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    Clinical Trial Results:
    A Phase III Randomized Trial of MK-3475 (Pembrolizumab) versus Standard Treatment in Subjects with Recurrent or Metastatic Head and Neck Cancer

    Summary
    EudraCT number
    		 2014-001749-26
    Trial protocol
    		 IE   LT   DE   BE   PT   NL   HU   IT   ES   FR   PL   SE  
    Global end of trial date
    15 Aug 2022

    Results information
    Results version number
    		 v3(current)
    This version publication date
    05 Aug 2023
    First version publication date
    18 May 2018
    Other versions
    		 v1 , v2
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    3475-040
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02252042
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme LLC
    Sponsor organisation address
    126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ, United States, 07065
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Aug 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 May 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Aug 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a study of pembrolizumab (MK-3475) versus standard treatment (methotrexate, docetaxel or cetuximab) for the treatment of recurrent or metastatic head and neck squamous cell cancer (HNSCC). Participants will be randomly assigned to receive either pembrolizumab or Investigator's choice of standard treatment. The primary study hypothesis is that pembrolizumab treatment prolongs Overall Survival (OS) when compared to standard treatment.
    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
    17 Nov 2014
    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
    Australia: 5
    Country: Number of subjects enrolled
    Belgium: 17
    Country: Number of subjects enrolled
    Canada: 33
    Country: Number of subjects enrolled
    France: 51
    Country: Number of subjects enrolled
    Germany: 24
    Country: Number of subjects enrolled
    Hungary: 19
    Country: Number of subjects enrolled
    Ireland: 4
    Country: Number of subjects enrolled
    Italy: 29
    Country: Number of subjects enrolled
    Korea, Republic of: 22
    Country: Number of subjects enrolled
    Lithuania: 7
    Country: Number of subjects enrolled
    Mexico: 6
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Poland: 21
    Country: Number of subjects enrolled
    Portugal: 30
    Country: Number of subjects enrolled
    Russian Federation: 30
    Country: Number of subjects enrolled
    Spain: 26
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Switzerland: 18
    Country: Number of subjects enrolled
    United Kingdom: 54
    Country: Number of subjects enrolled
    United States: 94
    Worldwide total number of subjects
    495
    EEA total number of subjects
    233
    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)
    332
    From 65 to 84 years
    162
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 495 participants were randomized 1:1 to receive either pembrolizumab or standard treatment. Per protocol, response/progression or adverse events (AEs) that occurred during the second course of pembrolizumab 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 intravenous (IV) on Day 1 of each 3-week cycle. Eligible participants who stopped the initial course of pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475, Keytruda®
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg intravenous (IV) on Day 1 of each 3-week cycle.

    Arm title
    		 Standard Treatment
    Arm description
    		 Participants received standard treatment of either methotrexate 40 mg/m^2 IV (could be escalated to 60 mg/m^2 maximum dose) on Days 1, 8, and 15 of each 3-week cycle; or docetaxel 75 mg/m^2 IV on Day 1 of each 3- week cycle; or cetuximab 400 mg/m^2 IV loading dose on Day 1 and 250 mg/m^2 IV on Days 8 and 15 of Cycle 1, followed by cetuximab 250 mg/m^2 on Days 1, 8, and 15 of each subsequent 3-week cycle.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    OTREXUP™, RASUVO®, RHEUMATREX®, TREXALL™
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    40 mg/m^2 IV (may be escalated to 60 mg/m^2 maximum dose) on Days 1, 8, and 15 of each 3-week cycle

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    ERBITUX®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    400 mg/m^2 IV loading dose on Day 1 and 250 mg/m^2 IV on Days 8 and 15 of Cycle 1, followed by 250 mg/m^2 on Days 1, 8, and 15 of each subsequent 3-week cycle.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    TAXOTERE®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    75 mg/m^2 IV on Day 1 of each 3- week cycle

    Number of subjects in period 1
    		Pembrolizumab Standard Treatment
    Started
    247
    248
    Received First Course of Pembrolizumab
    246
    234
    Received Second Course of Pembrolizumab
    2
    0
    Completed
    0
    0
    Not completed
    247
    248
         Consent withdrawn by subject
    15
    20
         Physician decision
    -
    2
         Adverse event, non-fatal
    9
    6
         Death
    209
    217
         Transferred to Extension Study
    7
    1
         Did Not Continue on Extension Study
    7
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pembrolizumab
    Reporting group description
    		 Participants received pembrolizumab 200 mg intravenous (IV) on Day 1 of each 3-week cycle. Eligible participants who stopped the initial course of pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.

    Reporting group title
    Standard Treatment
    Reporting group description
    		 Participants received standard treatment of either methotrexate 40 mg/m^2 IV (could be escalated to 60 mg/m^2 maximum dose) on Days 1, 8, and 15 of each 3-week cycle; or docetaxel 75 mg/m^2 IV on Day 1 of each 3- week cycle; or cetuximab 400 mg/m^2 IV loading dose on Day 1 and 250 mg/m^2 IV on Days 8 and 15 of Cycle 1, followed by cetuximab 250 mg/m^2 on Days 1, 8, and 15 of each subsequent 3-week cycle.

