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    Clinical Trial Results:
    A Randomized Open-Label Phase III Study of Single Agent Pembrolizumab versus Single Agent Chemotherapy per Physician’s Choice for Metastatic Triple Negative Breast Cancer (mTNBC) – (KEYNOTE-119)

    Summary
    EudraCT number
    		 2015-001020-27
    Trial protocol
    		 DE   SE   NL   BE   FR   GB   PL   ES   IT  
    Global end of trial date
    10 Nov 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Nov 2021
    First version publication date
    25 Nov 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    3475-119
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02555657
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., 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
    10 Nov 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Apr 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Nov 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    In this study, participants with metastatic triple negative breast cancer (mTNBC) were randomly assigned to receive either single agent pembrolizumab or single agent chemotherapy chosen by the treating physician (Treatment of Physician's Choice, TPC) in accordance with local regulations and guidelines, consisting of either capecitabine, eribulin, gemcitabine, or vinorelbine. The primary study hypothesis was that pembrolizumab extends overall survival compared to TPC.
    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
    13 Oct 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 7
    Country: Number of subjects enrolled
    Australia: 21
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Brazil: 27
    Country: Number of subjects enrolled
    Colombia: 3
    Country: Number of subjects enrolled
    France: 33
    Country: Number of subjects enrolled
    Germany: 33
    Country: Number of subjects enrolled
    Guatemala: 5
    Country: Number of subjects enrolled
    Hong Kong: 5
    Country: Number of subjects enrolled
    Ireland: 7
    Country: Number of subjects enrolled
    Italy: 28
    Country: Number of subjects enrolled
    Japan: 90
    Country: Number of subjects enrolled
    Korea, Republic of: 32
    Country: Number of subjects enrolled
    Malaysia: 14
    Country: Number of subjects enrolled
    Mexico: 22
    Country: Number of subjects enrolled
    Netherlands: 9
    Country: Number of subjects enrolled
    New Zealand: 2
    Country: Number of subjects enrolled
    Peru: 8
    Country: Number of subjects enrolled
    Philippines: 9
    Country: Number of subjects enrolled
    Poland: 25
    Country: Number of subjects enrolled
    Russian Federation: 45
    Country: Number of subjects enrolled
    Singapore: 13
    Country: Number of subjects enrolled
    South Africa: 4
    Country: Number of subjects enrolled
    Spain: 29
    Country: Number of subjects enrolled
    Sweden: 9
    Country: Number of subjects enrolled
    Switzerland: 4
    Country: Number of subjects enrolled
    Taiwan: 14
    Country: Number of subjects enrolled
    Thailand: 4
    Country: Number of subjects enrolled
    Turkey: 19
    Country: Number of subjects enrolled
    United Kingdom: 37
    Country: Number of subjects enrolled
    United States: 60
    Worldwide total number of subjects
    622
    EEA total number of subjects
    177
    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)
    524
    From 65 to 84 years
    97
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

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

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pembrolizumab
    Arm description
    		 Participants received pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations (up to ~2 years). Qualified participants who received first course of pembrolizumab but continued to experience disease progression may have, at investigator's discretion, initiated a second course of pembrolizumab at 200 mg IV Q3W for up to 17 administrations (up to ~1 year).
    Arm type
    		 Experimental

    Investigational medicinal product name
    pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475, KEYTRUDA®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants receive pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations (up to ~2 years). Qualified participants who received first course of pembrolizumab but continued to experience disease progression may have, at investigator's discretion, initiated a second course of pembrolizumab at 200 mg IV Q3W for up to 17 administrations (up to ~1 year).

    Arm title
    		 Chemotherapy
    Arm description
    		 Participants received capecitabine, eribulin, gemcitabine, or vinorelbine as single agent chemotherapy chosen by the treating physician (Treatment of Physician's Choice, TPC) in accordance with local regulations and guidelines.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    capecitabine
    Investigational medicinal product code
    Other name
    XELODA®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants receive capecitabine as TPC in accordance with local regulations and guidelines.

    Investigational medicinal product name
    eribulin
    Investigational medicinal product code
    Other name
    HALAVEN®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants receive eribulin as TPC in accordance with local regulations and guidelines.

