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    Clinical Trial Results:
    A Phase 2 Study of Pembrolizumab (MK-3475) as Monotherapy in Subjects With Advanced Hepatocellular Carcinoma (KEYNOTE-224)

    Summary
    EudraCT number
    		 2015-004566-28
    Trial protocol
    		 DE   SE   GB   BE   FR   IT  
    Global end of trial date
    29 Sep 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Sep 2024
    First version publication date
    04 Sep 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    3475-224
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02702414
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 MSD: KEYNOTE-224, JAPIC-CTI: 163434
    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
    29 Sep 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Sep 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a efficacy and safety study of pembrolizumab (MK-3475, KEYTRUDA®) as monotherapy in participants with hepatocellular carcinoma (HCC) in two cohorts: participants with advanced HCC and with no curative option after disease progression on sorafenib or intolerance of sorafenib (Cohort 1) or who had not received treatment for systemic disease (Cohort 2). Study participants may receive pembrolizumab once every 3 weeks for up to 35 initial cycles (up to approximately 2 years) and a potential additional 17 cycles in a re-treatment phase (approximately an additional 1 year of treatment) . The primary objective of this study is to determine the Objective Response Rate (ORR) of pembrolizumab given as monotherapy in participants with HCC. Effective with Amendment 7: 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
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Jun 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
    Belgium: 39
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    France: 32
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Japan: 11
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    United States: 33
    Worldwide total number of subjects
    156
    EEA total number of subjects
    97
    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)
    52
    From 65 to 84 years
    99
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study had 2 cohorts with each cohort starting treatment at a different time period during the study. One participant allocated to Cohort 1 withdrew from the study before receiving treatment. This participant was not eligible for safety or efficacy analysis.

    Pre-assignment
    Screening details
    		 Per protocol, final analyses of all outcome measures were planned to be performed during the first course of therapy and collection of adverse events and all-cause mortality were planned to be done in both first and second courses.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: HCC-Prior Systemic Therapy with Sorafenib
    Arm description
    		 Participants with previously systemically treated Hepatocellular Carcinoma (HCC) received a pembrolizumab 200 mg intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 administrations. Participants who stopped pembrolizumab as a result of obtaining a confirmed complete response (CR) or those who stopped after receiving 35 trial treatments were eligible for an additional 17 trial treatments (approximately an additional 1 year of treatment) after progressive disease if they met the criteria for re-treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475 KEYTRUDA®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use , Intravenous use
    Dosage and administration details
    IV Infusion

    Arm title
    		 Cohort 2: HCC-Systemic Therapy Naïve
    Arm description
    		 Participants with HCC who had not received treatment for systemic disease received a pembrolizumab 200 mg IV infusion on Day 1 of each 3-week cycle for up to 35 administrations. Participants who stopped pembrolizumab as a result of obtaining a confirmed complete response (CR) or those who stopped after receiving 35 trial treatments were eligible for an additional 17 trial treatments (approximately an additional 1 year of treatment) after progressive disease if they met the criteria for re-treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475 KEYTRUDA®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use , Intravenous use
    Dosage and administration details
    IV infusion

    Number of subjects in period 1
    		Cohort 1: HCC-Prior Systemic Therapy with Sorafenib Cohort 2: HCC-Systemic Therapy Naïve
    Started
    105
    51
    Treated
    104
    51
    Received Second Course of Pembrolizumab
    4
    1
    Completed
    0
    0
    Not completed
    105
    51
         Consent withdrawn by subject
    -
    1
         Death
    96
    42
         Sponsor Decision
    8
    7
         Lost to follow-up
    -
    1
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: HCC-Prior Systemic Therapy with Sorafenib
    Reporting group description
    		 Participants with previously systemically treated Hepatocellular Carcinoma (HCC) received a pembrolizumab 200 mg intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 administrations. Participants who stopped pembrolizumab as a result of obtaining a confirmed complete response (CR) or those who stopped after receiving 35 trial treatments were eligible for an additional 17 trial treatments (approximately an additional 1 year of treatment) after progressive disease if they met the criteria for re-treatment.

    Reporting group title
    Cohort 2: HCC-Systemic Therapy Naïve
    Reporting group description
    		 Participants with HCC who had not received treatment for systemic disease received a pembrolizumab 200 mg IV infusion on Day 1 of each 3-week cycle for up to 35 administrations. Participants who stopped pembrolizumab as a result of obtaining a confirmed complete response (CR) or those who stopped after receiving 35 trial treatments were eligible for an additional 17 trial treatments (approximately an additional 1 year of treatment) after progressive disease if they met the criteria for re-treatment.

