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    Clinical Trial Results:
    A Phase II Clinical Trial of Pembrolizumab (MK-3475) as Monotherapy for Metastatic Triple-Negative Breast Cancer (mTNBC) – (KEYNOTE-086)

    Summary
    EudraCT number
    		 2015-000294-13
    Trial protocol
    		 ES   DE   BE   FR  
    Global end of trial date
    31 Jan 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Jan 2021
    First version publication date
    01 Jan 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MK-3475-086
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02447003
    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
    31 Jan 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Feb 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jan 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a two-part study of pembrolizumab monotherapy in participants with metastatic triple-negative breast cancer (mTNBC). Part 1 of the study will examine the efficacy and safety of pembrolizumab monotherapy as first line or above treatment in participants who have received either no prior systemic treatment or at least one prior systemic treatment for metastatic breast cancer. Part 2 of the study, if done, will expand the investigation of pembrolizumab treatment in a subgroup of participants from Part 1 and will only start after enrollment in Part 1 has been completed. There will be no hypothesis testing in this study.
    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. The following additional measure defined for this individual study was in place for the protection of trial subjects: subjects were permitted to be given rescue medication for management of infusion reactions, including but not limited to the following: intravenous (IV) fluids, antihistamines, nonsteroidal anti inflammatory drugs (NSAIDS), acetaminophen, narcotics, oxygen, pressors, corticosteroids, epinephrine. These medications would be administered according to local standards and practice.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Jun 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 21
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Canada: 20
    Country: Number of subjects enrolled
    France: 15
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Israel: 10
    Country: Number of subjects enrolled
    Italy: 15
    Country: Number of subjects enrolled
    Japan: 31
    Country: Number of subjects enrolled
    New Zealand: 3
    Country: Number of subjects enrolled
    South Africa: 5
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    United Kingdom: 19
    Country: Number of subjects enrolled
    United States: 77
    Worldwide total number of subjects
    254
    EEA total number of subjects
    87
    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)
    188
    From 65 to 84 years
    64
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Per protocol, response or progression during the second pembrolizumab course was not counted towards efficacy outcome measures, and adverse events during the second pembrolizumab course were not counted towards safety outcome measures. Based on protocol-specified inclusion criteria and outcome analyses requirements, Part 2 was not conducted.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort A: Pembrolizumab
    Arm description
    		 Participants in Cohort A previously received at least one prior systemic treatment for metastatic breast cancer. Participants were administered pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles (up to ~2 years). Qualified participants who completed the first course of up to 35 administrations of pembrolizumab (~2 years) but progressed after discontinuation, initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 each 3-week cycle (Q3W), for up to 17 cycles (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
    IV infusion of 200 mg.

    Arm title
    		 Cohort B: Pembrolizumab
    Arm description
    		 Participants in Cohort B previously received no prior systemic treatment for metastatic breast cancer AND had a programmed cell death-ligand 1 (PD-L1) positive tumor expression. Participants were administered pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles (up to ~2 years). Qualified participants who completed the first course of up to 35 administrations of pembrolizumab (~2 years) but progressed after discontinuation, initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 of each 3-week cycle (Q3W), for up to 17 cycles (up to ~1 year).
    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
    IV infusion of 200 mg.

    Number of subjects in period 1
    		Cohort A: Pembrolizumab Cohort B: Pembrolizumab
    Started
    170
    84
    Completed
    0
    0
    Not completed
    170
    84
         Consent withdrawn by subject
    4
    3
         Physician decision
    -
    1
         Site discontinued
    -
    2
         Death
    154
    63
         Progressive Disease
    1
    -
         Unknown
    -
    4
         Sponsor Decision
    6
    11
         Lost to follow-up
    5
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A: Pembrolizumab
    Reporting group description
    		 Participants in Cohort A previously received at least one prior systemic treatment for metastatic breast cancer. Participants were administered pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles (up to ~2 years). Qualified participants who completed the first course of up to 35 administrations of pembrolizumab (~2 years) but progressed after discontinuation, initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 each 3-week cycle (Q3W), for up to 17 cycles (up to ~1 year).

    Reporting group title
    Cohort B: Pembrolizumab
    Reporting group description
    		 Participants in Cohort B previously received no prior systemic treatment for metastatic breast cancer AND had a programmed cell death-ligand 1 (PD-L1) positive tumor expression. Participants were administered pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles (up to ~2 years). Qualified participants who completed the first course of up to 35 administrations of pembrolizumab (~2 years) but progressed after discontinuation, initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 of each 3-week cycle (Q3W), for up to 17 cycles (up to ~1 year).