    Reporting group values
    		 Pembrolizumab Standard Treatment Total
    Number of subjects
    		 247 248 495
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 165 167 332
        From 65-84 years
    		 81 81 162
        85 years and over
    		 1 0 1
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 60.3 ( 9.8 ) 60.2 ( 8.6 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 40 43 83
        Male
    		 207 205 412
    Programmed Cell Death-Ligand 1 (PD-L1) Expression Level: Tumor Proportion Score (TPS)
    Participants were assessed for their PD-L1 tumor expression level by immunohistochemistry assay using tumor tissue from a newly obtained biopsy. Participants with a TPS ≥50% were classified as PD-L1 strongly positive and participants with a TPS <50% were classified as not strongly positive.
    Units: Subjects
        TPS = 0%
    		 103 93 196
        1% ≤ TPS <50%
    		 79 87 166
        TPS ≥ 50%
    		 64 65 129
        Missing
    		 1 3 4
    Race (NIH/OMB)
    The race of participants is presented.
    Units: Subjects
        American Indian or Alaska Native
    		 2 0 2
        Asian
    		 15 16 31
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 3 7 10
        White
    		 206 207 413
        More than one race
    		 4 3 7
        Unknown or Not Reported
    		 17 15 32
    Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
    Participants were assessed for ECOG PS: Grade 0: Fully active, able to carry on all pre-disease performance without restriction; Grade 1: Restricted in physically strenuous activity but ambulatory & able to carry out work of a light or sedentary nature; Grade 2: Ambulatory & capable of all selfcare but unable to carry out any work activities, up & about more than 50% of waking hours; Grade 3: Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours; Grade 4: Completely disabled, cannot carry on any selfcare, totally confined to bed or chair or Grade 5: Dead.
    Units: Subjects
        EGOG PS=0
    		 71 68 139
        ECOG PS=1
    		 176 179 355
        ECOG PS=2
    		 0 1 1
    Human Papillomavirus (HPV) Tumor Status
    Participants were assessed for the presence or absence of HPV in their tumors.
    Units: Subjects
        Positive HPV Status
    		 61 57 118
        Negative HPV Status
    		 186 191 377
    PD-L1 Combined Positive Score (CPS) Status
    Participants were assessed for their PD-L1 tumor expression level by immunohistochemistry assay using tumor tissue from a newly obtained biopsy. Participants with a CPS ≥1 were classified as PD-L1 positive and participants with a CPS <1 were classified as PD-L1 negative.
    Units: Subjects
        PD-L1 CPS <1
    		 50 54 104
        PD-L1 CPS ≥1
    		 196 191 387
        Missing
    		 1 3 4
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 21 12 33
        Not Hispanic or Latino
    		 182 195 377
        Unknown or Not Reported
    		 44 41 85

    End points

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    End points reporting groups
    Reporting group title
    Pembrolizumab
    Reporting group description
    		 Participants received pembrolizumab 200 mg intravenous (IV) on Day 1 of each 3-week cycle. Eligible participants who stopped the initial course of pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.

    Reporting group title
    Standard Treatment
    Reporting group description
    		 Participants received standard treatment of either methotrexate 40 mg/m^2 IV (could be escalated to 60 mg/m^2 maximum dose) on Days 1, 8, and 15 of each 3-week cycle; or docetaxel 75 mg/m^2 IV on Day 1 of each 3- week cycle; or cetuximab 400 mg/m^2 IV loading dose on Day 1 and 250 mg/m^2 IV on Days 8 and 15 of Cycle 1, followed by cetuximab 250 mg/m^2 on Days 1, 8, and 15 of each subsequent 3-week cycle.

    Primary: Initial Overall Survival (OS) for All Participants

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    End point title
    		 Initial Overall Survival (OS) for All Participants
    End point description
    OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were to be censored at the date of the last follow-up. The OS for all participants is presented. These initial OS results are based on a data cut-off date of 15-May-2017 with a database lock date of 04-Jun-2017. At the time of the database lock of 04-Jun-2017, there was incomplete collection of survival data for 12 participants. The efficacy population consisted of all randomized participants. Participants are included in the treatment group to which they were randomized.
    End point type
    Primary
    End point timeframe
    Up to approximately 2 years
    End point values
    		 Pembrolizumab Standard Treatment
    Number of subjects analysed
    247
    248
    Units: Months
        median (confidence interval 95%)
    8.4 (6.5 to 9.4)
    7.1 (5.9 to 8.1)
    Statistical analysis title
    		 OS: All Participants (Initial Analysis)
    Comparison groups
    Pembrolizumab v Standard Treatment
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0316
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.01

    Primary: Updated Final OS for All Participants

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    End point title
    		 Updated Final OS for All Participants
    End point description
    OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were to be censored at the date of the last follow-up. The updated OS for all participants is presented. These OS results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017. The efficacy population consisted of all randomized participants. Participants are included in the treatment group to which they were randomized.
    End point type
    Primary
    End point timeframe
    Up to approximately 2 years
    End point values
    		 Pembrolizumab Standard Treatment
    Number of subjects analysed
    247
    248
    Units: Months
        median (confidence interval 95%)
    8.4 (6.4 to 9.4)
    6.9 (5.9 to 8.0)
    Statistical analysis title
    		 OS: All Participants (Updated Final Analysis)
    Comparison groups
    Pembrolizumab v Standard Treatment
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.01605 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 0.98
    Notes
    [1] - Nominal p-value

    Secondary: Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 for All Participants

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    End point title
    		 Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 for All Participants
    End point description
    PFS was defined as the time from randomization to the first documented disease progression per RECIST 1.1 based on blinded independent central review (BICR) or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered progression. The PFS per RECIST 1.1 for all participants is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017. The efficacy population consisted of all randomized participants. Participants are included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years
    End point values
    		 Pembrolizumab Standard Treatment
    Number of subjects analysed
    247
    248
    Units: Months
        median (confidence interval 95%)
    2.1 (2.1 to 2.3)
    2.3 (2.1 to 2.8)
    Statistical analysis title
    		 PFS: All Participants
    Comparison groups
    Pembrolizumab v Standard Treatment
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.32504
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 1.16