    Reporting group values
    		 Cohort 1: HCC-Prior Systemic Therapy with Sorafenib Cohort 2: HCC-Systemic Therapy Naïve Total
    Number of subjects
    		 105 51 156
    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)
    		 34 18 52
        From 65-84 years
    		 69 30 99
        85 years and over
    		 2 3 5
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 67.4 ( 8.2 ) 67.7 ( 10.3 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 19 7 26
        Male
    		 86 44 130
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 14 2 16
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Black or African American
    		 3 1 4
        White
    		 85 48 133
        More than one race
    		 1 0 1
        Unknown or Not Reported
    		 1 0 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 3 2 5
        Not Hispanic or Latino
    		 99 45 144
        Unknown or Not Reported
    		 3 4 7

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: HCC-Prior Systemic Therapy with Sorafenib
    Reporting group description
    		 Participants with previously systemically treated Hepatocellular Carcinoma (HCC) received a pembrolizumab 200 mg intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 administrations. Participants who stopped pembrolizumab as a result of obtaining a confirmed complete response (CR) or those who stopped after receiving 35 trial treatments were eligible for an additional 17 trial treatments (approximately an additional 1 year of treatment) after progressive disease if they met the criteria for re-treatment.

    Reporting group title
    Cohort 2: HCC-Systemic Therapy Naïve
    Reporting group description
    		 Participants with HCC who had not received treatment for systemic disease received a pembrolizumab 200 mg IV infusion on Day 1 of each 3-week cycle for up to 35 administrations. Participants who stopped pembrolizumab as a result of obtaining a confirmed complete response (CR) or those who stopped after receiving 35 trial treatments were eligible for an additional 17 trial treatments (approximately an additional 1 year of treatment) after progressive disease if they met the criteria for re-treatment.

    Subject analysis set title
    Cohort 1: HCC-Prior Systemic Therapy with Sorafenib
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants with previously systemically treated HCC received a pembrolizumab 200 mg IV infusion on Day 1 of each 3-week cycle for up to 35 administrations. Participants who stopped pembrolizumab as a result of obtaining a confirmed complete response (CR) or those who stopped after receiving 35 trial treatments were eligible for an additional 17 trial treatments (approximately an additional 1 year of treatment) after progressive disease if they met the criteria for re-treatment.

    Subject analysis set title
    Cohort 1: HCC-Prior Systemic Therapy with Sorafenib
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants with previously systemically treated HCC received a pembrolizumab 200 mg IV infusion on Day 1 of each 3-week cycle for up to 35 administrations. Participants who stopped pembrolizumab as a result of obtaining a confirmed complete response (CR) or those who stopped after receiving 35 trial treatments were eligible for an additional 17 trial treatments (approximately an additional 1 year of treatment) after progressive disease if they met the criteria for re-treatment.

    Subject analysis set title
    Cohort 2: HCC-Systemic Therapy Naïve
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants with HCC who had not received treatment for systemic disease received a pembrolizumab 200 mg IV infusion on Day 1 of each 3-week cycle for up to 35 administrations. Participants who stopped pembrolizumab as a result of obtaining a confirmed complete response (CR) or those who stopped after receiving 35 trial treatments were eligible for an additional 17 trial treatments (approximately an additional 1 year of treatment) after progressive disease if they met the criteria for re-treatment.

    Primary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR) [1] [2]
    End point description
    ORR was defined as the percentage of participants who had a confirmed Complete Response (CR: Disappearance of all target and non-target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target and non-target lesions) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded central imaging vendor. Participants with missing data were considered non-responders. The percentage of participants who experienced a CR or PR per RECIST 1.1 is presented. The analysis population included all participants who received at least one dose of study treatment during the first course of therapy.
    End point type
    Primary
    End point timeframe
    Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No between-arm analysis was conducted for this endpoint.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No between-arm analysis was conducted for this endpoint.
    End point values
    		 Cohort 2: HCC-Systemic Therapy Naïve Cohort 1: HCC-Prior Systemic Therapy with Sorafenib
    Number of subjects analysed
    51
    104
    Units: Percentage of participants
        number (confidence interval 95%)
    15.7 (7.0 to 28.6)
    18.3 (11.4 to 27.1)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR)