    Investigational medicinal product name
    gemcitabine
    Investigational medicinal product code
    Other name
    GEMZAR®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants receive gemcitabine as TPC in accordance with local regulations and guidelines.

    Investigational medicinal product name
    vinorelbine
    Investigational medicinal product code
    Other name
    NAVELBINE®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants receive vinorelbine as TPC in accordance with local regulations and guidelines.

    Number of subjects in period 1
    		Pembrolizumab Chemotherapy
    Started
    312
    310
    Treated
    309
    292
    Completed
    0
    0
    Not completed
    312
    310
         Consent withdrawn by subject
    11
    32
         Physician decision
    -
    1
         Death
    274
    262
         Sponsor Decision
    27
    15

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pembrolizumab
    Reporting group description
    		 Participants received pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations (up to ~2 years). Qualified participants who received first course of pembrolizumab but continued to experience disease progression may have, at investigator's discretion, initiated a second course of pembrolizumab at 200 mg IV Q3W for up to 17 administrations (up to ~1 year).

    Reporting group title
    Chemotherapy
    Reporting group description
    		 Participants received capecitabine, eribulin, gemcitabine, or vinorelbine as single agent chemotherapy chosen by the treating physician (Treatment of Physician's Choice, TPC) in accordance with local regulations and guidelines.

    Reporting group values
    		 Pembrolizumab Chemotherapy Total
    Number of subjects
    		 312 310 622
    Age categorical
    Units: Subjects
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 51.4 ( 11.4 ) 52.6 ( 11.2 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 312 308 620
        Male
    		 0 2 2
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 4 4 8
        Asian
    		 87 101 188
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 13 4 17
        White
    		 183 180 363
        More than one race
    		 12 12 24
        Unknown or Not Reported
    		 13 9 22

    End points

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    End points reporting groups
    Reporting group title
    Pembrolizumab
    Reporting group description
    		 Participants received pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations (up to ~2 years). Qualified participants who received first course of pembrolizumab but continued to experience disease progression may have, at investigator's discretion, initiated a second course of pembrolizumab at 200 mg IV Q3W for up to 17 administrations (up to ~1 year).

    Reporting group title
    Chemotherapy
    Reporting group description
    		 Participants received capecitabine, eribulin, gemcitabine, or vinorelbine as single agent chemotherapy chosen by the treating physician (Treatment of Physician's Choice, TPC) in accordance with local regulations and guidelines.

    Primary: Overall Survival in Participants With Programmed Cell Death Ligand 1 (PD-L1) With Combined Positive Score (CPS) ≥10

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    End point title
    		 Overall Survival in Participants With Programmed Cell Death Ligand 1 (PD-L1) With Combined Positive Score (CPS) ≥10
    End point description
    Overall survival (OS) was defined as the time from randomization to death due to any cause. The analysis population for this endpoint consisted of all participants with PD-L1 CPS ≥10 who were included in a treatment group at randomization.
    End point type
    Primary
    End point timeframe
    Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)
    End point values
    		 Pembrolizumab Chemotherapy
    Number of subjects analysed
    96
    98
    Units: Months
        median (confidence interval 95%)
    12.7 (9.9 to 16.3)
    11.6 (8.3 to 13.7)
    Statistical analysis title
    		 OS Hazard Ratio
    Comparison groups
    Chemotherapy v Pembrolizumab
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0574
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 1.06

    Primary: Overall Survival in Participants With PD-L1 CPS ≥1

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    End point title
    		 Overall Survival in Participants With PD-L1 CPS ≥1
    End point description
    Overall survival (OS) was defined as the time from randomization to death due to any cause. The analysis population for this endpoint consisted of all participants with PD-L1 CPS ≥1 who were included in a treatment group at randomization.
    End point type
    Primary
    End point timeframe
    Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)
    End point values
    		 Pembrolizumab Chemotherapy
    Number of subjects analysed
    203
    202
    Units: Months
        median (confidence interval 95%)
    10.7 (9.3 to 12.5)
    10.2 (7.9 to 12.6)
    Statistical analysis title
    		 OS Hazard Ratio
    Comparison groups
    Pembrolizumab v Chemotherapy
    Number of subjects included in analysis
    405
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0728
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.06