    Reporting group values
    		 Cohort A: Pembrolizumab Cohort B: Pembrolizumab Total
    Number of subjects
    		 170 84 254
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 126 62 188
        From 65-84 years
    		 43 21 64
        85 years and over
    		 1 1 2
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 54.6 ( 12.8 ) 54.2 ( 14.1 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 170 84 254
        Male
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 10 6 16
        Not Hispanic or Latino
    		 146 74 220
        Unknown or Not Reported
    		 14 4 18
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 1
        Asian
    		 24 15 39
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 12 14 26
        White
    		 129 53 182
        More than one race
    		 3 0 3
        Unknown or Not Reported
    		 1 2 3

    End points

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    End points reporting groups
    Reporting group title
    Cohort A: Pembrolizumab
    Reporting group description
    		 Participants in Cohort A previously received at least one prior systemic treatment for metastatic breast cancer. Participants were administered pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles (up to ~2 years). Qualified participants who completed the first course of up to 35 administrations of pembrolizumab (~2 years) but progressed after discontinuation, initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 each 3-week cycle (Q3W), for up to 17 cycles (up to ~1 year).

    Reporting group title
    Cohort B: Pembrolizumab
    Reporting group description
    		 Participants in Cohort B previously received no prior systemic treatment for metastatic breast cancer AND had a programmed cell death-ligand 1 (PD-L1) positive tumor expression. Participants were administered pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles (up to ~2 years). Qualified participants who completed the first course of up to 35 administrations of pembrolizumab (~2 years) but progressed after discontinuation, initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 of each 3-week cycle (Q3W), for up to 17 cycles (up to ~1 year).

    Subject analysis set title
    Cohort A: Pembrolizumab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants in Cohort A previously received at least one prior systemic treatment for metastatic breast cancer. Participants were administered pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles (up to ~2 years).

    Subject analysis set title
    Cohort B: Pembrolizumab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants in Cohort B previously received no prior systemic treatment for metastatic breast cancer AND had a programmed cell death-ligand 1 (PD-L1) positive tumor expression. Participants were administered pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles (up to ~2 years).

    Subject analysis set title
    Cohort A: Pembrolizumab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants in Cohort A previously received at least one prior systemic treatment for metastatic breast cancer. Participants were administered pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles (up to ~2 years).

    Subject analysis set title
    Cohort A: Pembrolizumab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants in Cohort A previously received at least one prior systemic treatment for metastatic breast cancer. Participants were administered pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles (up to ~2 years).

    Subject analysis set title
    Cohort B: Pembrolizumab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants in Cohort B previously received no prior systemic treatment for metastatic breast cancer AND had a programmed cell death-ligand 1 (PD-L1) positive tumor expression. Participants were administered pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles (up to ~2 years).

    Subject analysis set title
    Cohort A: Pembrolizumab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants in Cohort A previously received at least one prior systemic treatment for metastatic breast cancer. Participants were administered pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles (up to ~2 years).

    Subject analysis set title
    Cohort A: Pembrolizumab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants in Cohort A previously received at least one prior systemic treatment for metastatic breast cancer. Participants were administered pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles (up to ~2 years).

    Primary: Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Central Imaging Vendor (CIV) in All Cohort A Participants

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    End point title
    		 Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Central Imaging Vendor (CIV) in All Cohort A Participants [1]
    End point description
    ORR was defined as the percentage of participants who had Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in sum of diameters [SOD] of target lesions) per RECIST 1.1 by CIV. ORR was estimated by Agresti-Coull (A-C) method. The percentage of participants who had CR or PR is reported here as the protocol-specified ORR for the first pembrolizumab course, assessed from enrolment/treatment initiation and analyzed by Cohort, for all participants in Cohort A who got ≥1 dose of study drug. Per protocol final ORR analysis in all Cohort A participants was done at the time of final statistical efficacy analysis with a 10-November (Nov)-2017 cutoff. Per protocol ORR per RECIST 1.1 by CIV in all Cohort A participants was planned and conducted as a pre-specified primary outcome analysis and ORR per RECIST 1.1 by CIV in all Cohort B participants was analyzed separately as a pre-specified secondary outcome analysis and reported later in the record.
    End point type
    Primary
    End point timeframe
    Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical comparisons between reported cohorts of the current study were planned for this endpoint.
    End point values
    		 Cohort A: Pembrolizumab Cohort B: Pembrolizumab
    Number of subjects analysed
    170
    0 [2]
    Units: Percentage of participants
        number (confidence interval 95%)
    5.3 (2.7 to 9.9)
    ( to )
    Notes
    [2] - Per protocol ORR in Cohort B was analyzed separately and reported later in the record.
    No statistical analyses for this end point

