEs was adjusted to account for actual treatment received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Pembrolizumab + Best Supportive Care
    Reporting group description
    		 Participants received pembrolizumab 200 mg by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC. Participants who complete 35 administrations or achieve a complete response (CR) but progress after discontinuation can initiate a second course of pembrolizumab for up to 17 cycles (approximately 1 additional year).

    Reporting group title
    Pembrolizumab Second Course
    Reporting group description
    		 Participants who completed the first course of up to 35 administrations of pembrolizumab (~2 years) but progressed after discontinuation, initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 17 cycles (up to ~1 year).

    Reporting group title
    Placebo + Best Supportive Care
    Reporting group description
    		 Participants received placebo by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC.

    Serious adverse events
    		 Pembrolizumab + Best Supportive Care Pembrolizumab Second Course Placebo + Best Supportive Care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    106 / 279 (37.99%)
    3 / 7 (42.86%)
    37 / 134 (27.61%)
         number of deaths (all causes)
    246
    3
    124
         number of deaths resulting from adverse events
    1
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Insulinoma
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Oral neoplasm
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour rupture
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Fatigue
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 279 (0.72%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Contrast media allergy
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    3 / 279 (1.08%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 279 (0.72%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 279 (0.72%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    2 / 279 (0.72%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 279 (2.51%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    5 / 7
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    9 / 279 (3.23%)
    0 / 7 (0.00%)
    4 / 134 (2.99%)
         occurrences causally related to treatment / all
    5 / 9
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    8 / 279 (2.87%)
    0 / 7 (0.00%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    3 / 8
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular procedure complication
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 279 (0.72%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pericardial effusion
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 279 (1.08%)
    0 / 7 (0.00%)
    5 / 134 (3.73%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune thrombocytopenia
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Blindness unilateral
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Macular hole
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal vein occlusion
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    2 / 279 (0.72%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    13 / 279 (4.66%)
    0 / 7 (0.00%)
    5 / 134 (3.73%)
         occurrences causally related to treatment / all
    1 / 14
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    2 / 279 (0.72%)
    1 / 7 (14.29%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 279 (0.72%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticular fistula
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroduodenal ulcer
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 279 (0.00%)
    1 / 7 (14.29%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intra-abdominal haemorrhage
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    3 / 279 (1.08%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    3 / 279 (1.08%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    3 / 279 (1.08%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    2 / 279 (0.72%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    2 / 279 (0.72%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    2 / 279 (0.72%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Hepatic cyst
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    2 / 279 (0.72%)
    0 / 7 (0.00%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Hepatic haemorrhage
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 279 (0.72%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    3 / 279 (1.08%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema multiforme
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lichenoid keratosis
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 279 (1.08%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypophysitis
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    1 / 279 (0.36%)
    1 / 7 (14.29%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 279 (0.00%)
    1 / 7 (14.29%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 279 (0.00%)