    Primary: Overall Survival in All Participants

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    End point title
    		 Overall Survival in All Participants
    End point description
    Overall survival (OS) was defined as the time from randomization to death due to any cause. The analysis population for this endpoint consisted of all participants who were included in a treatment group at randomization.
    End point type
    Primary
    End point timeframe
    Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)
    End point values
    		 Pembrolizumab Chemotherapy
    Number of subjects analysed
    312
    310
    Units: Months
        median (confidence interval 95%)
    9.9 (8.3 to 11.4)
    10.8 (9.1 to 12.6)
    Statistical analysis title
    		 OS Hazard Ratio
    Comparison groups
    Pembrolizumab v Chemotherapy
    Number of subjects included in analysis
    622
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3802
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.15

    Secondary: Overall Response Rate per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With PD-L1 CPS ≥10

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    End point title
    		 Overall Response Rate per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With PD-L1 CPS ≥10
    End point description
    Overall Response Rate (ORR), based on a Blinded Independent Central Review (BICR) assessment per RECIST 1.1, was defined as the percentage of participants who had a confirmed Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions). The analysis population for this endpoint consisted of all participants with PD-L1 CPS ≥10 who were included in a treatment group at randomization.
    End point type
    Secondary
    End point timeframe
    Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)
    End point values
    		 Pembrolizumab Chemotherapy
    Number of subjects analysed
    96
    98
    Units: Percentage of participants
        number (confidence interval 95%)
    17.7 (10.7 to 26.8)
    9.2 (4.3 to 16.7)
    Statistical analysis title
    		 Difference in Percentages
    Comparison groups
    Pembrolizumab v Chemotherapy
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0457
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Difference in percentages
    Point estimate
    8.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 18.4

    Secondary: Overall Response Rate per RECIST 1.1 in Participants With PD-L1 CPS ≥1

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    End point title
    		 Overall Response Rate per RECIST 1.1 in Participants With PD-L1 CPS ≥1
    End point description
    Overall Response Rate (ORR), based on BICR assessment per RECIST 1.1, was defined as the percentage of participants who had a confirmed Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions). The analysis population for this endpoint consisted of all participants with PD-L1 CPS ≥1 who were included in a treatment group at randomization.
    End point type
    Secondary
    End point timeframe
    Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)
    End point values
    		 Pembrolizumab Chemotherapy
    Number of subjects analysed
    203
    202
    Units: Percentage of participants
        number (confidence interval 95%)
    12.3 (8.1 to 17.6)
    9.4 (5.8 to 14.3)
    Statistical analysis title
    		 Difference in Percentages
    Comparison groups
    Pembrolizumab v Chemotherapy
    Number of subjects included in analysis
    405
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1752
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Difference in percentages
    Point estimate
    2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.3
         upper limit
    		 9.2

    Secondary: Overall Response Rate per RECIST 1.1 in All Participants

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    End point title
    		 Overall Response Rate per RECIST 1.1 in All Participants
    End point description
    Overall Response Rate (ORR), based on BICR assessment per RECIST 1.1, was defined as the percentage of participants who had a confirmed Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions). The analysis population for this endpoint consisted of all participants who were included in a treatment group at randomization.
    End point type
    Secondary
    End point timeframe
    Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)
    End point values
    		 Pembrolizumab Chemotherapy
    Number of subjects analysed
    312
    310
    Units: Percentage of participants
        number (confidence interval 95%)
    9.6 (6.6 to 13.4)
    10.6 (7.4 to 14.6)
    Statistical analysis title
    		 Difference in Percentages
    Comparison groups
    Pembrolizumab v Chemotherapy
    Number of subjects included in analysis
    622
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6629
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Difference in percentages
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.9
         upper limit
    		 3.8

    Secondary: Progression-Free Survival per RECIST 1.1 in Participants With PD-L1 CPS ≥10