    Secondary: OS for Participants With Programmed Cell Death-Ligand 1 (PD-L1)-Positive Expression Defined by ≥1% Combined Positive Score (CPS)(PD-L1 ≥1% CPS)

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    End point title
    		 OS for Participants With Programmed Cell Death-Ligand 1 (PD-L1)-Positive Expression Defined by ≥1% Combined Positive Score (CPS)(PD-L1 ≥1% CPS)
    End point description
    OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. The OS for all participants with PD-L1 expression ≥1% CPS was presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017. The efficacy population consisted of all randomized participants with PD-L1 ≥1% CPS. Participants are included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years
    End point values
    		 Pembrolizumab Standard Treatment
    Number of subjects analysed
    196
    191
    Units: Months
        median (confidence interval 95%)
    8.7 (6.9 to 11.4)
    7.1 (5.7 to 8.3)
    Statistical analysis title
    		 OS: PD-L1 ≥1% CPS
    Comparison groups
    Pembrolizumab v Standard Treatment
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.00493
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 0.93

    Secondary: PFS per RECIST 1.1 in Participants With PD-L1 ≥1% CPS

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    End point title
    		 PFS per RECIST 1.1 in Participants With PD-L1 ≥1% CPS
    End point description
    PFS was defined as the time from randomization to the first documented disease progression per RECIST 1.1 based on BICR or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered progression. The PFS per RECIST 1.1 for all participants with PD-L1 expression ≥1% CPS is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017. The efficacy population consisted of all randomized participants with PD-L1 ≥1% CPS. Participants are included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years
    End point values
    		 Pembrolizumab Standard Treatment
    Number of subjects analysed
    196
    191
    Units: Months
        median (confidence interval 95%)
    2.2 (2.1 to 3.0)
    2.3 (2.1 to 3.0)
    Statistical analysis title
    		 PFS: PD-L1 ≥1% CPS
    Comparison groups
    Pembrolizumab v Standard Treatment
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.07736
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.06

    Secondary: Objective Response Rate (ORR) per RECIST 1.1 in All Participants

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    End point title
    		 Objective Response Rate (ORR) per RECIST 1.1 in All Participants
    End point description
    ORR was defined as the percentage of the participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 based on BICR with or without confirmation. The ORR per RECIST 1.1 for all participants is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017. The efficacy population consisted of all randomized participants. Participants are included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years
    End point values
    		 Pembrolizumab Standard Treatment
    Number of subjects analysed
    247
    248
    Units: Percentage of Participants
        number (confidence interval 95%)
    14.6 (10.4 to 19.6)
    10.1 (6.6 to 14.5)
    Statistical analysis title
    		 ORR: All Participants
    Comparison groups
    Pembrolizumab v Standard Treatment
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.061
    Method
    		 Logrank
    Parameter type
    		 Difference in percentages
    Point estimate
    4.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 10.6

    Secondary: DOR per RECIST 1.1 in Participants With PD-L1 ≥1% CPS

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    End point title
    		 DOR per RECIST 1.1 in Participants With PD-L1 ≥1% CPS
    End point description
    For participants who demonstrated a confirmed CR or PR per RECIST 1.1, DOR was defined as time from first documented evidence of a confirmed CR or PR per RECIST 1.1 until disease progression per RECIST 1.1 or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease was defined as a ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered progression. DOR assessments were based on BICR with confirmation. The DOR per RECIST 1.1 for all participants with PD-L1 ≥1% CPS who experienced a confirmed CR or PR is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017. All randomized PD-L1 ≥1% CPS participants with confirmed CR or PR were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years
    End point values
    		 Pembrolizumab Standard Treatment
    Number of subjects analysed
    26
    15
    Units: Months
        median (full range (min-max))
    18.4 (2.7 to 18.4)
    9.6 (1.4 to 18.8)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) per RECIST 1.1 in All Participants

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    End point title
    		 Duration of Response (DOR) per RECIST 1.1 in All Participants
    End point description
    For participants who demonstrated a confirmed CR or PR per RECIST 1.1, DOR was defined as the time from first documented evidence of a confirmed CR or PR per RECIST 1.1 until disease progression per RECIST 1.1 or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. DOR assessments were based on BICR with confirmation. The DOR per RECIST 1.1 for all participants who experienced a confirmed CR or PR is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017. All randomized participants with confirmed CR or PR were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years
    End point values
    		 Pembrolizumab Standard Treatment
    Number of subjects analysed
    26
    18
    Units: Months
        median (full range (min-max))
    18.4 (2.7 to 18.4)
    5.0 (1.4 to 18.8)
    No statistical analyses for this end point

    Secondary: ORR per RECIST 1.1 in Participants With PD-L1 ≥1% CPS

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    End point title
    		 ORR per RECIST 1.1 in Participants With PD-L1 ≥1% CPS
    End point description
    ORR was defined as the percentage of the participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions per RECIST 1.1 based on BICR with or without confirmation. The ORR per RECIST 1.1 for all participants with PD-L1 expression ≥1% CPS is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017. The efficacy population consisted of all randomized participants with PD-L1 ≥1% CPS. Participants are included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years
    End point values
    		 Pembrolizumab Standard Treatment
    Number of subjects analysed
    196
    191
    Units: Percentage of Participants
        number (confidence interval 95%)
    17.3 (12.3 to 23.4)
    9.9 (6.1 to 15.1)
    Statistical analysis title
    		 ORR: PD-L1 ≥1% CPS
    Comparison groups
    Pembrolizumab v Standard Treatment
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0171
    Method
    		 Logrank
    Parameter type
    		 Difference in percentages
    Point estimate
    7.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 14.6