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    End point title
    		 Disease Control Rate (DCR) [3]
    End point description
    DCR was defined as the percentage of participants who had a CR (disappearance of all target and non-target lesions), PR (at least a 30% decrease in the sum of diameters of target and non-target lesions), or Stable Disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease [PD was at least 20% increase in SD of target lesions and an absolute increase of at least 5 mm, OR unequivocal progression for non-target lesions, OR appearance of one or more new lesions.]). CR, PR, and SD were evaluated per RECIST 1.1 as assessed by BICR. Participants with missing data were considered as participants whose disease was not under control. The percentage of participants who experienced a confirmed CR, PR, or SD was reported. The analysis population included all participants who received at least one dose of study treatment during the first course of therapy.
    End point type
    Secondary
    End point timeframe
    Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No between-arm analysis was conducted for this endpoint.
    End point values
    		 Cohort 2: HCC-Systemic Therapy Naïve Cohort 1: HCC-Prior Systemic Therapy with Sorafenib
    Number of subjects analysed
    51
    104
    Units: Percentage of participants
        number (confidence interval 95%)
    56.9 (42.2 to 70.7)
    61.5 (51.5 to 70.9)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR) [4]
    End point description
    For participants who demonstrated a confirmed CR (disappearance of all target & non-target lesions) or PR (≥30% decrease in the sum of diameters [SD] of target & non-target lesions) per RECIST 1.1 as assessed by BICR; DOR was defined as time from first documented evidence of CR or PR until progressive disease (PD) or death. Participants who had not progressed, started new anti-cancer therapy, been lost to follow-up, or died at the time of analysis were censored at tumor assessment date. Per RECIST 1.1, PD was at least 20% increase in SD of target lesions & an absolute increase of at least 5 mm, OR unequivocal progression for non-target lesions, OR appearance of one or more new lesions. The DOR for all participants who had a confirmed CR or PR was presented. The analysis population included all participants who received at least 1 dose of study treatment & who had a confirmed CR or confirmed PR during the first course of therapy. A value of 9999 indicates that no data were calculated.
    End point type
    Secondary
    End point timeframe
    Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No between-arm analysis was conducted for this endpoint.
    End point values
    		 Cohort 2: HCC-Systemic Therapy Naïve Cohort 1: HCC-Prior Systemic Therapy with Sorafenib
    Number of subjects analysed
    8
    19
    Units: Months
        median (confidence interval 95%)
    16.2 (3.1 to 9999)
    21.0 (10.7 to 9999)
    No statistical analyses for this end point

    Secondary: Time to Progression (TTP)