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    End point title
    		 Progression-Free Survival per RECIST 1.1 in Participants With PD-L1 CPS ≥10
    End point description
    Progression-Free Survival (PFS), based on BICR assessment per RECIST 1.1, was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The analysis population for this endpoint consisted of all participants with PD-L1 CPS ≥10 who were included in a treatment group at randomization.
    End point type
    Secondary
    End point timeframe
    Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)
    End point values
    		 Pembrolizumab Chemotherapy
    Number of subjects analysed
    96
    98
    Units: Months
        median (confidence interval 95%)
    2.1 (2.0 to 2.5)
    3.4 (2.3 to 4.1)
    Statistical analysis title
    		 PFS Hazard Ratio
    Comparison groups
    Pembrolizumab v Chemotherapy
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7936
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.59

    Secondary: Progression-Free Survival per RECIST 1.1 in Participants With PD-L1 CPS ≥1

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    End point title
    		 Progression-Free Survival per RECIST 1.1 in Participants With PD-L1 CPS ≥1
    End point description
    Progression-Free Survival (PFS), based on BICR assessment per RECIST 1.1, was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The analysis population for this endpoint consisted of all participants with PD-L1 CPS ≥1 who were included in a treatment group at randomization.
    End point type
    Secondary
    End point timeframe
    Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)
    End point values
    		 Pembrolizumab Chemotherapy
    Number of subjects analysed
    203
    202
    Units: Months
        median (confidence interval 95%)
    2.1 (2.0 to 2.1)
    3.1 (2.3 to 4.0)
    Statistical analysis title
    		 PFS Hazard Ratio
    Comparison groups
    Pembrolizumab v Chemotherapy
    Number of subjects included in analysis
    405
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.9964
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.08
         upper limit
    		 1.68

    Secondary: Progression-Free Survival per RECIST 1.1 in All Participants

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    End point title
    		 Progression-Free Survival per RECIST 1.1 in All Participants
    End point description
    Progression-Free Survival (PFS), based on BICR assessment per RECIST 1.1, was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The analysis population for this endpoint consisted of all participants who were included in a treatment group at randomization.
    End point type
    Secondary
    End point timeframe
    Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)
    End point values
    		 Pembrolizumab Chemotherapy
    Number of subjects analysed
    312
    310
    Units: Months
        median (confidence interval 95%)
    2.1 (2.0 to 2.1)
    3.3 (2.7 to 4.0)
    Statistical analysis title
    		 PFS Hazard Ratio
    Comparison groups
    Pembrolizumab v Chemotherapy
    Number of subjects included in analysis
    622
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 1
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.33
         upper limit
    		 1.92

    Secondary: Duration of Response per RECIST 1.1 in Participants With PD-L1 CPS ≥10 Who Had a Confirmed Response

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    End point title
    		 Duration of Response per RECIST 1.1 in Participants With PD-L1 CPS ≥10 Who Had a Confirmed Response
    End point description
    For participants with PD-L1 CPS ≥10 who demonstrated a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, Duration of Response (DOR) was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions as well as an absolute increase of at least a 5 mm in the sum of diameters. The appearance of one or more new lesions was also considered PD. DOR assessments were based on BICR. The analysis population for this endpoint consisted of all randomized participants with PD-L1 CPS ≥10, whether or not they received study treatment, who demonstrated a confirmed response (CR or PR). Participants were included in the treatment arm to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 36 months (from time of first documented evidence of CR or PR through Final Analysis database cutoff date of 11-April-2019)
    End point values
    		 Pembrolizumab Chemotherapy
    Number of subjects analysed
    17
    9
    Units: Months
        median (full range (min-max))
    9999 (2.2 to 9999)
    7.1 (3.8 to 9999)
    No statistical analyses for this end point

    Secondary: Duration of Response per RECIST 1.1 in Participants With PD-L1 CPS ≥1 Who Had a Confirmed Response

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    End point title
    		 Duration of Response per RECIST 1.1 in Participants With PD-L1 CPS ≥1 Who Had a Confirmed Response
    End point description
    For participants with PD-L1 CPS ≥1 who demonstrated a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, Duration of Response (DOR) was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions as well as an absolute increase of at least a 5 mm in the sum of diameters. The appearance of one or more new lesions was also considered PD. DOR assessments were based on BICR. The analysis population for this endpoint consisted of all randomized participants with PD-L1 CPS ≥1, regardless of whether or not they received study treatment, who demonstrated a confirmed response (CR or PR). Participants were included in the treatment arm to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 36 months (from time of first documented evidence of CR or PR through Final Analysis database cutoff date of 11-April-2019)
    End point values
    		 Pembrolizumab Chemotherapy
    Number of subjects analysed
    25
    19
    Units: Months
        median (full range (min-max))
    12.2 (2.2 to 9999)
    9999 (9999 to 9999)
    No statistical analyses for this end point