    Primary: ORR per RECIST 1.1 by CIV in Subgroup of Cohort A Participants with Programmed Cell Death- Ligand 1 (PD-L1) Positive Tumor Expression

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    End point title
    		 ORR per RECIST 1.1 by CIV in Subgroup of Cohort A Participants with Programmed Cell Death- Ligand 1 (PD-L1) Positive Tumor Expression [3]
    End point description
    ORR was defined as the percentage of participants who had a CR (disappearance of all target lesions) or a PR (≥30% decrease in SOD of target lesions) per RECIST 1.1 by CIV. ORR was estimated by A-C method. The percentage of participants who had CR or PR is reported here as the protocol-specified ORR, for the first pembrolizumab course, assessed from enrolment/treatment initiation and analyzed by Cohort for the subgroup of Cohort A participants with tumor immunohistochemistry (IHC) defined-PD-L1 positive expression (PD-L1+) who got ≥1 dose of study drug. Per protocol final ORR analysis in the Cohort A PD-L1+ subgroup was done at the time of final statistical efficacy analysis with a 10-Nov-2017 cutoff. Per protocol all Cohort B participants were PD-L1+ and ORR per RECIST 1.1 by CIV in all Cohort B participants was analyzed separately as a pre-specified secondary outcome analysis and reported later in the record.
    End point type
    Primary
    End point timeframe
    Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical comparisons between reported cohorts of the current study were planned for this endpoint.
    End point values
    		 Cohort B: Pembrolizumab Cohort A: Pembrolizumab
    Number of subjects analysed
    0 [4]
    105
    Units: Percentage of participants
        number (confidence interval 95%)
    ( to )
    5.7 (2.4 to 12.2)
    Notes
    [4] - Per protocol ORR in Cohort B was analyzed separately and reported later in the record.
    No statistical analyses for this end point

    Primary: Number of Participants Who Experienced at Least One Adverse Event (AE)

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    End point title
    		 Number of Participants Who Experienced at Least One Adverse Event (AE) [5]
    End point description
    An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and which 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 or protocol-specified procedure. Any worsening of a pre-existing condition that is temporally associated with the use of the Sponsor’s product is also an AE. Per protocol the number of participants who experienced at least one AE, for the first pembrolizumab course, was assessed from enrollment/treatment initiation of a participant and analyzed by Cohort and is reported here for all participants in Cohort A and Cohort B who received ≥1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to ~31 months
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical comparisons between reported cohorts of the current study were planned for this endpoint.
    End point values
    		 Cohort A: Pembrolizumab Cohort B: Pembrolizumab
    Number of subjects analysed
    170
    84
    Units: Participants
    161
    83
    No statistical analyses for this end point

    Primary: Number of Participants Who Discontinued Study Drug Due to an AE

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    End point title
    		 Number of Participants Who Discontinued Study Drug Due to an AE [6]
    End point description
    An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and which 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 or protocol-specified procedure. Any worsening of a pre-existing condition that is temporally associated with the use of the Sponsor’s product is also an AE. Per protocol the number of participants who discontinued study drug due to an AE, in the first pembrolizumab course, was assessed from enrolment/treatment initiation of a participant and analyzed by Cohort and is reported here for all participants in Cohort A and Cohort B who received ≥1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to ~31 months
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical comparisons between reported cohorts of the current study were planned for this endpoint.
    End point values
    		 Cohort A: Pembrolizumab Cohort B: Pembrolizumab
    Number of subjects analysed
    170
    84
    Units: Participants
    8
    3
    No statistical analyses for this end point

    Secondary: ORR per RECIST 1.1 by CIV in All Cohort B Participants

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    End point title
    		 ORR per RECIST 1.1 by CIV in All Cohort B Participants
    End point description
    ORR was defined as the percentage of participants who had a CR (disappearance of all target lesions) or a PR (≥30% decrease in SOD of target lesions) per RECIST 1.1 by CIV. ORR was estimated by A-C method. The percentage of participants who had CR or PR is reported here as the protocol-specified ORR, for the first pembrolizumab course, assessed from enrolment/treatment initiation and analyzed by Cohort for all participants in Cohort B who got ≥1 dose of study drug. Per protocol final ORR analysis in all Cohort B participants was done at the time of final statistical efficacy analysis, with a 10-Nov-2017 cutoff. Per protocol ORR per RECIST 1.1 by CIV in all Cohort B participants was planned and conducted as a pre-specified secondary outcome analysis. Per protocol ORR per RECIST 1.1 by CIV in all Cohort A participants was analyzed separately as a pre-specified primary outcome analysis and reported earlier in the record.
    End point type
    Secondary
    End point timeframe
    Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
    End point values
    		 Cohort A: Pembrolizumab Cohort B: Pembrolizumab
    Number of subjects analysed
    0 [7]
    84
    Units: Percentage of participants
        number (confidence interval 95%)
    ( to )
    21.4 (13.9 to 31.4)
    Notes
    [7] - Per protocol ORR in Cohort A was analyzed separately and reported earlier in the record.
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) per RECIST 1.1 by CIV in All Cohort A and Cohort B Participants

