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Study of Pembrolizumab (MK-3475) as Monotherapy in Participants With Advanced Hepatocellular Carcinoma (MK-3475-224/KEYNOTE-224)

Sponsor
Merck Sharp & Dohme LLC (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT02702414
Collaborator
(none)
156
Enrollment
2
Arms
85
Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
  • Biological: Pembrolizumab
 Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
156 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 2 Study of Pembrolizumab (MK-3475) as Monotherapy in Subjects With Advanced Hepatocellular Carcinoma (KEYNOTE-224)
Actual Study Start Date :
May 31, 2016
Actual Primary Completion Date :
Jan 19, 2021
Anticipated Study Completion Date :
Jun 30, 2023

Arms and Interventions

Arm Intervention/Treatment
Experimental: Cohort 1: Hepatocellular Carcinoma (HCC)-Prior Systemic Therapy with Sorafenib

Participants with previously systemically treated 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.

Biological: Pembrolizumab
Intravenous (IV) infusion
Other Names:
  • MK-3475
  • KEYTRUDA®

    		•
    Experimental: Cohort 2: HCC-Systemic Therapy Naïve

    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.

    Biological: Pembrolizumab
    Intravenous (IV) infusion
    Other Names:
  • MK-3475
  • KEYTRUDA®

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Objective Response Rate (ORR) [Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2]

      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.

    Secondary Outcome Measures

    1. Duration of Response (DOR) [Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2]

      DOR was determined in participants who demonstrated a confirmed Complete Response (CR: disappearance of all target and non-target lesions) or Partial Response (PR: ≥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. DOR was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. Participants who had not progressed, started a new anti-cancer therapy, been lost to follow-up, or died at the time of analysis were censored at the date of their last tumor assessment. Per RECIST 1.1, PD was at least a 20% increase in the sum of diameters 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. The DOR per RECIST 1.1 for all participants who had a confirmed CR or PR is presented.

    2. Disease Control Rate (DCR) [Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2]

      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 a 20% increase in the sum of diameters 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 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 as participants whose disease was not under control. The percentage of participants who experienced a confirmed CR, PR, or SD is reported.

    3. Time to Progression (TTP) [Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2]

      TTP was defined as the time from the first dose to the first documented disease progression per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded central imaging vendor. PD was at least a 20% increase in the sum of diameters 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 is presented.

    4. Progression-Free Survival (PFS) [Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2]

      PFS was defined as the time from the first dose to the first documented progressive disease (PD) or death due to any cause, whichever occurred first, per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded central imaging vendor. PD was at least a 20% increase in the sum of diameters 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 is presented.

    5. Overall Survival (OS) [Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2]

      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.

    6. Number of Participants Who Experienced At Least One Adverse Event (AE) [Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2]

      An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event. The number of participants who experienced at least one AE is presented. Per protocol, final analysis for this outcome measure was planned to be performed during the first course of therapy only.

    7. Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) [Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2]

      An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event. The number of participants who discontinued study treatment due to an AE is presented. Per protocol, final analysis for this outcome measure was planned to be performed during the first course of therapy only.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • For Cohort 1: has histologically or cytologically confirmed diagnosis of HCC (fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible) based on pathology report

    • For Cohort 2: has an HCC diagnosis confirmed by radiology, histology, or cytology (fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible)

    • Has Barcelona Clinic Liver Cancer (BCLC) Stage C disease or BCLC Stage B disease not amenable to locoregional therapy or refractory to locoregional therapy, and not amenable to a curative treatment approach

    • Has a Child-Pugh Class A liver score within 7 days of first dose of study drug

    • Has a predicted life expectancy >3 months

    • Has measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as confirmed by the blinded central imaging vendor

    • Has a performance status of 0 or 1 using the Eastern Cooperative Oncology Group (ECOG) Performance Scale within 7 days of first dose of study drug

    • For Cohort 1: has documented objective radiographic progression after stopping treatment with sorafenib or else intolerance to sorafenib

    • Is willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study drug (male and female participants of childbearing potential)

    • Demonstrates adequate organ function

    Exclusion Criteria:

    • Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy, herbal/complementary oral or IV medicine, or used an investigational device within 4 weeks of the first dose of study drug. Participant must also have recovered from associated therapy (i.e., to Grade ≤1 or baseline) and from adverse events due to any prior therapy

    • For Cohort 1: has received sorafenib within 14 days of first dose of study drug

    • Has had esophageal or gastric variceal bleeding within the last 6 months

    • Has clinically apparent ascites on physical examination

    • Has portal vein invasion at the main portal (Vp4), inferior vena cava, or cardiac involvement of HCC based on imaging

    • Has had encephalopathy in the last 6 months. Participants on rifaximin or lactulose to control their encephalopathy are not allowed