    Secondary: Duration of Response per RECIST 1.1 in All Participants Who Had a Confirmed Response

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    End point title
    		 Duration of Response per RECIST 1.1 in All Participants Who Had a Confirmed Response
    End point description
    For participants who demonstrated a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, Duration of Response (DOR) was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions as well as an absolute increase of at least a 5 mm in the sum of diameters. The appearance of one or more new lesions was also considered PD. DOR assessments were based on BICR. The analysis population for this endpoint consisted of all randomized participants, regardless of whether or not they received study treatment, who demonstrated a confirmed response (CR or PR). Participants were included in the treatment arm to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 36 months (from time of first documented evidence of CR or PR through Final Analysis database cutoff date of 11-April-2019)
    End point values
    		 Pembrolizumab Chemotherapy
    Number of subjects analysed
    30
    33
    Units: Months
        median (full range (min-max))
    12.2 (2.2 to 9999)
    9999 (9999 to 9999)
    No statistical analyses for this end point

    Secondary: Disease Control Rate per RECIST 1.1 in Participants With PD-L1 CPS ≥10

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    End point title
    		 Disease Control Rate per RECIST 1.1 in Participants With PD-L1 CPS ≥10
    End point description
    Disease Control Rate (DCR), based on BICR assessment per RECIST 1.1, was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) or Stable Disease for at least 24 weeks (SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease [PD: At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD.]) The analysis population for this endpoint consisted of all participants with PD-L1 CPS ≥10 who were included in a treatment group at randomization.
    End point type
    Secondary
    End point timeframe
    Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)
    End point values
    		 Pembrolizumab Chemotherapy
    Number of subjects analysed
    96
    98
    Units: Percentage of participants
        number (confidence interval 95%)
    19.8 (12.4 to 29.2)
    17.3 (10.4 to 26.3)
    Statistical analysis title
    		 Difference in Percentages
    Comparison groups
    Pembrolizumab v Chemotherapy
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3388
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Difference in percentages
    Point estimate
    2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.7
         upper limit
    		 13.5

    Secondary: Disease Control Rate per RECIST 1.1 in Participants With PD-L1 CPS ≥1

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    End point title
    		 Disease Control Rate per RECIST 1.1 in Participants With PD-L1 CPS ≥1
    End point description
    Disease Control Rate (DCR), based on BICR assessment per RECIST 1.1, was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) or Stable Disease for at least 24 weeks (SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease [PD: At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD.]) The analysis population for this endpoint consisted of all participants with PD-L1 CPS ≥1 who were included in a treatment group at randomization.
    End point type
    Secondary
    End point timeframe
    Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)
    End point values
    		 Pembrolizumab Chemotherapy
    Number of subjects analysed
    203
    202
    Units: Percentage of participants
        number (confidence interval 95%)
    14.3 (9.8 to 19.9)
    15.8 (11.1 to 21.6)
    Statistical analysis title
    		 Difference in Percentages
    Comparison groups
    Pembrolizumab v Chemotherapy
    Number of subjects included in analysis
    405
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6701
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Difference in percentages
    Point estimate
    -1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.6
         upper limit
    		 5.5

    Secondary: Disease Control Rate per RECIST 1.1 in All Participants

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    End point title
    		 Disease Control Rate per RECIST 1.1 in All Participants
    End point description
    Disease Control Rate (DCR), based on BICR assessment per RECIST 1.1, was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) or Stable Disease for at least 24 weeks (SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease [PD: At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD.]) The analysis population for this endpoint consisted of all participants who were included in a treatment group at randomization.
    End point type
    Secondary
    End point timeframe
    Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)
    End point values
    		 Pembrolizumab Chemotherapy
    Number of subjects analysed
    312
    310
    Units: Percentage of participants
        number (confidence interval 95%)
    12.2 (8.8 to 16.3)
    18.7 (14.5 to 23.5)
    Statistical analysis title
    		 Difference in Percentages
    Comparison groups
    Pembrolizumab v Chemotherapy
    Number of subjects included in analysis
    622
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.9877
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Difference in percentages
    Point estimate
    -6.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.2
         upper limit
    		 -0.8