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    End point title
    		 Duration of Response (DOR) per RECIST 1.1 by CIV in All Cohort A and Cohort B Participants
    End point description
    For participants who had CR (disappearance of all target lesions) or PR (≥30% target lesion SOD decrease) per RECIST 1.1 by CIV, DOR was defined as time from first documented CR or PR until progressive disease (PD: ≥20% target lesion SOD increase, ≥5 mm absolute SOD increase; PD is also ≥1 new lesion appearance) or death. DOR for those who didn’t progress/die at time of analysis was censored at last tumor assessment. Per protocol DOR for the first pembrolizumab course, assessed from enrolment/treatment initiation, estimated by Kaplan-Meier (KM) method and analyzed by cohort is reported here for all participants in Cohort A and Cohort B who had CR or PR per RECIST 1.1 by CIV and got ≥1 dose of study drug. Per protocol final DOR analysis in all Cohort A and Cohort B participants was done at the time of final statistical efficacy analysis with a 10-Nov-2017 cutoff. "99999" indicates no PD by last assessment.
    End point type
    Secondary
    End point timeframe
    Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
    End point values
    		 Cohort A: Pembrolizumab Cohort B: Pembrolizumab
    Number of subjects analysed
    9
    18
    Units: Months
        median (full range (min-max))
    99999 (99999 to 99999)
    10.4 (4.2 to 99999)
    No statistical analyses for this end point

    Secondary: DOR per RECIST 1.1 by CIV in Subgroup of Cohort A Participants with PD-L1 Positive Tumor Expression

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    End point title
    		 DOR per RECIST 1.1 by CIV in Subgroup of Cohort A Participants with PD-L1 Positive Tumor Expression
    End point description
    For participants who had CR (disappearance of all target lesions) or PR (≥30% target lesion SOD decrease) per RECIST 1.1 by CIV, DOR was the time from first CR or PR until PD (≥20% target lesion SOD increase, ≥5 mm absolute SOD increase; PD is also ≥1 new lesion appearance) or death. DOR for those who didn’t progress by analysis was censored at last assessment. Per protocol DOR for first pembrolizumab course assessed from enrolment/treatment initiation, estimated by KM method and analyzed by Cohort is reported for subgroup of Cohort A participants with tumor IHC defined-PD-L1 positive expression (PD-L1+) and CR/PR per RECIST 1.1 by CIV who got ≥1 dose of study drug. Per protocol final DOR analysis in Cohort A PD-L1+ subgroup was done with a final statistical efficacy analysis cutoff of 10-Nov-2017. Per protocol all Cohort B participants were PD-L1+; DOR in all Cohort B participants was analyzed separately and reported earlier in the record. “99999” indicates no PD by last assessment.
    End point type
    Secondary
    End point timeframe
    Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
    End point values
    		 Cohort B: Pembrolizumab Cohort A: Pembrolizumab
    Number of subjects analysed
    0 [8]
    6
    Units: Months
        median (full range (min-max))
    ( to )
    99999 (6.3 to 99999)
    Notes
    [8] - Per protocol DOR in Cohort B was analyzed separately and reported earlier in the record.
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR) per RECIST 1.1 by CIV in All Cohort A and Cohort B Participants

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    End point title
    		 Disease Control Rate (DCR) per RECIST 1.1 by CIV in All Cohort A and Cohort B Participants
    End point description
    DCR was defined as the percentage of participants in the analysis population who have CR (disappearance of all target lesions) or PR (≥30% target lesion SOD decrease) or SD (not sufficient shrinkage for PR or sufficient increase for PD [≥20% target lesion SOD increase, ≥5 mm absolute SOD increase; PD is also ≥1 new lesion appearance]) for ≥24 weeks per RECIST 1.1 by CIV. Per protocol percentage of participants who had CR, PR or SD per RECIST 1.1 by CIV is reported here as DCR, for the first pembrolizumab course, assessed from enrolment/treatment initiation, estimated by A-C method and analyzed by Cohort, for all participants in Cohort A and Cohort B who got ≥1 dose of study drug. Per protocol final DCR analysis in all Cohort A and Cohort B participants was done at the time of final statistical efficacy analysis, with a 10-Nov-2017 cutoff.
    End point type
    Secondary
    End point timeframe
    Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
    End point values
    		 Cohort A: Pembrolizumab Cohort B: Pembrolizumab
    Number of subjects analysed
    170
    84
    Units: Percentage of participants
        number (confidence interval 95%)
    7.6 (4.4 to 12.7)
    23.8 (15.9 to 34.0)
    No statistical analyses for this end point