    Secondary: Time to Progression (TTP) per RECIST 1.1 in All Participants

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    End point title
    		 Time to Progression (TTP) per RECIST 1.1 in All Participants
    End point description
    TTP was defined as the time from randomization to the first documented disease progression based on assessments by BICR per RECIST 1.1. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered progression. The TTP per RECIST 1.1 for all participants is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017. The efficacy population consisted of all randomized participants. Participants are included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years
    End point values
    		 Pembrolizumab Standard Treatment
    Number of subjects analysed
    247
    248
    Units: Months
        median (confidence interval 95%)
    2.2 (2.1 to 3.3)
    2.2 (2.1 to 3.4)
    Statistical analysis title
    		 TTP: All Participants
    Comparison groups
    Pembrolizumab v Standard Treatment
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.14545 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.12
    Notes
    [2] - p-value stratified by ECOG PS (0 vs. 1), HPV status (Positive vs. Negative) & PD-L1 status (Strongly Positive, Not Strongly Positive)

    Secondary: PFS per Modified RECIST in All Participants

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    End point title
    		 PFS per Modified RECIST in All Participants
    End point description
    PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 based on BICR 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 have demonstrated an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions was also considered PD. Modified RECIST is similar to RECIST 1.1 with the exception that a confirmation assessment of PD (>4 weeks after the initial PD) is required for participants who remain on treatment following a documented PD per RECIST 1.1. The PFS per modified RECIST for all participants is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017. All randomized participants were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years
    End point values
    		 Pembrolizumab Standard Treatment
    Number of subjects analysed
    247
    248
    Units: Months
        median (confidence interval 95%)
    3.5 (3.1 to 4.4)
    4.8 (4.1 to 5.7)
    Statistical analysis title
    		 PFS per mRECIST: All Participants
    Comparison groups
    Pembrolizumab v Standard Treatment
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.65759
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.27

    Secondary: PFS per Modified RECIST 1.1 in Participants With PD-L1 ≥1% CPS

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    End point title
    		 PFS per Modified RECIST 1.1 in Participants With PD-L1 ≥1% CPS
    End point description
    PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 based on BICR 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 have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Modified RECIST is similar to RECIST 1.1 with the exception that a confirmation assessment of PD (>4 weeks after the initial PD) is required for participants who remain on treatment following a documented PD per RECIST 1.1. The PFS per modified RECIST for all participants with PD-L1 ≥1% CPS is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017. All randomized participants with PD-L1 ≥1% CPS were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years
    End point values
    		 Pembrolizumab Standard Treatment
    Number of subjects analysed
    196
    191
    Units: Months
        median (confidence interval 95%)
    3.6 (3.1 to 4.6)
    4.8 (4.1 to 5.7)
    Statistical analysis title
    		 PFS per mRECIST: PD-L1 ≥1% CPS
    Comparison groups
    Pembrolizumab v Standard Treatment
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.51982
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.26

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

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    End point title
    		 Number of Participants Who Experienced At Least One Adverse Event (AE) in All Participants
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. The number of all participants who experienced at least one AE is presented. The safety population consisted of all randomized participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 33 months
    End point values
    		 Pembrolizumab Standard Treatment
    Number of subjects analysed
    246
    234
    Units: Participants
    240
    227
    No statistical analyses for this end point

    Secondary: TTP per RECIST 1.1 in Participants With PD-L1 ≥1% CPS

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    End point title
    		 TTP per RECIST 1.1 in Participants With PD-L1 ≥1% CPS
    End point description
    TTP was defined as the time from randomization to the first documented disease progression based on assessments by BICR per RECIST 1.1. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered progression. The TTP per RECIST 1.1 for all participants with PD-L1 ≥1% CPS is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017. The efficacy population consisted of all randomized participants with PD-L1 ≥1% CPS. Participants are included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years
    End point values
    		 Pembrolizumab Standard Treatment
    Number of subjects analysed
    196
    191
    Units: Months
        median (full range (min-max))
    2.7 (2.1 to 3.5)
    2.3 (2.1 to 3.4)
    Statistical analysis title
    		 TTP: PD-L1 ≥1% CPS
    Comparison groups
    Pembrolizumab v Standard Treatment
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.05851 [3]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.06
    Notes
    [3] - p-value stratified by ECOG PS (0 vs. 1), HPV status (Positive vs. Negative) & PD-L1 status (Strongly Positive, Not Strongly Positive)

    Secondary: Number of Participants Who Experienced At Least One AE in Participants With PD-L1 ≥1% CPS

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    End point title
    		 Number of Participants Who Experienced At Least One AE in Participants With PD-L1 ≥1% CPS
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. The number of all participants with PD-L1 ≥1% CPS who experienced at least one AE is presented. The safety population consisted of all randomized participants with PD-L1 ≥1% CPS who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 33 months
    End point values
    		 Pembrolizumab Standard Treatment
    Number of subjects analysed
    195
    183
    Units: Participants
    193
    178
    No statistical analyses for this end point

    Secondary: Number of Participants Who Discontinued Study Treatment Due to an AE in All Participants

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    End point title
    		 Number of Participants Who Discontinued Study Treatment Due to an AE in All Participants
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. The number of all participants who discontinued study treatment due to an AE is presented. The safety population consisted of all randomized participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 30 months
    End point values
    		 Pembrolizumab Standard Treatment
    Number of subjects analysed
    246
    234
    Units: Participants
    30
    36
    No statistical analyses for this end point

    Secondary: Number of Participants Who Discontinued Study Treatment Due to an AE in Participants With PD-L1 ≥1% CPS

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    End point title
    		 Number of Participants Who Discontinued Study Treatment Due to an AE in Participants With PD-L1 ≥1% CPS
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. The number of all participants with PD-L1 ≥1% CPS who discontinued study treatment due to an AE is presented. The safety population consisted of all randomized participants with PD-L1 ≥1% CPS who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 30 months
    End point values
    		 Pembrolizumab Standard Treatment
    Number of subjects analysed
    195
    183
    Units: Participants
    25
    29
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 92 months
    Adverse event reporting additional description
    Deaths (all-causes) reported for all randomized participants (N=247, 248, 2). Serious and NonSerious AEs reported for all randomized participants who received ≥1 dose of study treatment. Per protocol, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" unrelated to study drug are excluded as AEs
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Pembrolizumab First Course
    Reporting group description
    		 Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to approximately 24 months.