    Secondary: Number of Participants Who Experienced One or More Adverse Events

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    End point title
    		 Number of Participants Who Experienced One or More Adverse Events
    End point description
    An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. The analysis population for this endpoint consisted of all randomized participants who received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 60 months
    End point values
    		 Pembrolizumab Chemotherapy
    Number of subjects analysed
    309
    292
    Units: Participants
    285
    281
    No statistical analyses for this end point

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

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    End point title
    		 Number of Participants Who Discontinued Study Treatment Due to an Adverse Event
    End point description
    An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. The analysis population for this endpoint consisted of all randomized participants who received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 60 months
    End point values
    		 Pembrolizumab Chemotherapy
    Number of subjects analysed
    309
    292
    Units: Participants
    14
    16
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-Cause Mortality and Adverse Events (including first and second courses): Up to approximately 60 months
    Adverse event reporting additional description
    All-cause mortality includes all randomized participants. Serious and other AEs include participants who received at least 1 dose of study treatment. MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" unrelated to drug were excluded as AEs.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Pembrolizumab First Course
    Reporting group description
    		 Participants received pembrolizumab 200 mg IV Q3W for up to 35 administrations (up to ~2 years).

    Reporting group title
    Chemotherapy
    Reporting group description
    		 Participants received capecitabine, eribulin, gemcitabine, or vinorelbine as TPC in accordance with local regulations and guidelines.

    Reporting group title
    Pembrolizumab Second Course
    Reporting group description
    		 Qualified participants who received the first course of pembrolizumab 200 mg IV Q3W for up to 35 administrations (up to ~2 years), but experienced disease progression, initiated a second course of pembrolizumab at the investigator's discretion, at 200 mg IV Q3W for up to 17 administrations (up to ~1 year).