    Secondary: DCR per RECIST 1.1 by CIV in Subgroup of Cohort A Participants with PD-L1 Positive Tumor Expression

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    End point title
    		 DCR per RECIST 1.1 by CIV in Subgroup of Cohort A Participants with PD-L1 Positive Tumor Expression
    End point description
    DCR was the percentage of participants who have CR (disappearance of all target lesions) or PR (≥30% target lesion SOD decrease) or SD (not sufficient shrinkage for PR or sufficient increase for PD [≥20% target lesion SOD increase, ≥5 mm absolute SOD increase; PD is also ≥1 new lesion appearance]) for ≥24 weeks per RECIST 1.1 by CIV. Per protocol percentage of participants who had CR, PR or SD per RECIST 1.1 by CIV is reported as DCR for the first pembrolizumab course assessed from enrolment/treatment initiation, estimated by A-C method and analyzed by Cohort for subgroup of Cohort A participants with tumor IHC defined-PD-L1 positive expression (PD-L1+) who got ≥1 dose of study drug. Per protocol final DCR analysis in Cohort A PD-L1+ subgroup was done with a final statistical efficacy analysis cutoff of 10-Nov-2017. Per protocol all Cohort B participants were PD-L1+; DCR per RECIST 1.1 by CIV in all Cohort B participants was analyzed separately and reported earlier in the record.
    End point type
    Secondary
    End point timeframe
    Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
    End point values
    		 Cohort B: Pembrolizumab Cohort A: Pembrolizumab
    Number of subjects analysed
    0 [9]
    105
    Units: Percentage of participants
        number (confidence interval 95%)
    ( to )
    9.5 (5.1 to 16.8)
    Notes
    [9] - Per protocol DCR in Cohort B was analyzed separately and reported earlier in the record.
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) per RECIST 1.1 by CIV in All Cohort A and Cohort B Participants

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    End point title
    		 Progression Free Survival (PFS) per RECIST 1.1 by CIV in All Cohort A and Cohort B Participants
    End point description
    PFS was defined as the time from first dose of study drug to the first documented PD per RECIST 1.1 by CIV, or death due to any cause, whichever occurred first. Per RECIST 1.1 PD was defined as ≥20% increase in SOD of target lesions and absolute SOD increase of ≥5 mm. Appearance of ≥1 new lesion is also PD. PFS was estimated by KM method. Per protocol PFS, for the first pembrolizumab course, assessed from enrolment/treatment initiation and analyzed by Cohort is reported here for all participants in Cohort A and Cohort B who got ≥1 dose of study drug. Per protocol final PFS analysis in all Cohort A and Cohort B participants was done at the time of final statistical efficacy analysis with a 10-Nov-2017 cutoff.
    End point type
    Secondary
    End point timeframe
    Up to ~28 months (through pre-specified final statistical analysis cut-off date of 10-Nov-2017)
    End point values
    		 Cohort A: Pembrolizumab Cohort B: Pembrolizumab
    Number of subjects analysed
    170
    84
    Units: Months
        median (confidence interval 95%)
    2.0 (1.9 to 2.0)
    2.1 (2.0 to 2.2)
    No statistical analyses for this end point

    Secondary: PFS per RECIST 1.1 by CIV in Subgroup of Cohort A Participants with PD-L1 Positive Tumor Expression

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    End point title
    		 PFS per RECIST 1.1 by CIV in Subgroup of Cohort A Participants with PD-L1 Positive Tumor Expression
    End point description
    PFS was defined as the time from first dose of study drug to the first documented PD per RECIST 1.1 by CIV, or death due to any cause, whichever occurred first. Per RECIST 1.1 PD was defined as ≥20% increase in SOD of target lesions and absolute SOD increase of ≥5 mm. Appearance of ≥1 new lesion is also PD. PFS was estimated by KM method. Per protocol PFS, for the first pembrolizumab course, assessed from enrolment/treatment initiation and analyzed by Cohort is reported here for the subgroup of Cohort A participants with tumor IHC defined-PD-L1 positive expression (PD-L1+) who got ≥1 dose of study drug. Per protocol final PFS analysis in the Cohort A PD-L1+ subgroup was done at the time of final statistical efficacy analysis with a 10-Nov-2017 cutoff. Per protocol all Cohort B participants were PD-L1+ and PFS per RECIST 1.1 by CIV in all Cohort B participants was analyzed separately and reported earlier in the record.
    End point type
    Secondary
    End point timeframe
    Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
    End point values
    		 Cohort B: Pembrolizumab Cohort A: Pembrolizumab
    Number of subjects analysed
    0 [10]
    105
    Units: Months
        median (confidence interval 95%)
    ( to )
    2.0 (1.9 to 2.1)
    Notes
    [10] - Per protocol PFS in Cohort B was analyzed separately and reported earlier in the record.
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) in All Cohort A and Cohort B Participants