    • Had a solid organ or hematologic transplant

    • For Cohort 1: had prior systemic therapy for HCC other than sorafenib, or intercurrent local therapy to the liver tumor between sorafenib and study drug

    • For Cohort 2: had prior systemic therapy in the advanced disease setting

    • Has active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs)

    • Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug

    • Has a diagnosed additional malignancy within 5 years for Cohort 1 and 3 years for Cohort 2 prior to first dose of study treatment with the exception of curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or curatively resected in situ cervical and/or breast cancers

    • Has radiographically detectable central nervous system (CNS) metastases and/or carcinomatous meningitis

    • Has evidence or history of interstitial lung disease or active noninfectious pneumonitis

    • Has an active infection requiring systemic therapy

    • Has a known severe hypersensitivity to pembrolizumab, its active substance and/or any of its excipients

    • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study

    • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment

    • Has received prior immunotherapy including anti-programmed death-1 (anti-PD-1), anti-PD-ligand-1 (anti-PD-L1), or anti-PD-L2 agents, or if the participant has previously participated in clinical studies with pembrolizumab (MK-3475)

    • Has a known history of human immunodeficiency virus (HIV)

    • Has untreated active Hepatitis B virus (HBV)

    • For Cohort 1: has dual infection with HBV/Hepatitis C virus (HCV) or other hepatitis combinations at study entry

    • For Cohort 2: has dual active HBV infection (Hepatitis B surface antigen positive and/or detectable HBV deoxyribonucleic acid [DNA]) and HCV infection (detectable HCV ribonucleic acid [RNA]) at study entry

    • Has received a live vaccine within 30 days of planned start of study drug (Cycle 1, Day 1)

    Contacts and Locations

    Locations

    No locations specified.

    Sponsors and Collaborators

    • Merck Sharp & Dohme LLC

    Investigators

    • Study Director: Medical Director, Merck Sharp & Dohme LLC

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Merck Sharp & Dohme LLC
    ClinicalTrials.gov Identifier:
    NCT02702414
    Other Study ID Numbers:
    • 3475-224
    • MK-3475-224
    • KEYNOTE-224
    • 163434
    • 2015-004566-28
    First Posted:
    Mar 8, 2016
    Last Update Posted:
    Jul 1, 2022
    Last Verified:
    Jun 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Merck Sharp & Dohme LLC
    Programmed Cell Death 1 (PD1, PD-1)
    Programmed Cell Death Ligand 1 (PDL1, PD-L1)
    Programmed Cell Death Ligand 2 (PDL2, PD-L2)
    Additional relevant MeSH terms:
    Carcinoma
    Carcinoma, Hepatocellular
    Pembrolizumab

    Study Results

    Participant Flow

    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 Detail Participants were eligible to receive second course treatment with pembrolizumab if they met criteria for re-treatment. There was 1 participant in Cohort 1 and no participants in Cohort 2 who received second course treatment with pembrolizumab. 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.
    Arm/Group Title Cohort 1: Hepatocellular Carcinoma (HCC)-Prior Systemic Therapy With Sorafenib Cohort 2: HCC-Systemic Therapy Naïve
    Arm/Group Description Participants with previously systemically treated 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. 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.
    Period Title: Overall Study
    STARTED 105 51
    Treated 104 51
    COMPLETED 0 0
    NOT COMPLETED 105 51

    Baseline Characteristics

    Arm/Group Title Cohort 1: HCC-Prior Systemic Therapy With Sorafenib Cohort 2: HCC-Systemic Therapy Naïve Total
    Arm/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. 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. Total of all reporting groups
    Overall Participants 104 51 155
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    67.4
    (8.2)
    67.7
    (10.3)
    67.5
    (8.9)
    Sex: Female, Male (Count of Participants)
    Female
    18
    17.3%
    7
    13.7%
    25
    16.1%
    Male
    86
    82.7%
    44
    86.3%
    130
    83.9%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    2
    1.9%
    2
    3.9%
    4
    2.6%
    Not Hispanic or Latino
    98
    94.2%
    45
    88.2%
    143
    92.3%
    Unknown or Not Reported
    4
    3.8%
    4
    7.8%
    8
    5.2%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    Asian
    14
    13.5%
    2
    3.9%
    16
    10.3%
    Native Hawaiian or Other Pacific Islander
    1
    1%
    0
    0%
    1
    0.6%
    Black or African American
    3
    2.9%
    1
    2%
    4
    2.6%
    White
    84
    80.8%
    48
    94.1%
    132
    85.2%
    More than one race
    1
    1%
    0
    0%
    1
    0.6%
    Unknown or Not Reported
    1
    1%
    0
    0%
    1
    0.6%