    Serious adverse events
    		 Pembrolizumab First Course Chemotherapy Pembrolizumab Second Course
    Total subjects affected by serious adverse events
         subjects affected / exposed
    65 / 309 (21.04%)
    60 / 292 (20.55%)
    1 / 8 (12.50%)
         number of deaths (all causes)
    283
    289
    0
         number of deaths resulting from adverse events
    1
    2
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    3 / 309 (0.97%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Infected neoplasm
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inflammatory carcinoma of the breast
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic neoplasm
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 309 (0.32%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 309 (0.00%)
    2 / 292 (0.68%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 309 (0.00%)
    4 / 292 (1.37%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    Fatigue
         subjects affected / exposed
    3 / 309 (0.97%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 309 (0.00%)
    2 / 292 (0.68%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 309 (1.29%)
    2 / 292 (0.68%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 309 (0.97%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    8 / 309 (2.59%)
    3 / 292 (1.03%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 8
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 309 (0.65%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 309 (0.65%)
    2 / 292 (0.68%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 309 (0.65%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood corticotrophin abnormal
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radiation associated pain
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    2 / 309 (0.65%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Horner's syndrome
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post herpetic neuralgia
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 309 (0.65%)
    2 / 292 (0.68%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 309 (0.32%)
    5 / 292 (1.71%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    6 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 309 (0.32%)
    4 / 292 (1.37%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    5 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 309 (0.32%)
    3 / 292 (1.03%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 309 (0.32%)
    2 / 292 (0.68%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal achalasia
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 309 (0.00%)
    0 / 292 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 309 (0.00%)
    2 / 292 (0.68%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Secondary adrenocortical insufficiency
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 309 (0.65%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterococcal sepsis
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 309 (0.32%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngotonsillitis
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 309 (1.94%)
    8 / 292 (2.74%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    2 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 309 (0.65%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic candida
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 309 (0.00%)
    2 / 292 (0.68%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 292 (0.34%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 292 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pembrolizumab First Course Chemotherapy Pembrolizumab Second Course
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    259 / 309 (83.82%)
    263 / 292 (90.07%)
    4 / 8 (50.00%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    36 / 309 (11.65%)
    38 / 292 (13.01%)
    0 / 8 (0.00%)
         occurrences all number
    40
    42
    0
    Malaise
         subjects affected / exposed
    9 / 309 (2.91%)
    15 / 292 (5.14%)
    0 / 8 (0.00%)
         occurrences all number
    9
    17
    0
    Fatigue
         subjects affected / exposed
    55 / 309 (17.80%)
    54 / 292 (18.49%)
    1 / 8 (12.50%)
         occurrences all number
    67
    61
    2
    Oedema peripheral
         subjects affected / exposed
    16 / 309 (5.18%)
    14 / 292 (4.79%)
    0 / 8 (0.00%)
         occurrences all number
    17
    17
    0
    Mucosal inflammation
         subjects affected / exposed
    1 / 309 (0.32%)
    22 / 292 (7.53%)
    0 / 8 (0.00%)
         occurrences all number
    1
    22
    0
    Pyrexia
         subjects affected / exposed
    35 / 309 (11.33%)
    34 / 292 (11.64%)
    0 / 8 (0.00%)
         occurrences all number
    46
    49
    0
    Influenza like illness
         subjects affected / exposed
    3 / 309 (0.97%)
    4 / 292 (1.37%)
    1 / 8 (12.50%)
         occurrences all number
    4
    4
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    53 / 309 (17.15%)
    31 / 292 (10.62%)
    0 / 8 (0.00%)
         occurrences all number
    60
    33
    0
    Dyspnoea
         subjects affected / exposed
    37 / 309 (11.97%)
    32 / 292 (10.96%)
    0 / 8 (0.00%)
         occurrences all number
    41
    39
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    9 / 309 (2.91%)
    17 / 292 (5.82%)
    0 / 8 (0.00%)
         occurrences all number
    9
    18
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    22 / 309 (7.12%)
    24 / 292 (8.22%)
    1 / 8 (12.50%)
         occurrences all number
    25
    43
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    32 / 309 (10.36%)
    28 / 292 (9.59%)
    1 / 8 (12.50%)
         occurrences all number
    39
    51
    1
    Neutrophil count decreased
         subjects affected / exposed
    3 / 309 (0.97%)
    44 / 292 (15.07%)
    0 / 8 (0.00%)
         occurrences all number
    8
    144
    0
    White blood cell count decreased