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    End point title
    		 Overall Survival (OS) in All Cohort A and Cohort B Participants
    End point description
    OS was defined as the time from the first dose of study drug to death due to any cause. OS was estimated by KM method. Per protocol OS, for the first pembrolizumab course, assessed from enrolment/treatment initiation and analyzed by Cohort is reported here for all participants in Cohort A and Cohort B who got ≥1 dose of study drug. Per protocol final OS analysis in all Cohort A and Cohort B participants was done at the time of final statistical efficacy analysis with a 10-Nov-2017 cutoff.
    End point type
    Secondary
    End point timeframe
    Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
    End point values
    		 Cohort A: Pembrolizumab Cohort B: Pembrolizumab
    Number of subjects analysed
    170
    84
    Units: Months
        median (confidence interval 95%)
    9.0 (7.6 to 11.2)
    18.0 (12.9 to 23.0)
    No statistical analyses for this end point

    Secondary: OS in Subgroup of Cohort A Participants with PD-L1 Positive Tumor Expression

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    End point title
    		 OS in Subgroup of Cohort A Participants with PD-L1 Positive Tumor Expression
    End point description
    OS was defined as the time from the first dose of study drug to death due to any cause. OS was estimated by KM method. Per protocol OS, for the first pembrolizumab course, assessed from enrolment/treatment initiation and analyzed by Cohort, is reported here for the subgroup of Cohort A participants with tumor IHC defined-PD-L1 positive expression (PD-L1+) who got ≥1 dose of study drug. Per protocol final OS analysis in the Cohort A PD-L1+ subgroup was done at the time of final statistical efficacy analysis with a 10-Nov-2017 cutoff. Per protocol all Cohort B participants were PD-L1+ and OS in all Cohort B participants was analyzed separately and reported earlier in the record.
    End point type
    Secondary
    End point timeframe
    Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
    End point values
    		 Cohort B: Pembrolizumab Cohort A: Pembrolizumab
    Number of subjects analysed
    0 [11]
    105
    Units: Months
        median (confidence interval 95%)
    ( to )
    8.8 (7.1 to 11.2)
    Notes
    [11] - Per protocol OS in Cohort B was analyzed separately and reported earlier in the record.
    No statistical analyses for this end point

    Secondary: Odds Ratio of Association Between PD-L1 Tumor Expression and Objective Response (OR) per RECIST 1.1 by CIV in Cohort A Participants

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    End point title
    		 Odds Ratio of Association Between PD-L1 Tumor Expression and Objective Response (OR) per RECIST 1.1 by CIV in Cohort A Participants
    End point description
    OR comprises CR (disappearance of all target lesions) or PR (≥30% target lesion SOD decrease) per RECIST 1.1 by CIV. PD-L1 expression is assessed by IHC-defined combined positive score (CPS). Association between (b/w) PD-L1 CPS and OR was assessed by odds ratio by a logistic regression model and calculated as ratio of odds of OR per unit CPS increase in a single arm (odds ratio=1: no association; odds ratio<1: negative association [increase in CPS lowers odds of OR]; odds ratio >1: positive association [increase in CPS raises odds of OR]). Per protocol odds ratio for the first pembrolizumab course, assessed from enrolment/treatment initiation and analyzed by Cohort is reported here in a single arm of Cohort A participants with PD-L1 CPS who got ≥1 dose of study drug. Per protocol odds ratio was analyzed with a final statistical efficacy analysis cutoff of 10-Nov-2017. Per protocol odds ratio of association b/w PD-L1 expression and OR was not planned or done in Cohort B participants.
    End point type
    Secondary
    End point timeframe
    Up to ~28 months (through pre-specified statistical analysis cut-off date of 10-Nov-2017)
    End point values
    		 Cohort B: Pembrolizumab Cohort A: Pembrolizumab
    Number of subjects analysed
    0 [12]
    169
    Units: Odds Ratio
        number (confidence interval 95%)
    ( to )
    1.017 (0.991 to 1.043)
    Notes
    [12] - Per protocol odds ratio analysis was not planned or done in Cohort B.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Safety: Up to ~31 months for pembrolizumab first course; up to additional ~15 months for second course (SAEs: up to 90 days post treatment; NSAEs: up to 30 days post treatment); All-cause mortality (ACM): Up to ~54 months for first and second course
    Adverse event reporting additional description
    Safety, ACM were analyzed by Cohort (A, B) and course (first, second) in participants assessed from treatment initiation, who got ≥1 study drug dose. Per protocol disease progression (DP) wasn’t an AE unless related to study drug; MedDRA preferred terms "Neoplasm progression (NP)", "Malignant NP", "DP" unrelated to study drug are excluded as AEs.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Cohort A: Pembrolizumab First Course
    Reporting group description
    		 Participants in Cohort A previously received at least one prior systemic treatment for metastatic breast cancer. Participants were administered pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles (up to ~2 years).