    Outcome Measures

    1. Primary Outcome
    Title Objective Response Rate (ORR)
    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.
    Time Frame Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least one dose of study treatment during the first course of therapy.
    Arm/Group Title Cohort 1: HCC-Prior Systemic Therapy With Sorafenib Cohort 2: HCC-Systemic Therapy Naïve
    Arm/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. 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.
    Measure Participants 104 51
    Number (95% Confidence Interval) [Percentage of participants]
    18.3
    17.6%
    15.7
    30.8%
    2. Secondary Outcome
    Title Duration of Response (DOR)
    Description DOR was determined in participants who demonstrated a confirmed Complete Response (CR: disappearance of all target and non-target lesions) or Partial Response (PR: ≥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. DOR was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. Participants who had not progressed, started a new anti-cancer therapy, been lost to follow-up, or died at the time of analysis were censored at the date of their last tumor assessment. Per RECIST 1.1, PD was at least a 20% increase in the sum of diameters 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. The DOR per RECIST 1.1 for all participants who had a confirmed CR or PR is presented.
    Time Frame Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least one dose of study treatment and who had a confirmed CR or confirmed PR during the first course of therapy.
    Arm/Group Title Cohort 1: HCC-Prior Systemic Therapy With Sorafenib Cohort 2: HCC-Systemic Therapy Naïve
    Arm/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. 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.
    Measure Participants 19 8
    Median (95% Confidence Interval) [Months]
    21.0
    16.2
    3. Secondary Outcome
    Title Disease Control Rate (DCR)
    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 a 20% increase in the sum of diameters 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 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 as participants whose disease was not under control. The percentage of participants who experienced a confirmed CR, PR, or SD is reported.
    Time Frame Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least one dose of study treatment during the first course of therapy.
    Arm/Group Title Cohort 1: HCC-Prior Systemic Therapy With Sorafenib Cohort 2: HCC-Systemic Therapy Naïve
    Arm/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. 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.
    Measure Participants 104 51
    Number (95% Confidence Interval) [Percentage of participants]
    61.5
    59.1%
    56.9
    111.6%
    4. Secondary Outcome
    Title Time to Progression (TTP)
    Description TTP was defined as the time from the first dose to the first documented disease progression per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded central imaging vendor. PD was at least a 20% increase in the sum of diameters 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 is presented.
    Time Frame Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least one dose of study treatment during the first course of therapy.
    Arm/Group Title Cohort 1: HCC-Prior Systemic Therapy With Sorafenib Cohort 2: HCC-Systemic Therapy Naïve
    Arm/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. 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.
    Measure Participants 104 51
    Median (95% Confidence Interval) [Months]
    4.8
    4.4
    5. Secondary Outcome
    Title Progression-Free Survival (PFS)
    Description PFS was defined as the time from the first dose to the first documented progressive disease (PD) or death due to any cause, whichever occurred first, per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded central imaging vendor. PD was at least a 20% increase in the sum of diameters 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 is presented.
    Time Frame Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least one dose of study treatment during the first course of therapy.
    Arm/Group Title Cohort 1: HCC-Prior Systemic Therapy With Sorafenib Cohort 2: HCC-Systemic Therapy Naïve
    Arm/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. 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.
    Measure Participants 104 51
    Median (95% Confidence Interval) [Months]
    4.9
    4.3
    6. Secondary Outcome
    Title Overall Survival (OS)
    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.
    Time Frame Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least one dose of study treatment during the first course of therapy.
    Arm/Group Title Cohort 1: HCC-Prior Systemic Therapy With Sorafenib Cohort 2: HCC-Systemic Therapy Naïve
    Arm/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. 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.
    Measure Participants 104 51
    Median (95% Confidence Interval) [Months]
    13.2
    16.9
    7. Secondary Outcome
    Title Number of Participants Who Experienced At Least One Adverse Event (AE)
    Description An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event. The number of participants who experienced at least one AE is presented. Per protocol, final analysis for this outcome measure was planned to be performed during the first course of therapy only.
    Time Frame Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least one dose of study treatment during the first course of therapy.
    Arm/Group Title Cohort 1: HCC-Prior Systemic Therapy With Sorafenib Cohort 2: HCC-Systemic Therapy Naïve
    Arm/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. 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.
    Measure Participants 104 51
    Count of Participants [Participants]
    101
    97.1%
    49
    96.1%
    8. Secondary Outcome
    Title Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
    Description An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event. The number of participants who discontinued study treatment due to an AE is presented. Per protocol, final analysis for this outcome measure was planned to be performed during the first course of therapy only.
    Time Frame Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least one dose of study treatment during the first course of therapy.
    Arm/Group Title Cohort 1: HCC-Prior Systemic Therapy With Sorafenib Cohort 2: HCC-Systemic Therapy Naïve
    Arm/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. 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.
    Measure Participants 104 51
    Count of Participants [Participants]
    23
    22.1%
    8
    15.7%