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    End point title
    		 Time to Progression (TTP) [5]
    End point description
    TTP was defined as time from the first dose to the first documented disease progression per RECIST 1.1 as assessed by BICR. PD was at least a 20% increase in the SD of target lesions and an absolute increase of at least 5 mm, OR unequivocal progression for non-target lesions, OR appearance of one or more new lesions. 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 was presented. The analysis population included all participants who received at least one dose of study treatment during the first course of therapy.
    End point type
    Secondary
    End point timeframe
    Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No between-arm analysis was conducted for this endpoint.
    End point values
    		 Cohort 2: HCC-Systemic Therapy Naïve Cohort 1: HCC-Prior Systemic Therapy with Sorafenib
    Number of subjects analysed
    51
    104
    Units: Months
        median (confidence interval 95%)
    4.4 (2.5 to 8.6)
    4.8 (3.9 to 7.0)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS) [6]
    End point description
    OS was determined for all participants and was defined as the time from the first dose to death due to any cause. Participants were censored at the last known alive date. The OS was analyzed using the product-limit (Kaplan-Meier) method for censored data. The OS is presented. The analysis population included all participants who received at least one dose of study treatment during the first course of therapy.
    End point type
    Secondary
    End point timeframe
    Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No between-arm analysis was conducted for this endpoint.
    End point values
    		 Cohort 2: HCC-Systemic Therapy Naïve Cohort 1: HCC-Prior Systemic Therapy with Sorafenib
    Number of subjects analysed
    51
    104
    Units: Months
        median (confidence interval 95%)
    16.9 (8.3 to 23.1)
    13.2 (9.7 to 15.3)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS) [7]
    End point description
    PFS was defined as the time from the first dose to the first documented PD or death due to any cause, whichever occurred first, per RECIST 1.1 as assessed by BICR. PD was at least a 20% increase in SD of target lesions and an absolute increase of at least 5 mm, OR unequivocal progression for non-target lesions, OR appearance of one or more new lesions. 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. PFS was presented. The analysis population included all participants who received at least one dose of study treatment during the first course of therapy.
    End point type
    Secondary
    End point timeframe
    Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No between-arm analysis was conducted for this endpoint.
    End point values
    		 Cohort 2: HCC-Systemic Therapy Naïve Cohort 1: HCC-Prior Systemic Therapy with Sorafenib
    Number of subjects analysed
    51
    104
    Units: Months
        median (confidence interval 95%)
    4.3 (2.1 to 7.8)
    4.9 (3.5 to 6.7)
    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) [8]
    End point description
    An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE could be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any worsening (i.e., any clinically significant adverse change infrequency and/or intensity) of a preexisting condition that was temporally associated with the use of study treatment, was also an AE. Per protocol, the number of participants who experienced at least one AE was presented for first course of therapy only. The analysis population included all participants who received at least one dose of study treatment during the first course of therapy.
    End point type
    Secondary
    End point timeframe
    Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No between-arm analysis was conducted for this endpoint.
    End point values
    		 Cohort 2: HCC-Systemic Therapy Naïve Cohort 1: HCC-Prior Systemic Therapy with Sorafenib
    Number of subjects analysed
    51
    104
    Units: Participants
    49
    101
    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) [9]
    End point description
    An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE could be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any worsening (i.e., any clinically significant adverse change infrequency and/or intensity) of a preexisting condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who discontinued study treatment due to an AE was presented for first course of therapy only. The analysis population included all participants who received at least one dose of study treatment during the first course of therapy.
    End point type
    Secondary
    End point timeframe
    Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No between-arm analysis was conducted for this endpoint.
    End point values
    		 Cohort 2: HCC-Systemic Therapy Naïve Cohort 1: HCC-Prior Systemic Therapy with Sorafenib
    Number of subjects analysed
    51
    104
    Units: Participants
    8
    23
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 87 months
    Adverse event reporting additional description
    All-cause mortality (ACM)=all allocated participants (n=156); AEs=all participants who received ≥1 dose of treatment. Disease progression was not considered an AE unless treatment related. Neoplasm progression (NP), malignant NP, and disease progression unrelated to treatment were excluded. The 1st and 2nd courses were reported separately.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Cohort1:HCC-Prior Systemic Therapy with Sorafenib‌-1st Course
    Reporting group description
    		 Participants with previously systemically treated HCC received a pembrolizumab 200 mg IV infusion on Day 1 of each 3-week cycle for up to 35 administrations. Participants who stopped pembrolizumab as a result of obtaining a confirmed complete response (CR) or those who stopped after receiving 35 trial treatments were eligible for an additional 17 trial treatments (approximately an additional 1 year of treatment) after progressive disease if they met the criteria for re-treatment.

    Reporting group title
    Cohort 2: HCC-Systemic Therapy Naïve-2nd Course
    Reporting group description
    		 Participants from Cohort 2 who met the criteria for re-treatment received a pembrolizumab 200 mg IV infusion on Day 1 of each 3-week cycle for up to 17 administrations.

    Reporting group title
    Cohort1:HCC-Prior Systemic Therapy with Sorafenib-2nd Course
    Reporting group description
    		 Participants from Cohort 1 who met the criteria for re-treatment received a pembrolizumab 200 mg IV infusion on Day 1 of each 3-week cycle for up to 17 administrations.

    Reporting group title
    Cohort 2: HCC-Systemic Therapy Naïve‌-1st Course
    Reporting group description
    		 Participants with HCC who had not received treatment for systemic disease received a pembrolizumab 200 mg IV infusion on Day 1 of each 3-week cycle for up to 35 administrations. Participants who stopped pembrolizumab as a result of obtaining a confirmed complete response (CR) or those who stopped after receiving 35 trial treatments were eligible for an additional 17 trial treatments (approximately an additional 1 year of treatment) after progressive disease if they met the criteria for re-treatment.