    1 / 7 (14.29%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Polymyalgia rheumatica
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 279 (0.72%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mycobacterial infection
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Peritonitis bacterial
         subjects affected / exposed
    2 / 279 (0.72%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural infection
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 279 (2.15%)
    0 / 7 (0.00%)
    3 / 134 (2.24%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia mycoplasmal
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 279 (0.72%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis septic
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 7 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pembrolizumab + Best Supportive Care Pembrolizumab Second Course Placebo + Best Supportive Care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    240 / 279 (86.02%)
    7 / 7 (100.00%)
    109 / 134 (81.34%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    10 / 279 (3.58%)
    0 / 7 (0.00%)
    8 / 134 (5.97%)
         occurrences all number
    10
    0
    14
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    26 / 279 (9.32%)
    0 / 7 (0.00%)
    15 / 134 (11.19%)
         occurrences all number
    35
    0
    17
    Fatigue
         subjects affected / exposed
    51 / 279 (18.28%)
    2 / 7 (28.57%)
    31 / 134 (23.13%)
         occurrences all number
    60
    2
    32
    Oedema peripheral
         subjects affected / exposed
    32 / 279 (11.47%)
    1 / 7 (14.29%)
    17 / 134 (12.69%)
         occurrences all number
    39
    1
    20
    Pyrexia
         subjects affected / exposed
    25 / 279 (8.96%)
    0 / 7 (0.00%)
    15 / 134 (11.19%)
         occurrences all number
    27
    0
    22
    Reproductive system and breast disorders
    Penile erythema
         subjects affected / exposed
    1 / 279 (0.36%)
    1 / 7 (14.29%)
    0 / 134 (0.00%)
         occurrences all number
    2
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    24 / 279 (8.60%)
    1 / 7 (14.29%)
    24 / 134 (17.91%)
         occurrences all number
    32
    1
    27
    Dyspnoea
         subjects affected / exposed
    19 / 279 (6.81%)
    0 / 7 (0.00%)
    14 / 134 (10.45%)
         occurrences all number
    19
    0
    16
    Nasal congestion
         subjects affected / exposed
    2 / 279 (0.72%)
    1 / 7 (14.29%)
    1 / 134 (0.75%)
         occurrences all number
    2
    1
    2
    Rhinorrhoea
         subjects affected / exposed
    1 / 279 (0.36%)
    1 / 7 (14.29%)
    3 / 134 (2.24%)
         occurrences all number
    1
    1
    3
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    1 / 279 (0.36%)
    1 / 7 (14.29%)
    0 / 134 (0.00%)
         occurrences all number
    1
    1
    0
    Insomnia
         subjects affected / exposed
    12 / 279 (4.30%)
    0 / 7 (0.00%)
    8 / 134 (5.97%)
         occurrences all number
    12
    0
    10
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    45 / 279 (16.13%)
    0 / 7 (0.00%)
    12 / 134 (8.96%)
         occurrences all number
    49
    0
    12
    Aspartate aminotransferase increased
         subjects affected / exposed
    55 / 279 (19.71%)
    0 / 7 (0.00%)
    18 / 134 (13.43%)
         occurrences all number
    58
    0
    21
    Blood alkaline phosphatase increased
         subjects affected / exposed
    20 / 279 (7.17%)
    0 / 7 (0.00%)
    9 / 134 (6.72%)
         occurrences all number
    20
    0
    9
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    18 / 279 (6.45%)
    0 / 7 (0.00%)
    7 / 134 (5.22%)
         occurrences all number
    19
    0
    7
    Blood bilirubin increased
         subjects affected / exposed
    46 / 279 (16.49%)
    0 / 7 (0.00%)
    16 / 134 (11.94%)
         occurrences all number
    59
    0
    18
    Platelet count decreased
         subjects affected / exposed
    13 / 279 (4.66%)
    1 / 7 (14.29%)
    2 / 134 (1.49%)
         occurrences all number
    16
    1
    2
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    3 / 279 (1.08%)
    1 / 7 (14.29%)
    0 / 134 (0.00%)
         occurrences all number
    3
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    20 / 279 (7.17%)
    0 / 7 (0.00%)
    5 / 134 (3.73%)
         occurrences all number
    23
    0
    7
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    27 / 279 (9.68%)
    0 / 7 (0.00%)
    11 / 134 (8.21%)
         occurrences all number
    29
    0
    18
    Lymphadenopathy
         subjects affected / exposed
    1 / 279 (0.36%)
    1 / 7 (14.29%)
    1 / 134 (0.75%)
         occurrences all number
    1
    1
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    39 / 279 (13.98%)
    0 / 7 (0.00%)
    9 / 134 (6.72%)
         occurrences all number
    51
    0
    9
    Abdominal pain upper
         subjects affected / exposed
    25 / 279 (8.96%)
    0 / 7 (0.00%)
    10 / 134 (7.46%)
         occurrences all number
    27
    0
    14
    Ascites