    Adverse Events

    Time Frame Cohort 1 First Course: Up to approximately 34 months Cohort 2 First Course: Up to approximately 28 months Cohort 1 Second Course: Up to approximately 5 months
    Adverse Event Reporting Description All-cause mortality (ACM)=all allocated participants; AEs=all participants who received ≥1 dose of treatment. Per protocol, disease progression was not considered an AE unless related to treatment. Medical Dictionary for Regulatory Activities (MedDRA) terms neoplasm progression (NP), malignant NP, and disease progression not related to treatment were excluded. MedDRA version: Cohort 1=22.0; Cohort 2 =23.1. Per protocol, collection of AEs and ACM were planned for both first and second courses.
    Arm/Group Title Cohort 1: HCC-Prior Systemic Therapy With Sorafenib Cohort 2: HCC-Systemic Therapy Naïve Cohort 1: HCC-Prior Systemic Therapy With Sorafenib-Second Course Cohort 2: HCC-Systemic Therapy Naïve-Second Course
    Arm/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. 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. 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. 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
    All Cause Mortality
    Cohort 1: HCC-Prior Systemic Therapy With Sorafenib Cohort 2: HCC-Systemic Therapy Naïve Cohort 1: HCC-Prior Systemic Therapy With Sorafenib-Second Course Cohort 2: HCC-Systemic Therapy Naïve-Second Course
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 77/105 (73.3%) 34/51 (66.7%) 0/1 (0%) 0/0 (NaN)
    Serious Adverse Events
    Cohort 1: HCC-Prior Systemic Therapy With Sorafenib Cohort 2: HCC-Systemic Therapy Naïve Cohort 1: HCC-Prior Systemic Therapy With Sorafenib-Second Course Cohort 2: HCC-Systemic Therapy Naïve-Second Course
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 44/104 (42.3%) 21/51 (41.2%) 0/1 (0%) 0/0 (NaN)
    Blood and lymphatic system disorders
    Anaemia 3/104 (2.9%) 4 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Cardiac disorders
    Acute myocardial infarction 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Atrioventricular block second degree 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Cardiac failure 1/104 (1%) 1 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Cardiogenic shock 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Chronic left ventricular failure 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Myocarditis 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Ventricular fibrillation 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Endocrine disorders
    Adrenal insufficiency 2/104 (1.9%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Hypophysitis 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Eye disorders
    Retinal vein occlusion 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Gastrointestinal disorders
    Abdominal pain 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Ascites 4/104 (3.8%) 4 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Autoimmune colitis 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Colitis 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Constipation 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Gastric ulcer 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Gastritis haemorrhagic 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Gastrooesophageal reflux disease 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Melaena 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Oesophageal varices haemorrhage 2/104 (1.9%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Umbilical hernia 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Upper gastrointestinal haemorrhage 3/104 (2.9%) 3 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Varices oesophageal 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    General disorders
    Asthenia 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Chest pain 1/104 (1%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Death 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Fatigue 1/104 (1%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    General physical health deterioration 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Multiple organ dysfunction syndrome 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Pyrexia 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Ulcer haemorrhage 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Hepatobiliary disorders
    Hepatic failure 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Hepatic haemorrhage 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Hepatocellular injury 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Immune-mediated hepatitis 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Jaundice 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Jaundice cholestatic 2/104 (1.9%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Infections and infestations
    Bacteraemia 1/104 (1%) 1 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Cellulitis 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Device related infection 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Gastroenteritis 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Gastroenteritis viral 1/104 (1%) 1 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Lung infection 2/104 (1.9%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Pneumonia bacterial 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Sepsis 3/104 (2.9%) 3 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Septic shock 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Urinary tract infection 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Viral infection 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Large intestine infection 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Injury, poisoning and procedural complications
    Hip fracture 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Investigations
    Alanine aminotransferase increased 2/104 (1.9%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Aspartate aminotransferase increased 4/104 (3.8%) 4 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Blood bilirubin increased 1/104 (1%) 1 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Blood creatinine increased 1/104 (1%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Diabetic metabolic decompensation 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Failure to thrive 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Hyperkalaemia 2/104 (1.9%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Type 1 diabetes mellitus 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Musculoskeletal and connective tissue disorders