    Serious adverse events
    		 Cohort1:HCC-Prior Systemic Therapy with Sorafenib‌-1st Course Cohort 2: HCC-Systemic Therapy Naïve-2nd Course Cohort1:HCC-Prior Systemic Therapy with Sorafenib-2nd Course Cohort 2: HCC-Systemic Therapy Naïve‌-1st Course
    Total subjects affected by serious adverse events
         subjects affected / exposed
    44 / 104 (42.31%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    21 / 51 (41.18%)
         number of deaths (all causes)
    94
    0
    2
    42
         number of deaths resulting from adverse events
    11
    0
    0
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour necrosis
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypovolaemic shock
         subjects affected / exposed
    2 / 104 (1.92%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulcer haemorrhage
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 104 (1.92%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 104 (1.92%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 104 (3.85%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic left ventricular failure
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    2 / 51 (3.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 104 (2.88%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal vein occlusion
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    4 / 104 (3.85%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Gastritis haemorrhagic
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune colitis
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    3 / 104 (2.88%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    2 / 104 (1.92%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic cytolysis
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hepatic haemorrhage
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    2 / 104 (1.92%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Lichenoid keratosis
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 104 (1.92%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypophysitis
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    2 / 104 (1.92%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pathological fracture
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cellulitis
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine infection
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 104 (1.92%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 104 (2.88%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    2 / 104 (1.92%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Diabetic metabolic decompensation
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort1:HCC-Prior Systemic Therapy with Sorafenib‌-1st Course Cohort 2: HCC-Systemic Therapy Naïve-2nd Course Cohort1:HCC-Prior Systemic Therapy with Sorafenib-2nd Course Cohort 2: HCC-Systemic Therapy Naïve‌-1st Course
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    96 / 104 (92.31%)
    0 / 1 (0.00%)
    4 / 4 (100.00%)
    46 / 51 (90.20%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    16 / 104 (15.38%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    7 / 51 (13.73%)
         occurrences all number
    19
    0
    1
    8
    Fatigue
         subjects affected / exposed
    30 / 104 (28.85%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    21 / 51 (41.18%)
         occurrences all number
    40
    0
    0
    23
    Mucosal inflammation
         subjects affected / exposed
    2 / 104 (1.92%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    3
    0
    0
    4
    Pyrexia
         subjects affected / exposed
    5 / 104 (4.81%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    5 / 51 (9.80%)
         occurrences all number
    6
    0
    0
    6
    Oedema peripheral
         subjects affected / exposed
    20 / 104 (19.23%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    14 / 51 (27.45%)
         occurrences all number
    21
    0
    1
    15
    Respiratory, thoracic and mediastinal disorders
    Productive cough
         subjects affected / exposed
    6 / 104 (5.77%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    6
    0
    0
    0
    Pleural effusion
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    1 / 51 (1.96%)
         occurrences all number
    1
    0
    1
    1
    Dyspnoea
         subjects affected / exposed
    11 / 104 (10.58%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    6 / 51 (11.76%)
         occurrences all number
    15
    0
    1
    6
    Cough
         subjects affected / exposed
    19 / 104 (18.27%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    8 / 51 (15.69%)
         occurrences all number
    21
    0
    0
    10
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    7 / 104 (6.73%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    4 / 51 (7.84%)
         occurrences all number
    7
    0
    1
    4
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    23 / 104 (22.12%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    27
    0
    0
    3
    Alanine aminotransferase increased
         subjects affected / exposed
    13 / 104 (12.50%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    16
    0
    0
    3
    Blood alkaline phosphatase increased
         subjects affected / exposed
    6 / 104 (5.77%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    2 / 51 (3.92%)
         occurrences all number
    7
    0
    1
    2
    Weight decreased
         subjects affected / exposed
    6 / 104 (5.77%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    6
    0
    0
    0
    Serum ferritin decreased
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood bilirubin increased
         subjects affected / exposed
    9 / 104 (8.65%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    10
    0
    0
    3
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 104 (1.92%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 104 (6.73%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    10
    0
    0
    1
    Dizziness
         subjects affected / exposed
    4 / 104 (3.85%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    0 / 51 (0.00%)
         occurrences all number
    4
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    11 / 104 (10.58%)
    0 / 1 (0.00%)
    2 / 4 (50.00%)
    1 / 51 (1.96%)
         occurrences all number
    12
    0
    2
    1