    Reporting group title
    Pembrolizumab Second Course
    Reporting group description
    		 Eligible participants who stopped the initial course of pembrolizumab (200 mg IV Q3W for up to approximately 24 months) with SD or better but progressed after discontinuation initiated a second course of pembrolizumab at the investigator's discretion for up to approximately 1 additional year.

    Reporting group title
    Standard Treatment First Course
    Reporting group description
    		 Participants received standard treatment of either methotrexate 40 mg/m^2 IV (could be escalated to 60 mg/m^2 maximum dose) on Days 1, 8, and 15 of each 3-week cycle; or docetaxel 75 mg/m^2 IV on Day 1 of each 3- week cycle; or cetuximab 400 mg/m^2 IV loading dose on Day 1 and 250 mg/m^2 IV on Days 8 and 15 of Cycle 1, followed by cetuximab 250 mg/m^2 on Days 1, 8, and 15 of each subsequent 3-week cycle.

    Serious adverse events
    		 Pembrolizumab First Course Pembrolizumab Second Course Standard Treatment First Course
    Total subjects affected by serious adverse events
         subjects affected / exposed
    110 / 247 (44.53%)
    0 / 2 (0.00%)
    92 / 248 (37.10%)
         number of deaths (all causes)
    228
    2
    243
         number of deaths resulting from adverse events
    23
    0
    25
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed [1]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed [2]
    9 / 246 (3.66%)
    0 / 2 (0.00%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    Rectal cancer
         subjects affected / exposed [3]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Paraneoplastic syndrome
         subjects affected / exposed [4]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed [5]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    Infected neoplasm
         subjects affected / exposed [6]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Basal cell carcinoma
         subjects affected / exposed [7]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Astrocytoma, low grade
         subjects affected / exposed [8]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed [9]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Squamous cell carcinoma of skin
         subjects affected / exposed [10]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Oropharyngeal neoplasm
         subjects affected / exposed [11]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Angiodysplasia
         subjects affected / exposed [12]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Deep vein thrombosis
         subjects affected / exposed [13]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Haemorrhage
         subjects affected / exposed [14]
    2 / 246 (0.81%)
    0 / 2 (0.00%)
    0 / 234 (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
    Jugular vein thrombosis
         subjects affected / exposed [15]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Euthanasia
         subjects affected / exposed [16]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Ill-defined disorder
         subjects affected / exposed [17]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed [18]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Face oedema
         subjects affected / exposed [19]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed [20]
    5 / 246 (2.03%)
    0 / 2 (0.00%)
    4 / 234 (1.71%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    1 / 5
    0 / 0
    0 / 4
    Asthenia
         subjects affected / exposed [21]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Malaise
         subjects affected / exposed [22]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed [23]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    3 / 234 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed [24]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed [25]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Anaphylactic reaction
         subjects affected / exposed [26]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed [27]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Eosinophilic pneumonia
         subjects affected / exposed [28]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Dyspnoea
         subjects affected / exposed [29]
    4 / 246 (1.63%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Chronic obstructive pulmonary disease
         subjects affected / exposed [30]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed [31]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Asphyxia
         subjects affected / exposed [32]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Acute respiratory failure
         subjects affected / exposed [33]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed [34]
    2 / 246 (0.81%)
    0 / 2 (0.00%)
    0 / 234 (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
    Respiratory disorder
         subjects affected / exposed [35]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed [36]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pneumothorax
         subjects affected / exposed [37]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed [38]
    5 / 246 (2.03%)
    0 / 2 (0.00%)
    3 / 234 (1.28%)
         occurrences causally related to treatment / all
    4 / 5
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract haemorrhage
         subjects affected / exposed [39]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Lung disorder
         subjects affected / exposed [40]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngeal stenosis
         subjects affected / exposed [41]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Laryngeal obstruction
         subjects affected / exposed [42]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Hypoxia
         subjects affected / exposed [43]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Haemoptysis
         subjects affected / exposed [44]
    2 / 246 (0.81%)
    0 / 2 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed [45]
    2 / 246 (0.81%)
    0 / 2 (0.00%)
    0 / 234 (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
    Oropharyngeal fistula
         subjects affected / exposed [46]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed [47]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed [48]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    White blood cell count decreased
         subjects affected / exposed [49]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed [50]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Neutrophil count decreased
         subjects affected / exposed [51]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    3 / 234 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed [52]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed [53]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Platelet count decreased
         subjects affected / exposed [54]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed [55]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Femoral neck fracture
         subjects affected / exposed [56]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed [57]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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 fracture
         subjects affected / exposed [58]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stoma site haemorrhage
         subjects affected / exposed [59]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stoma site ulcer
         subjects affected / exposed [60]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Accidental overdose
         subjects affected / exposed [61]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alcohol poisoning
         subjects affected / exposed [62]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Tracheostomy malfunction
         subjects affected / exposed [63]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural fever
         subjects affected / exposed [64]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Post procedural hypotension
         subjects affected / exposed [65]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed [66]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Nervous system disorders
    Subarachnoid haemorrhage
         subjects affected / exposed [67]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed [68]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Cerebrovascular accident
         subjects affected / exposed [69]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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 [70]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed [71]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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 [72]
    2 / 246 (0.81%)
    0 / 2 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vocal cord paresis
         subjects affected / exposed [73]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed [74]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed [75]
    5 / 246 (2.03%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia of malignant disease