    Myositis 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Pathological fracture 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Colon cancer 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Squamous cell carcinoma 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Tumour necrosis 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Nervous system disorders
    Encephalopathy 0/104 (0%) 0 2/51 (3.9%) 2 0/1 (0%) 0 0/0 (NaN) 0
    Hepatic encephalopathy 1/104 (1%) 2 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Ischaemic stroke 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Presyncope 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Radiculopathy 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Syncope 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Renal and urinary disorders
    Acute kidney injury 1/104 (1%) 1 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Renal failure 2/104 (1.9%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 2/104 (1.9%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Pleural effusion 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Pulmonary embolism 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Skin and subcutaneous tissue disorders
    Lichenoid keratosis 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Rash 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Vascular disorders
    Hypovolaemic shock 2/104 (1.9%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Other (Not Including Serious) Adverse Events
    Cohort 1: HCC-Prior Systemic Therapy With Sorafenib Cohort 2: HCC-Systemic Therapy Naïve Cohort 1: HCC-Prior Systemic Therapy With Sorafenib-Second Course Cohort 2: HCC-Systemic Therapy Naïve-Second Course
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 99/104 (95.2%) 49/51 (96.1%) 1/1 (100%) 0/0 (NaN)
    Blood and lymphatic system disorders
    Anaemia 11/104 (10.6%) 12 1/51 (2%) 1 1/1 (100%) 1 0/0 (NaN) 0
    Iron deficiency anaemia 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Leukocytosis 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Leukopenia 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Neutropenia 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Thrombocytopenia 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Microcytic anaemia 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Cardiac disorders
    Angina pectoris 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Arrhythmia 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Atrial fibrillation 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Bradycardia 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Cardiac failure 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Palpitations 1/104 (1%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Pericardial effusion 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Ear and labyrinth disorders
    Ear discomfort 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Ear pain 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Paraesthesia ear 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Tinnitus 0/104 (0%) 0 2/51 (3.9%) 2 0/1 (0%) 0 0/0 (NaN) 0
    Vertigo 2/104 (1.9%) 2 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Endocrine disorders
    Hypothyroidism 8/104 (7.7%) 9 6/51 (11.8%) 6 0/1 (0%) 0 0/0 (NaN) 0
    Goitre 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Hyperthyroidism 1/104 (1%) 1 2/51 (3.9%) 2 0/1 (0%) 0 0/0 (NaN) 0
    Hypophysitis 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Thyroiditis 2/104 (1.9%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Adrenal insufficiency 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Eye disorders
    Cataract 2/104 (1.9%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Dry eye 4/104 (3.8%) 4 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Erythema of eyelid 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Retinal detachment 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Retinal vein occlusion 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Vision blurred 3/104 (2.9%) 3 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Visual acuity reduced 1/104 (1%) 1 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Gastrointestinal disorders
    Abdominal pain 16/104 (15.4%) 18 8/51 (15.7%) 9 1/1 (100%) 1 0/0 (NaN) 0
    Abdominal pain upper 10/104 (9.6%) 13 2/51 (3.9%) 2 0/1 (0%) 0 0/0 (NaN) 0
    Ascites 12/104 (11.5%) 12 6/51 (11.8%) 6 0/1 (0%) 0 0/0 (NaN) 0
    Constipation 18/104 (17.3%) 18 4/51 (7.8%) 4 0/1 (0%) 0 0/0 (NaN) 0
    Diarrhoea 17/104 (16.3%) 21 13/51 (25.5%) 15 1/1 (100%) 1 0/0 (NaN) 0
    Dry mouth 5/104 (4.8%) 5 4/51 (7.8%) 4 0/1 (0%) 0 0/0 (NaN) 0
    Dyspepsia 3/104 (2.9%) 3 3/51 (5.9%) 3 0/1 (0%) 0 0/0 (NaN) 0
    Nausea 21/104 (20.2%) 21 4/51 (7.8%) 6 0/1 (0%) 0 0/0 (NaN) 0
    Varices oesophageal 1/104 (1%) 1 0/51 (0%) 0 1/1 (100%) 1 0/0 (NaN) 0
    Vomiting 9/104 (8.7%) 15 3/51 (5.9%) 3 0/1 (0%) 0 0/0 (NaN) 0
    Abdominal discomfort 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Abdominal distension 3/104 (2.9%) 3 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Abdominal pain lower 3/104 (2.9%) 3 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Abdominal tenderness 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Aphthous ulcer 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Colitis 1/104 (1%) 1 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Dental caries 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Dysphagia 3/104 (2.9%) 3 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Faeces soft 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Flatulence 2/104 (1.9%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Gastric ulcer 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Gastritis 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Gastrooesophageal reflux disease 2/104 (1.9%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Gingival pain 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Haemorrhoids 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Impaired gastric emptying 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Inguinal hernia 1/104 (1%) 1 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Lip dry 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Lip ulceration 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Melaena 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Noninfective gingivitis 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Stomatitis 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Toothache 2/104 (1.9%) 3 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    General disorders
    Asthenia 16/104 (15.4%) 19 7/51 (13.7%) 8 1/1 (100%) 1 0/0 (NaN) 0
    Fatigue 30/104 (28.8%) 40 21/51 (41.2%) 23 0/1 (0%) 0 0/0 (NaN) 0
    Mucosal inflammation 2/104 (1.9%) 3 3/51 (5.9%) 4 0/1 (0%) 0 0/0 (NaN) 0