    Reporting group title
    Cohort B: Pembrolizumab First Course
    Reporting group description
    		 Participants in Cohort B previously received no prior systemic treatment for metastatic breast cancer AND had a programmed cell death-ligand 1 (PD-L1) positive tumor expression. Participants were administered pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles (up to ~2 years).

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

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

    Serious adverse events
    		 Cohort A: Pembrolizumab First Course Cohort B: Pembrolizumab First Course Cohort A: Pembrolizumab Second Course Cohort B: Pembrolizumab Second Course
    Total subjects affected by serious adverse events
         subjects affected / exposed
    46 / 170 (27.06%)
    19 / 84 (22.62%)
    0 / 1 (0.00%)
    2 / 4 (50.00%)
         number of deaths (all causes)
    154
    63
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 170 (0.59%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colorectal cancer
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infected neoplasm
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    2 / 170 (1.18%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 170 (0.59%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 170 (1.18%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    8 / 170 (4.71%)
    3 / 84 (3.57%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 170 (1.18%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 170 (1.76%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary thrombosis
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device failure
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative ileus
         subjects affected / exposed
    0 / 170 (0.00%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac tamponade
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    2 / 170 (1.18%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis eosinophilic
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 170 (0.59%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    2 / 170 (1.18%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 170 (2.94%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superinfection
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 170 (1.18%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 170 (1.18%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort A: Pembrolizumab First Course Cohort B: Pembrolizumab First Course Cohort A: Pembrolizumab Second Course Cohort B: Pembrolizumab Second Course
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    147 / 170 (86.47%)
    79 / 84 (94.05%)
    1 / 1 (100.00%)
    4 / 4 (100.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    8 / 170 (4.71%)
    6 / 84 (7.14%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    8
    6
    0
    0
    Lymphoedema
         subjects affected / exposed
    9 / 170 (5.29%)
    4 / 84 (4.76%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    10
    4
    0
    0
    Hypertension
         subjects affected / exposed
    2 / 170 (1.18%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    3
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    19 / 170 (11.18%)
    8 / 84 (9.52%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    20
    9
    0
    1
    Chest pain
         subjects affected / exposed
    11 / 170 (6.47%)
    6 / 84 (7.14%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    13
    7
    0
    0
    Fatigue
         subjects affected / exposed
    49 / 170 (28.82%)
    30 / 84 (35.71%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    59
    40
    0
    1
    Oedema peripheral
         subjects affected / exposed
    15 / 170 (8.82%)
    7 / 84 (8.33%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    18
    8
    0
    0
    Pain
         subjects affected / exposed
    5 / 170 (2.94%)
    5 / 84 (5.95%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    5
    5
    0
    0
    Pyrexia
         subjects affected / exposed
    19 / 170 (11.18%)
    10 / 84 (11.90%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    25
    12
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    39 / 170 (22.94%)
    20 / 84 (23.81%)
    0 / 1 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    45
    22
    0
    2
    Dyspnoea
         subjects affected / exposed
    25 / 170 (14.71%)
    17 / 84 (20.24%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    26
    21
    0
    1
    Pleural effusion
         subjects affected / exposed
    9 / 170 (5.29%)
    3 / 84 (3.57%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    11
    5
    0
    0
    Bronchial wall thickening
         subjects affected / exposed
    0 / 170 (0.00%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    0
    1
    Pneumonitis
         subjects affected / exposed
    5 / 170 (2.94%)
    2 / 84 (2.38%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    5
    2
    0
    1
    Sneezing
         subjects affected / exposed
    1 / 170 (0.59%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    0
    1
    Upper-airway cough syndrome
         subjects affected / exposed
    2 / 170 (1.18%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    0
    1
    Wheezing
         subjects affected / exposed
    4 / 170 (2.35%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    4
    1
    0
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    11 / 170 (6.47%)
    3 / 84 (3.57%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    11
    3
    0
    0
    Depression
         subjects affected / exposed
    8 / 170 (4.71%)
    5 / 84 (5.95%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    8
    5
    0