         subjects affected / exposed [76]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed [77]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    9 / 234 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    8 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymph node haemorrhage
         subjects affected / exposed [78]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed [79]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Incarcerated inguinal hernia
         subjects affected / exposed [80]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed [81]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Large intestine perforation
         subjects affected / exposed [82]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Malignant dysphagia
         subjects affected / exposed [83]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed [84]
    4 / 246 (1.63%)
    0 / 2 (0.00%)
    3 / 234 (1.28%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Gastrointestinal inflammation
         subjects affected / exposed [85]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed [86]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed [87]
    3 / 246 (1.22%)
    0 / 2 (0.00%)
    3 / 234 (1.28%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed [88]
    5 / 246 (2.03%)
    0 / 2 (0.00%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    5 / 7
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed [89]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed [90]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed [91]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed [92]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed [93]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed [94]
    2 / 246 (0.81%)
    0 / 2 (0.00%)
    3 / 234 (1.28%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed [95]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral discharge
         subjects affected / exposed [96]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed [97]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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 obstruction
         subjects affected / exposed [98]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Autoimmune colitis
         subjects affected / exposed [99]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed [100]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Cholelithiasis
         subjects affected / exposed [101]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Cirrhosis alcoholic
         subjects affected / exposed [102]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Skin and subcutaneous tissue disorders
    Acute febrile neutrophilic dermatosis
         subjects affected / exposed [103]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Fungating wound
         subjects affected / exposed [104]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Pruritus
         subjects affected / exposed [105]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         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 ulcer
         subjects affected / exposed [106]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Stevens-Johnson syndrome
         subjects affected / exposed [107]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed [108]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Urinary retention
         subjects affected / exposed [109]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypercalcaemia of malignancy
         subjects affected / exposed [110]
    3 / 246 (1.22%)
    0 / 2 (0.00%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Kyphosis
         subjects affected / exposed [111]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Soft tissue haemorrhage
         subjects affected / exposed [112]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Muscular weakness
         subjects affected / exposed [113]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Arthralgia
         subjects affected / exposed [114]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Infections and infestations
    Infection
         subjects affected / exposed [115]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected fistula
         subjects affected / exposed [116]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed [117]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epiglottitis
         subjects affected / exposed [118]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disseminated tuberculosis
         subjects affected / exposed [119]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed [120]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed [121]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed [122]
    3 / 246 (1.22%)
    0 / 2 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Candida sepsis
         subjects affected / exposed [123]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Bronchitis
         subjects affected / exposed [124]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed [125]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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 tract infection
         subjects affected / exposed [126]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed [127]
    4 / 246 (1.63%)
    0 / 2 (0.00%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed [128]
    22 / 246 (8.94%)
    0 / 2 (0.00%)
    17 / 234 (7.26%)
         occurrences causally related to treatment / all
    1 / 23
    0 / 0
    5 / 19
         deaths causally related to treatment / all
    0 / 6
    0 / 0
    1 / 6
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed [129]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed [130]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed [131]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Neutropenic sepsis
         subjects affected / exposed [132]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed [133]
    2 / 246 (0.81%)
    0 / 2 (0.00%)
    0 / 234 (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
    Klebsiella infection
         subjects affected / exposed [134]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Influenza
         subjects affected / exposed [135]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed [136]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Oral bacterial infection
         subjects affected / exposed [137]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Stoma site infection
         subjects affected / exposed [138]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed [139]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed [140]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed [141]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed [142]
    2 / 246 (0.81%)
    0 / 2 (0.00%)
    0 / 234 (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
    Wound infection
         subjects affected / exposed [143]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed [144]
    6 / 246 (2.44%)
    0 / 2 (0.00%)
    3 / 234 (1.28%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed [145]
    7 / 246 (2.85%)
    0 / 2 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed [146]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed [147]
    2 / 246 (0.81%)
    0 / 2 (0.00%)
    3 / 234 (1.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed [148]
    4 / 246 (1.63%)
    0 / 2 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed [149]
    3 / 246 (1.22%)
    0 / 2 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed [150]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    0 / 234 (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
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [8] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [9] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [10] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [11] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [12] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [13] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [14] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [15] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [16] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [17] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [18] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [19] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [20] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [21] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [22] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [23] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [24] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [25] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [26] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [27] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [28] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [29] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [30] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [31] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [32] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [33] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [34] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [35] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [36] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [37] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [38] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [39] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [40] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [41] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [42] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [43] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [44] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [45] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [46] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [47] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [48] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [49] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [50] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [51] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [52] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [53] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [54] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [55] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [56] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [57] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [58] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [59] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [60] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [61] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [62] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [63] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [64] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [65] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [66] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [67] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [68] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [69] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [70] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [71] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [72] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [73] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [74] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [75] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [76] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [77] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [78] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [79] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [80] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [81] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [82] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [83] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [84] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [85] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [86] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [87] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [88] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [89] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [90] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [91] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [92] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [93] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [94] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [95] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [96] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [97] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [98] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [99] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [100] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [101] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [102] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [103] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [104] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [105] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [106] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [107] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [108] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [109] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [110] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [111] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [112] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [113] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [114] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [115] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [116] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [117] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [118] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [119] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [120] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [121] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [122] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [123] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [124] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [125] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [126] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [127] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [128] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [129] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [130] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [131] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [132] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [133] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [134] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [135] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [136] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [137] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [138] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [139] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [140] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [141] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [142] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [143] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [144] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [145] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [146] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [147] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [148] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [149] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [150] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pembrolizumab First Course Pembrolizumab Second Course Standard Treatment First Course
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    215 / 247 (87.04%)
    0 / 2 (0.00%)
    211 / 248 (85.08%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed [151]
    13 / 246 (5.28%)
    0 / 2 (0.00%)
    7 / 234 (2.99%)
         occurrences all number
    13
    0
    8
    Vascular disorders
    Hypotension
         subjects affected / exposed [152]
    13 / 246 (5.28%)
    0 / 2 (0.00%)
    12 / 234 (5.13%)
         occurrences all number
    13
    0
    16
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed [153]
    24 / 246 (9.76%)
    0 / 2 (0.00%)
    25 / 234 (10.68%)
         occurrences all number
    38
    0
    36
    Mucosal inflammation
         subjects affected / exposed [154]
    17 / 246 (6.91%)
    0 / 2 (0.00%)
    36 / 234 (15.38%)
         occurrences all number
    21
    0
    51
    Fatigue
         subjects affected / exposed [155]
    49 / 246 (19.92%)
    0 / 2 (0.00%)
    63 / 234 (26.92%)
         occurrences all number
    53
    0
    81
    Asthenia
         subjects affected / exposed [156]
    40 / 246 (16.26%)
    0 / 2 (0.00%)
    42 / 234 (17.95%)
         occurrences all number
    50
    0
    54
    Respiratory, thoracic and mediastinal disorders
    Productive cough
         subjects affected / exposed [157]
    15 / 246 (6.10%)
    0 / 2 (0.00%)
    5 / 234 (2.14%)
         occurrences all number
    16
    0
    7
    Haemoptysis
         subjects affected / exposed [158]
    13 / 246 (5.28%)
    0 / 2 (0.00%)
    7 / 234 (2.99%)
         occurrences all number
    15
    0
    9
    Dyspnoea
         subjects affected / exposed [159]
    31 / 246 (12.60%)
    0 / 2 (0.00%)
    26 / 234 (11.11%)
         occurrences all number
    33
    0
    31
    Cough
         subjects affected / exposed [160]
    43 / 246 (17.48%)
    0 / 2 (0.00%)
    37 / 234 (15.81%)
         occurrences all number
    49
    0
    40
    Psychiatric disorders
    Insomnia
         subjects affected / exposed [161]
    22 / 246 (8.94%)
    0 / 2 (0.00%)
    18 / 234 (7.69%)
         occurrences all number
    22
    0
    18
    Anxiety
         subjects affected / exposed [162]
    13 / 246 (5.28%)
    0 / 2 (0.00%)
    7 / 234 (2.99%)
         occurrences all number
    13
    0
    7
    Investigations
    Weight decreased
         subjects affected / exposed [163]
    21 / 246 (8.54%)
    0 / 2 (0.00%)
    25 / 234 (10.68%)
         occurrences all number
    24
    0
    25
    Platelet count decreased
         subjects affected / exposed [164]
    7 / 246 (2.85%)
    0 / 2 (0.00%)
    13 / 234 (5.56%)
         occurrences all number
    7
    0
    19