    Oedema peripheral 19/104 (18.3%) 20 14/51 (27.5%) 15 0/1 (0%) 0 0/0 (NaN) 0
    Pyrexia 5/104 (4.8%) 6 5/51 (9.8%) 6 0/1 (0%) 0 0/0 (NaN) 0
    Catheter site eczema 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Chest discomfort 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Chest pain 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Chills 4/104 (3.8%) 4 2/51 (3.9%) 2 0/1 (0%) 0 0/0 (NaN) 0
    Feeling cold 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Gait disturbance 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    General physical health deterioration 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Influenza like illness 4/104 (3.8%) 7 2/51 (3.9%) 2 0/1 (0%) 0 0/0 (NaN) 0
    Injection site swelling 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Malaise 3/104 (2.9%) 3 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Mucosal dryness 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Peripheral swelling 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Temperature intolerance 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Hepatobiliary disorders
    Cholecystitis acute 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Cholelithiasis 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Hepatic cirrhosis 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Hepatic pain 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Hepatic vein thrombosis 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Hepatomegaly 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Hyperbilirubinaemia 4/104 (3.8%) 5 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Portal vein occlusion 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Portal vein thrombosis 1/104 (1%) 1 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Immune system disorders
    Contrast media allergy 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Hypersensitivity 0/104 (0%) 0 2/51 (3.9%) 2 0/1 (0%) 0 0/0 (NaN) 0
    Seasonal allergy 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Infections and infestations
    Nasopharyngitis 3/104 (2.9%) 3 4/51 (7.8%) 4 0/1 (0%) 0 0/0 (NaN) 0
    Rhinitis 1/104 (1%) 1 3/51 (5.9%) 3 0/1 (0%) 0 0/0 (NaN) 0
    Urinary tract infection 3/104 (2.9%) 3 3/51 (5.9%) 4 0/1 (0%) 0 0/0 (NaN) 0
    Abdominal infection 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Bronchiolitis 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Bronchitis 4/104 (3.8%) 4 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Candida infection 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Clostridium difficile infection 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Conjunctivitis 1/104 (1%) 1 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Cytomegalovirus infection 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Enteritis infectious 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Escherichia urinary tract infection 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Fungal skin infection 2/104 (1.9%) 2 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Gastroenteritis 1/104 (1%) 1 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Genital infection fungal 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Herpes zoster 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Infection 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Influenza 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Laryngitis 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Lower respiratory tract infection 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Oral bacterial infection 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Oral candidiasis 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Oral herpes 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Perichondritis 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Peritonitis bacterial 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Pharyngitis 2/104 (1.9%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Pneumonia 3/104 (2.9%) 3 2/51 (3.9%) 2 0/1 (0%) 0 0/0 (NaN) 0
    Rash pustular 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Respiratory tract infection 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Respiratory tract infection viral 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Sinusitis 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Soft tissue infection 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Tracheitis 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Tooth infection 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Upper respiratory tract infection 5/104 (4.8%) 5 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Viral infection 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Vulvovaginal candidiasis 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Vulvovaginal mycotic infection 1/104 (1%) 3 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Injury, poisoning and procedural complications
    Contusion 4/104 (3.8%) 5 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Eye contusion 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Eyelid injury 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Fall 5/104 (4.8%) 6 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Limb injury 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Muscle strain 1/104 (1%) 1 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Post procedural bile leak 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Skin abrasion 2/104 (1.9%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Suture related complication 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Wound 1/104 (1%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Wrist fracture 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Investigations
    Alanine aminotransferase increased 13/104 (12.5%) 16 3/51 (5.9%) 3 0/1 (0%) 0 0/0 (NaN) 0
    Aspartate aminotransferase increased 23/104 (22.1%) 27 3/51 (5.9%) 3 0/1 (0%) 0 0/0 (NaN) 0
    Blood alkaline phosphatase increased 6/104 (5.8%) 7 2/51 (3.9%) 2 0/1 (0%) 0 0/0 (NaN) 0
    Blood bilirubin increased 9/104 (8.7%) 10 3/51 (5.9%) 3 0/1 (0%) 0 0/0 (NaN) 0
    Serum ferritin decreased 0/104 (0%) 0 0/51 (0%) 0 1/1 (100%) 1 0/0 (NaN) 0