    0
    Insomnia
         subjects affected / exposed
    6 / 170 (3.53%)
    7 / 84 (8.33%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    6
    7
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 170 (3.53%)
    6 / 84 (7.14%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    7
    7
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    12 / 170 (7.06%)
    8 / 84 (9.52%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    14
    9
    0
    1
    Weight decreased
         subjects affected / exposed
    10 / 170 (5.88%)
    4 / 84 (4.76%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    10
    4
    0
    0
    Platelet count decreased
         subjects affected / exposed
    3 / 170 (1.76%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    3
    1
    0
    1
    Weight increased
         subjects affected / exposed
    1 / 170 (0.59%)
    1 / 84 (1.19%)
    1 / 1 (100.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    11 / 170 (6.47%)
    10 / 84 (11.90%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    11
    11
    0
    0
    Headache
         subjects affected / exposed
    13 / 170 (7.65%)
    16 / 84 (19.05%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    16
    18
    0
    0
    Paraesthesia
         subjects affected / exposed
    4 / 170 (2.35%)
    9 / 84 (10.71%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    4
    11
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    18 / 170 (10.59%)
    10 / 84 (11.90%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    22
    12
    0
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    3 / 170 (1.76%)
    5 / 84 (5.95%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    5
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    8 / 170 (4.71%)
    9 / 84 (10.71%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    8
    14
    0
    1
    Constipation
         subjects affected / exposed
    33 / 170 (19.41%)
    9 / 84 (10.71%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    36
    11
    0
    0
    Diarrhoea
         subjects affected / exposed
    22 / 170 (12.94%)
    16 / 84 (19.05%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    32
    24
    0
    1
    Dry mouth
         subjects affected / exposed
    11 / 170 (6.47%)
    2 / 84 (2.38%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    11
    2
    0
    0
    Nausea
         subjects affected / exposed
    34 / 170 (20.00%)
    23 / 84 (27.38%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    41
    29
    0
    0
    Vomiting
         subjects affected / exposed
    19 / 170 (11.18%)
    11 / 84 (13.10%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    24
    21
    0
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    21 / 170 (12.35%)
    8 / 84 (9.52%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    21
    10
    0
    0
    Rash
         subjects affected / exposed
    12 / 170 (7.06%)
    14 / 84 (16.67%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    14
    23
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    3 / 170 (1.76%)
    5 / 84 (5.95%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    8
    0
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    2 / 170 (1.18%)
    0 / 84 (0.00%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    0
    0
    1
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    9 / 170 (5.29%)
    4 / 84 (4.76%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    9
    5
    0
    0
    Hypothyroidism
         subjects affected / exposed
    19 / 170 (11.18%)
    9 / 84 (10.71%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    20
    10
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    29 / 170 (17.06%)
    15 / 84 (17.86%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    38
    20
    0
    0
    Back pain
         subjects affected / exposed
    17 / 170 (10.00%)
    16 / 84 (19.05%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    17
    19
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    13 / 170 (7.65%)
    4 / 84 (4.76%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    14
    4
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    12 / 170 (7.06%)
    6 / 84 (7.14%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    14
    7
    0
    0
    Myalgia
         subjects affected / exposed
    12 / 170 (7.06%)
    9 / 84 (10.71%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    14
    10
    0
    0
    Pain in extremity
         subjects affected / exposed
    15 / 170 (8.82%)
    7 / 84 (8.33%)
    1 / 1 (100.00%)
    0 / 4 (0.00%)
         occurrences all number
    18
    9
    1
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 170 (3.53%)
    6 / 84 (7.14%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    8
    6
    0
    0
    Urinary tract infection
         subjects affected / exposed
    4 / 170 (2.35%)
    7 / 84 (8.33%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    4
    7
    0
    1
    Pneumonia
         subjects affected / exposed
    3 / 170 (1.76%)
    1 / 84 (1.19%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    3
    1
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    28 / 170 (16.47%)
    12 / 84 (14.29%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    30
    14
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Aug 2016
    The primary reasons for amendment were increase in Cohort B participant number and updates to primary efficacy objectives.
    12 Jan 2018
    The primary reason for amendment was updates to dose modifications and survival assessment.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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