         subjects affected / exposed
    15 / 279 (5.38%)
    0 / 7 (0.00%)
    8 / 134 (5.97%)
         occurrences all number
    15
    0
    8
    Constipation
         subjects affected / exposed
    28 / 279 (10.04%)
    0 / 7 (0.00%)
    15 / 134 (11.19%)
         occurrences all number
    33
    0
    16
    Diarrhoea
         subjects affected / exposed
    49 / 279 (17.56%)
    0 / 7 (0.00%)
    20 / 134 (14.93%)
         occurrences all number
    74
    0
    24
    Gastrooesophageal reflux disease
         subjects affected / exposed
    5 / 279 (1.79%)
    1 / 7 (14.29%)
    2 / 134 (1.49%)
         occurrences all number
    6
    1
    2
    Nausea
         subjects affected / exposed
    33 / 279 (11.83%)
    0 / 7 (0.00%)
    20 / 134 (14.93%)
         occurrences all number
    41
    0
    21
    Toothache
         subjects affected / exposed
    3 / 279 (1.08%)
    1 / 7 (14.29%)
    0 / 134 (0.00%)
         occurrences all number
    4
    1
    0
    Pneumatosis intestinalis
         subjects affected / exposed
    0 / 279 (0.00%)
    1 / 7 (14.29%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    Vomiting
         subjects affected / exposed
    26 / 279 (9.32%)
    0 / 7 (0.00%)
    5 / 134 (3.73%)
         occurrences all number
    41
    0
    9
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    53 / 279 (19.00%)
    0 / 7 (0.00%)
    17 / 134 (12.69%)
         occurrences all number
    66
    0
    18
    Rash
         subjects affected / exposed
    35 / 279 (12.54%)
    0 / 7 (0.00%)
    7 / 134 (5.22%)
         occurrences all number
    42
    0
    8
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    2 / 279 (0.72%)
    1 / 7 (14.29%)
    1 / 134 (0.75%)
         occurrences all number
    2
    1
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    13 / 279 (4.66%)
    0 / 7 (0.00%)
    7 / 134 (5.22%)
         occurrences all number
    14
    0
    7
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    33 / 279 (11.83%)
    0 / 7 (0.00%)
    17 / 134 (12.69%)
         occurrences all number
    37
    0
    19
    Back pain
         subjects affected / exposed
    29 / 279 (10.39%)
    0 / 7 (0.00%)
    13 / 134 (9.70%)
         occurrences all number
    31
    0
    14
    Neck pain
         subjects affected / exposed
    4 / 279 (1.43%)
    1 / 7 (14.29%)
    0 / 134 (0.00%)
         occurrences all number
    4
    1
    0
    Flank pain
         subjects affected / exposed
    5 / 279 (1.79%)
    1 / 7 (14.29%)
    3 / 134 (2.24%)
         occurrences all number
    8
    1
    3
    Infections and infestations
    Herpes zoster
         subjects affected / exposed
    2 / 279 (0.72%)
    1 / 7 (14.29%)
    0 / 134 (0.00%)
         occurrences all number
    2
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    47 / 279 (16.85%)
    0 / 7 (0.00%)
    21 / 134 (15.67%)
         occurrences all number
    51
    0
    23
    Hyperglycaemia
         subjects affected / exposed
    12 / 279 (4.30%)
    0 / 7 (0.00%)
    7 / 134 (5.22%)
         occurrences all number
    21
    0
    7
    Hypoalbuminaemia
         subjects affected / exposed
    21 / 279 (7.53%)
    0 / 7 (0.00%)
    7 / 134 (5.22%)
         occurrences all number
    25
    0
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Mar 2016
    The primary reason for amendment 1 was removal of health economic assessment (HEA) from patient reported outcomes, removal of the option of including participants without confirmed diagnosis of HCC from inclusion criterion, removal of “target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions” from inclusion criterion and insertion of clarifying text 'negative for anti-HBs' (Hepatitis B surface antibody) to exclusion criteria. Other primary reasons included updates and corrections to prohibited concomitant medications, supportive care guidelines, participant withdrawal/discontinuation criteria, trial flow charts, investigational products and the appendix.
    03 Aug 2016
    The primary reason for amendment 2 was addition of participant eligibility by radiographic diagnosis for HCC and text to change percentage of participants to be enrolled in the specified populations and countries.
    16 Mar 2017
    The primary reason for amendment 3 was addition of 2nd interim analysis, updates to show survival status activities taking place throughout the trial and addition of “the trial will be deemed positive if either OS or PFS null hypothesis are rejected” to the primary objectives and hypothesis. Other primary reasons included updates and corrections to survival follow-up phase, dose modification guidelines and survival status.
    03 Mar 2021
    The primary reason for amendment 4 was addition of language to include the requirement of roll over of trial participants into an extension trial (if available) when this trial is completed, update to assessment by radiologic imaging from every 6 weeks (Q6W) to every 12 weeks (Q12W) and duration of follow-up phase.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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