    Weight decreased 6/104 (5.8%) 6 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Bilirubin conjugated increased 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Blood creatine phosphokinase increased 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Blood creatinine increased 2/104 (1.9%) 2 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Blood folate decreased 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Blood testosterone decreased 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Blood thyroid stimulating hormone increased 1/104 (1%) 1 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    C-reactive protein increased 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Gamma-glutamyltransferase increased 4/104 (3.8%) 4 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Heart rate increased 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Leukocyte alkaline phosphatase increased 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Lymphocyte count decreased 2/104 (1.9%) 3 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Myoglobin blood increased 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Neutrophil count decreased 1/104 (1%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Platelet count decreased 2/104 (1.9%) 3 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Prothrombin time shortened 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Vitamin D decreased 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Waist circumference increased 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Weight increased 2/104 (1.9%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    White blood cell count decreased 2/104 (1.9%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Metabolism and nutrition disorders
    Decreased appetite 16/104 (15.4%) 18 8/51 (15.7%) 9 0/1 (0%) 0 0/0 (NaN) 0
    Hyperglycaemia 3/104 (2.9%) 3 3/51 (5.9%) 3 0/1 (0%) 0 0/0 (NaN) 0
    Hypokalaemia 2/104 (1.9%) 2 3/51 (5.9%) 3 1/1 (100%) 1 0/0 (NaN) 0
    Hypophosphataemia 4/104 (3.8%) 4 1/51 (2%) 1 1/1 (100%) 1 0/0 (NaN) 0
    Vitamin D deficiency 1/104 (1%) 1 0/51 (0%) 0 1/1 (100%) 1 0/0 (NaN) 0
    Dehydration 1/104 (1%) 1 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Diabetes mellitus 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Diabetes mellitus inadequate control 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Fluid overload 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Fluid retention 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Hyperammonaemia 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Hypercreatininaemia 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Hyperkalaemia 5/104 (4.8%) 7 2/51 (3.9%) 4 0/1 (0%) 0 0/0 (NaN) 0
    Hyperlipasaemia 2/104 (1.9%) 7 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Hypoalbuminaemia 1/104 (1%) 1 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Hypocalcaemia 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Hypoglycaemia 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Hypomagnesaemia 2/104 (1.9%) 3 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Hyponatraemia 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Iron deficiency 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Malnutrition 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Type 2 diabetes mellitus 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Vitamin B12 deficiency 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Musculoskeletal and connective tissue disorders
    Arthralgia 18/104 (17.3%) 22 5/51 (9.8%) 7 0/1 (0%) 0 0/0 (NaN) 0
    Back pain 8/104 (7.7%) 9 2/51 (3.9%) 2 0/1 (0%) 0 0/0 (NaN) 0
    Muscle spasms 6/104 (5.8%) 8 2/51 (3.9%) 2 0/1 (0%) 0 0/0 (NaN) 0
    Myalgia 8/104 (7.7%) 16 5/51 (9.8%) 6 0/1 (0%) 0 0/0 (NaN) 0
    Arthritis 2/104 (1.9%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Bone pain 1/104 (1%) 1 2/51 (3.9%) 2 0/1 (0%) 0 0/0 (NaN) 0
    Chondrocalcinosis 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Costochondritis 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Flank pain 4/104 (3.8%) 4 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Joint stiffness 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Joint swelling 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Muscular weakness 1/104 (1%) 1 2/51 (3.9%) 2 0/1 (0%) 0 0/0 (NaN) 0
    Musculoskeletal chest pain 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Musculoskeletal discomfort 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Musculoskeletal pain 5/104 (4.8%) 9 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Musculoskeletal stiffness 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Osteoporosis 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Pain in extremity 4/104 (3.8%) 5 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Spondylitis 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Tendon disorder 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Tenosynovitis 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatic cancer 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Seborrhoeic keratosis 2/104 (1.9%) 2 2/51 (3.9%) 2 0/1 (0%) 0 0/0 (NaN) 0
    Skin papilloma 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Nervous system disorders
    Dizziness 4/104 (3.8%) 4 0/51 (0%) 0 1/1 (100%) 1 0/0 (NaN) 0
    Headache 7/104 (6.7%) 10 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Ageusia 2/104 (1.9%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Amnesia 2/104 (1.9%) 2 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Ataxia 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Balance disorder 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Brain oedema 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Carpal tunnel syndrome 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Dizziness postural 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Dysgeusia 1/104 (1%) 1 2/51 (3.9%) 2 0/1 (0%) 0 0/0 (NaN) 0
    Head discomfort 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Hepatic encephalopathy 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Memory impairment 2/104 (1.9%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Migraine with aura 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Neuropathy peripheral 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Paraesthesia 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Peripheral sensory neuropathy 1/104 (1%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Sciatica 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Syncope 1/104 (1%) 1 1/51 (2%) 2 0/1 (0%) 0 0/0 (NaN) 0
    Taste disorder 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Psychiatric disorders
    Insomnia 7/104 (6.7%) 7 4/51 (7.8%) 4 1/1 (100%) 1 0/0 (NaN) 0
    Anxiety 2/104 (1.9%) 2 2/51 (3.9%) 2 0/1 (0%) 0 0/0 (NaN) 0
    Confusional state 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Depressed mood 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Depression 3/104 (2.9%) 3 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Libido decreased 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Mood altered 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Sleep disorder 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Renal and urinary disorders