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    12 / 104 (11.54%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    6 / 51 (11.76%)
         occurrences all number
    12
    0
    0
    6
    Abdominal pain upper
         subjects affected / exposed
    10 / 104 (9.62%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    13
    0
    0
    2
    Abdominal pain
         subjects affected / exposed
    16 / 104 (15.38%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    8 / 51 (15.69%)
         occurrences all number
    18
    0
    1
    9
    Dyspepsia
         subjects affected / exposed
    3 / 104 (2.88%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    3
    0
    0
    3
    Nausea
         subjects affected / exposed
    21 / 104 (20.19%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    4 / 51 (7.84%)
         occurrences all number
    21
    0
    0
    6
    Varices oesophageal
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Vomiting
         subjects affected / exposed
    9 / 104 (8.65%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    15
    0
    0
    3
    Constipation
         subjects affected / exposed
    18 / 104 (17.31%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    4 / 51 (7.84%)
         occurrences all number
    18
    0
    1
    4
    Dry mouth
         subjects affected / exposed
    5 / 104 (4.81%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    4 / 51 (7.84%)
         occurrences all number
    5
    0
    0
    4
    Diarrhoea
         subjects affected / exposed
    17 / 104 (16.35%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    13 / 51 (25.49%)
         occurrences all number
    21
    0
    3
    15
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    14 / 104 (13.46%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    5 / 51 (9.80%)
         occurrences all number
    19
    0
    0
    5
    Dry skin
         subjects affected / exposed
    2 / 104 (1.92%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    2 / 51 (3.92%)
         occurrences all number
    2
    0
    1
    2
    Night sweats
         subjects affected / exposed
    6 / 104 (5.77%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    6
    0
    0
    1
    Pruritus
         subjects affected / exposed
    24 / 104 (23.08%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    6 / 51 (11.76%)
         occurrences all number
    29
    0
    1
    8
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    1 / 51 (1.96%)
         occurrences all number
    1
    0
    1
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    8 / 104 (7.69%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    6 / 51 (11.76%)
         occurrences all number
    9
    0
    0
    6
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    8 / 104 (7.69%)
    0 / 1 (0.00%)
    2 / 4 (50.00%)
    5 / 51 (9.80%)
         occurrences all number
    16
    0
    4
    6
    Muscle spasms
         subjects affected / exposed
    6 / 104 (5.77%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    8
    0
    0
    2
    Back pain
         subjects affected / exposed
    8 / 104 (7.69%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    8
    0
    0
    2
    Arthralgia
         subjects affected / exposed
    20 / 104 (19.23%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    5 / 51 (9.80%)
         occurrences all number
    31
    0
    1
    8
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    3 / 104 (2.88%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    3
    0
    0
    4
    Rhinitis
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    1
    0
    0
    3
    Pneumonia
         subjects affected / exposed
    3 / 104 (2.88%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    2 / 51 (3.92%)
         occurrences all number
    3
    0
    1
    2
    Nasopharyngitis
         subjects affected / exposed
    3 / 104 (2.88%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    4 / 51 (7.84%)
         occurrences all number
    3
    0
    0
    4
    Bronchitis
         subjects affected / exposed
    4 / 104 (3.85%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    1 / 51 (1.96%)
         occurrences all number
    4
    0
    1
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    16 / 104 (15.38%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    8 / 51 (15.69%)
         occurrences all number
    18
    0
    0
    9
    Dehydration
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    1 / 51 (1.96%)
         occurrences all number
    1
    0
    1
    1
    Vitamin D deficiency
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    3 / 104 (2.88%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    3
    0
    0
    3
    Hypokalaemia
         subjects affected / exposed
    2 / 104 (1.92%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    3 / 51 (5.88%)
         occurrences all number
    2
    0
    2
    3
    Hypophosphataemia
         subjects affected / exposed
    4 / 104 (3.85%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    1 / 51 (1.96%)
         occurrences all number
    4
    0
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Apr 2016
    The major changes of amendment 1 (AM1) were addition to inclusion criteria of having a diagnosis of HCC by pathology report, central confirmation of measurable disease assessed per RECIST 1.1 for identifying target lesions, corrections to the cycle time points for tumor imaging and blood for biomarkers.
    26 Jun 2017
    The major change of AM2 was to add language to exclude subjects with a hypersensitivity to study drug.
    23 Feb 2018
    The major changes of AM4 were to add guidelines for management of immune-related adverse events, addition of flexibility to perform survival status follow-up, and to allow the Sponsor to collect information as needed to support ongoing analysis of the study survival data.
    29 Jun 2018
    The major change of AM6 were addition of a cohort for first-line treatment, increasing the trial duration and enrollment of participants in the trail, added Cohort 2 for participants with no prior systemic treatment for HCC.
    12 Apr 2021
    The major change of AM7 was to include the requirement of roll over of trial participants into an extension trial.

    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
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