         subjects affected / exposed
    5 / 309 (1.62%)
    30 / 292 (10.27%)
    0 / 8 (0.00%)
         occurrences all number
    11
    103
    0
    Weight decreased
         subjects affected / exposed
    10 / 309 (3.24%)
    16 / 292 (5.48%)
    0 / 8 (0.00%)
         occurrences all number
    10
    16
    0
    Blood bilirubin increased
         subjects affected / exposed
    3 / 309 (0.97%)
    8 / 292 (2.74%)
    1 / 8 (12.50%)
         occurrences all number
    3
    9
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    14 / 309 (4.53%)
    20 / 292 (6.85%)
    0 / 8 (0.00%)
         occurrences all number
    15
    21
    0
    Headache
         subjects affected / exposed
    44 / 309 (14.24%)
    34 / 292 (11.64%)
    0 / 8 (0.00%)
         occurrences all number
    61
    43
    0
    Neuropathy peripheral
         subjects affected / exposed
    4 / 309 (1.29%)
    26 / 292 (8.90%)
    0 / 8 (0.00%)
         occurrences all number
    4
    28
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    6 / 309 (1.94%)
    19 / 292 (6.51%)
    0 / 8 (0.00%)
         occurrences all number
    6
    20
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    28 / 309 (9.06%)
    46 / 292 (15.75%)
    0 / 8 (0.00%)
         occurrences all number
    31
    80
    0
    Neutropenia
         subjects affected / exposed
    2 / 309 (0.65%)
    61 / 292 (20.89%)
    0 / 8 (0.00%)
         occurrences all number
    2
    146
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    18 / 309 (5.83%)
    15 / 292 (5.14%)
    0 / 8 (0.00%)
         occurrences all number
    18
    18
    0
    Constipation
         subjects affected / exposed
    50 / 309 (16.18%)
    51 / 292 (17.47%)
    0 / 8 (0.00%)
         occurrences all number
    56
    59
    0
    Diarrhoea
         subjects affected / exposed
    29 / 309 (9.39%)
    60 / 292 (20.55%)
    1 / 8 (12.50%)
         occurrences all number
    34
    83
    1
    Nausea
         subjects affected / exposed
    50 / 309 (16.18%)
    89 / 292 (30.48%)
    0 / 8 (0.00%)
         occurrences all number
    63
    117
    0
    Vomiting
         subjects affected / exposed
    23 / 309 (7.44%)
    33 / 292 (11.30%)
    0 / 8 (0.00%)
         occurrences all number
    30
    44
    0
    Stomatitis
         subjects affected / exposed
    6 / 309 (1.94%)
    23 / 292 (7.88%)
    0 / 8 (0.00%)
         occurrences all number
    7
    24
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    2 / 309 (0.65%)
    43 / 292 (14.73%)
    0 / 8 (0.00%)
         occurrences all number
    2
    44
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    2 / 309 (0.65%)
    36 / 292 (12.33%)
    0 / 8 (0.00%)
         occurrences all number
    2
    47
    0
    Pruritus
         subjects affected / exposed
    35 / 309 (11.33%)
    12 / 292 (4.11%)
    0 / 8 (0.00%)
         occurrences all number
    44
    12
    0
    Rash
         subjects affected / exposed
    23 / 309 (7.44%)
    13 / 292 (4.45%)
    0 / 8 (0.00%)
         occurrences all number
    25
    14
    0
    Renal and urinary disorders
    Leukocyturia
         subjects affected / exposed
    0 / 309 (0.00%)
    0 / 292 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    25 / 309 (8.09%)
    4 / 292 (1.37%)
    0 / 8 (0.00%)
         occurrences all number
    26
    4
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    37 / 309 (11.97%)
    24 / 292 (8.22%)
    1 / 8 (12.50%)
         occurrences all number
    46
    28
    1
    Back pain
         subjects affected / exposed
    22 / 309 (7.12%)
    30 / 292 (10.27%)
    0 / 8 (0.00%)
         occurrences all number
    24
    33
    0
    Pain in extremity
         subjects affected / exposed
    19 / 309 (6.15%)
    24 / 292 (8.22%)
    1 / 8 (12.50%)
         occurrences all number
    20
    28
    1
    Muscular weakness
         subjects affected / exposed
    4 / 309 (1.29%)
    4 / 292 (1.37%)
    1 / 8 (12.50%)
         occurrences all number
    4
    4
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    11 / 309 (3.56%)
    4 / 292 (1.37%)
    1 / 8 (12.50%)
         occurrences all number
    11
    4
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    18 / 309 (5.83%)
    14 / 292 (4.79%)
    0 / 8 (0.00%)
         occurrences all number
    22
    20
    0
    Urinary tract infection
         subjects affected / exposed
    16 / 309 (5.18%)
    20 / 292 (6.85%)
    0 / 8 (0.00%)
         occurrences all number
    18
    24
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    30 / 309 (9.71%)
    38 / 292 (13.01%)
    0 / 8 (0.00%)
         occurrences all number
    31
    43
    0
    Hyperglycaemia
         subjects affected / exposed
    12 / 309 (3.88%)
    17 / 292 (5.82%)
    0 / 8 (0.00%)
         occurrences all number
    14
    21
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jan 2016
    Amendment 1: The primary reason for this amendment was to update the description and proper formulation of eribulin in the Investigational Products section.
    08 Sep 2017
    Amendment 2: The primary reasons for this amendment were to revise the primary and secondary objectives, statistical analysis plan, and trial design of this study.
    25 Oct 2017
    Amendment 3: The primary reason for this amendment was to update the timing of the interim/final analysis and the target events for final analysis and sample size and power calculation in the Statistical Analysis Plan Summary section.
    22 Dec 2017
    Amendment 4: The primary reasons for this amendment were to update the Trial Summary, Trial Design, and several other sections of the protocol.
    03 Apr 2018
    Amendment 5: The primary reasons for this amendment were to revise the study objectives, hypotheses, and statistical analysis plan to include participants with PD-L1 positive tumors with a higher combined positive score (CPS) cutoff of ≥10 (CPS ≥10).

    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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