    Acute kidney injury 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Chromaturia 1/104 (1%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Dysuria 1/104 (1%) 1 2/51 (3.9%) 2 0/1 (0%) 0 0/0 (NaN) 0
    Haematuria 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Micturition urgency 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Pollakiuria 1/104 (1%) 1 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Proteinuria 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Renal failure 1/104 (1%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Renal impairment 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Urinary incontinence 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Urinary retention 1/104 (1%) 1 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Urine abnormality 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Reproductive system and breast disorders
    Balanoposthitis 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Breast discomfort 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Breast swelling 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Gynaecomastia 1/104 (1%) 1 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Nipple pain 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Prostatitis 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Prostatomegaly 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Vaginal haemorrhage 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Respiratory, thoracic and mediastinal disorders
    Cough 19/104 (18.3%) 21 8/51 (15.7%) 10 0/1 (0%) 0 0/0 (NaN) 0
    Dyspnoea 11/104 (10.6%) 15 6/51 (11.8%) 6 0/1 (0%) 0 0/0 (NaN) 0
    Productive cough 6/104 (5.8%) 6 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Asthma 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Bronchospasm 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Dysphonia 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Dyspnoea exertional 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Epistaxis 2/104 (1.9%) 2 2/51 (3.9%) 2 0/1 (0%) 0 0/0 (NaN) 0
    Haemoptysis 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Hiccups 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Laryngeal inflammation 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Nasal ulcer 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Oropharyngeal pain 3/104 (2.9%) 3 2/51 (3.9%) 2 0/1 (0%) 0 0/0 (NaN) 0
    Pleural effusion 1/104 (1%) 1 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Pleuritic pain 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Pneumonitis 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Rhinorrhoea 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Skin and subcutaneous tissue disorders
    Night sweats 6/104 (5.8%) 6 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Pruritus 23/104 (22.1%) 28 6/51 (11.8%) 8 0/1 (0%) 0 0/0 (NaN) 0
    Rash 13/104 (12.5%) 18 5/51 (9.8%) 5 0/1 (0%) 0 0/0 (NaN) 0
    Actinic keratosis 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Alopecia 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Dermal cyst 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Dermatitis 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Dermatitis acneiform 3/104 (2.9%) 3 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Dermatitis contact 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Dry skin 2/104 (1.9%) 2 2/51 (3.9%) 2 0/1 (0%) 0 0/0 (NaN) 0
    Eczema 3/104 (2.9%) 3 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Eczema asteatotic 2/104 (1.9%) 2 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Granulomatous dermatitis 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Hair colour changes 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Hyperhidrosis 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Hyperkeratosis 2/104 (1.9%) 3 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Lichenoid keratosis 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Milia 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Palmar-plantar erythrodysaesthesia syndrome 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Pruritus generalised 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Psoriasis 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Purpura 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Rash erythematous 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Rash generalised 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Rash macular 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Rash maculo-papular 5/104 (4.8%) 6 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Rash papular 1/104 (1%) 1 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Rash pruritic 2/104 (1.9%) 3 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Rosacea 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Skin burning sensation 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Skin exfoliation 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Skin hyperpigmentation 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Skin hypopigmentation 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Skin lesion 1/104 (1%) 1 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Skin plaque 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Skin ulcer 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Vitiligo 0/104 (0%) 0 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Vascular disorders
    Deep vein thrombosis 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Embolism 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Haematoma 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Hot flush 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Hypertension 0/104 (0%) 0 2/51 (3.9%) 2 0/1 (0%) 0 0/0 (NaN) 0
    Orthostatic hypotension 1/104 (1%) 1 1/51 (2%) 1 0/1 (0%) 0 0/0 (NaN) 0
    Peripheral venous disease 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Vena cava thrombosis 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0
    Venous occlusion 1/104 (1%) 1 0/51 (0%) 0 0/1 (0%) 0 0/0 (NaN) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this trial 45 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results. Sponsor review can be expedited to meet publication timelines.

    Results Point of Contact

    Name/Title Senior Vice President, Global Clinical Development
    Organization Merck Sharp & Dohme Corp.
    Phone 1-800-672-6372
    Email ClinicalTrialsDisclosure@merck.com
    Responsible Party:
    Merck Sharp & Dohme LLC
    ClinicalTrials.gov Identifier:
    NCT02702414
    Other Study ID Numbers:
    • 3475-224
    • MK-3475-224
    • KEYNOTE-224
    • 163434
    • 2015-004566-28
    First Posted:
    Mar 8, 2016
    Last Update Posted:
    Jul 1, 2022
    Last Verified:
    Jun 1, 2022