    Neutrophil count decreased
         subjects affected / exposed [165]
    4 / 246 (1.63%)
    0 / 2 (0.00%)
    24 / 234 (10.26%)
         occurrences all number
    11
    0
    29
    Aspartate aminotransferase increased
         subjects affected / exposed [166]
    10 / 246 (4.07%)
    0 / 2 (0.00%)
    13 / 234 (5.56%)
         occurrences all number
    10
    0
    18
    Lymphocyte count decreased
         subjects affected / exposed [167]
    13 / 246 (5.28%)
    0 / 2 (0.00%)
    10 / 234 (4.27%)
         occurrences all number
    16
    0
    13
    Nervous system disorders
    Headache
         subjects affected / exposed [168]
    21 / 246 (8.54%)
    0 / 2 (0.00%)
    23 / 234 (9.83%)
         occurrences all number
    25
    0
    25
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed [169]
    61 / 246 (24.80%)
    0 / 2 (0.00%)
    53 / 234 (22.65%)
         occurrences all number
    77
    0
    72
    Gastrointestinal disorders
    Stomatitis
         subjects affected / exposed [170]
    7 / 246 (2.85%)
    0 / 2 (0.00%)
    26 / 234 (11.11%)
         occurrences all number
    9
    0
    34
    Nausea
         subjects affected / exposed [171]
    36 / 246 (14.63%)
    0 / 2 (0.00%)
    44 / 234 (18.80%)
         occurrences all number
    45
    0
    52
    Abdominal pain
         subjects affected / exposed [172]
    9 / 246 (3.66%)
    0 / 2 (0.00%)
    12 / 234 (5.13%)
         occurrences all number
    12
    0
    12
    Dry mouth
         subjects affected / exposed [173]
    15 / 246 (6.10%)
    0 / 2 (0.00%)
    6 / 234 (2.56%)
         occurrences all number
    15
    0
    6
    Diarrhoea
         subjects affected / exposed [174]
    37 / 246 (15.04%)
    0 / 2 (0.00%)
    42 / 234 (17.95%)
         occurrences all number
    57
    0
    51
    Constipation
         subjects affected / exposed [175]
    43 / 246 (17.48%)
    0 / 2 (0.00%)
    37 / 234 (15.81%)
         occurrences all number
    49
    0
    43
    Dysphagia
         subjects affected / exposed [176]
    21 / 246 (8.54%)
    0 / 2 (0.00%)
    15 / 234 (6.41%)
         occurrences all number
    22
    0
    16
    Vomiting
         subjects affected / exposed [177]
    24 / 246 (9.76%)
    0 / 2 (0.00%)
    23 / 234 (9.83%)
         occurrences all number
    28
    0
    34
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed [178]
    26 / 246 (10.57%)
    0 / 2 (0.00%)
    41 / 234 (17.52%)
         occurrences all number
    33
    0
    92
    Pruritus
         subjects affected / exposed [179]
    19 / 246 (7.72%)
    0 / 2 (0.00%)
    17 / 234 (7.26%)
         occurrences all number
    24
    0
    40
    Dry skin
         subjects affected / exposed [180]
    4 / 246 (1.63%)
    0 / 2 (0.00%)
    17 / 234 (7.26%)
         occurrences all number
    4
    0
    19
    Dermatitis acneiform
         subjects affected / exposed [181]
    0 / 246 (0.00%)
    0 / 2 (0.00%)
    18 / 234 (7.69%)
         occurrences all number
    0
    0
    28
    Alopecia
         subjects affected / exposed [182]
    1 / 246 (0.41%)
    0 / 2 (0.00%)
    27 / 234 (11.54%)
         occurrences all number
    1
    0
    27
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed [183]
    41 / 246 (16.67%)
    0 / 2 (0.00%)
    10 / 234 (4.27%)
         occurrences all number
    45
    0
    10
    Musculoskeletal and connective tissue disorders
    Neck pain
         subjects affected / exposed [184]
    20 / 246 (8.13%)
    0 / 2 (0.00%)
    17 / 234 (7.26%)
         occurrences all number
    20
    0
    17
    Back pain
         subjects affected / exposed [185]
    23 / 246 (9.35%)
    0 / 2 (0.00%)
    8 / 234 (3.42%)
         occurrences all number
    24
    0
    8
    Arthralgia
         subjects affected / exposed [186]
    23 / 246 (9.35%)
    0 / 2 (0.00%)
    12 / 234 (5.13%)
         occurrences all number
    24
    0
    13
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed [187]
    31 / 246 (12.60%)
    0 / 2 (0.00%)
    45 / 234 (19.23%)
         occurrences all number
    37
    0
    50
    Hypercalcaemia
         subjects affected / exposed [188]
    14 / 246 (5.69%)
    0 / 2 (0.00%)
    13 / 234 (5.56%)
         occurrences all number
    16
    0
    14
    Hypokalaemia
         subjects affected / exposed [189]
    23 / 246 (9.35%)
    0 / 2 (0.00%)
    19 / 234 (8.12%)
         occurrences all number
    27
    0
    21
    Hypophosphataemia
         subjects affected / exposed [190]
    15 / 246 (6.10%)
    0 / 2 (0.00%)
    12 / 234 (5.13%)
         occurrences all number
    21
    0
    14
    Hyponatraemia
         subjects affected / exposed [191]
    12 / 246 (4.88%)
    0 / 2 (0.00%)
    16 / 234 (6.84%)
         occurrences all number
    14
    0
    17
    Hypomagnesaemia
         subjects affected / exposed [192]
    10 / 246 (4.07%)
    0 / 2 (0.00%)
    20 / 234 (8.55%)
         occurrences all number
    11
    0
    25
    Notes
    [151] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [152] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [153] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [154] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [155] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [156] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [157] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [158] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [159] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [160] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [161] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [162] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [163] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [164] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [165] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [166] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [167] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [168] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [169] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [170] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [171] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [172] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [173] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [174] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [175] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [176] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [177] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [178] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [179] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [180] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [181] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [182] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [183] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [184] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [185] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [186] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [187] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [188] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [189] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [190] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [191] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.
    [192] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis population includes all participants who received at least 1 dose of study treatment.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Feb 2015
    Major changes of Amendment (AM) 1 include increasing the sample size from 466 to 600 participants, adding hypotheses, revising eligibility criteria, and adding statistical analyses for the PD-L1 Strong Positive (TPS >50% PD-L1) population.
    20 Apr 2016
    Major changes of Amendment AM 10 include decreasing the sample size from 600 to 466, keeping OS in all participants as the single primary hypothesis and downgrading OS in the biomarker positive participants and PFS hypotheses to key secondary hypotheses, replacing hypotheses on the PD-L1 population with hypotheses on the CPS ≥1 population, promoting ORR to a key secondary endpoint, updating language to include PD-L1 status masking, and including the role of unblinded Sponsor personnel.
    07 Nov 2016
    Major changes of Amendment AM 11 include updating the alpha-spending language, power calculation, and timing of the final analysis to reflect the change to the number of death events at the final analysis.
    20 Feb 2018
    Major changes of Amendment AM 12 included updating the dose modification guidelines for pembrolizumab (for the management of myocarditis), updating the trial flow chart to enable survival follow-up activities throughout the study, and updating the plan for pharmacokinetic and anti-drug antibodies.
    31 May 2021
    Major changes of Amendment AM 13 included updating the dose modification and toxicity management guidelines for immune-related AEs.
    10 Dec 2021
    Major changes of Amendment AM 14 included adding language indicating that participants may be enrolled in a pembrolizumab extension trial upon trial completion.

    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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