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    Clinical Trial Results:
    A Phase III Randomized Open-Label Study of Single Agent Pembrolizumab vs. Physicians’ Choice of Single Agent Docetaxel, Paclitaxel, or Irinotecan in Subjects with Advanced/Metastatic Adenocarcinoma and Squamous Cell Carcinoma of the Esophagus that have Progressed after First-Line Standard Therapy (KEYNOTE-181)

    Summary
    EudraCT number
    		 2015-002782-32
    Trial protocol
    		 SE   NO   EE   PT   FI   ES   DE   DK   CZ   NL   FR   IE   IT  
    Global end of trial date
    14 Mar 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Mar 2023
    First version publication date
    10 Mar 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MK-3475-181
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02564263
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 JAPIC-CTI: 163145
    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
    14 Mar 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Oct 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Mar 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    In this study, participants with advanced or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or Siewert type I adenocarcinoma of the esophagogastric junction (EGJ) that had progressed after first-line standard therapy were randomized to receive either pembrolizumab (MK-3475) OR the Investigator's choice of standard chemotherapy with paclitaxel, docetaxel, or irinotecan. The primary study hypothesis was that treatment with pembrolizumab would prolong overall survival (OS) as compared to treatment with standard chemotherapy.
    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
    01 Dec 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 3
    Country: Number of subjects enrolled
    Australia: 20
    Country: Number of subjects enrolled
    Brazil: 23
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    China: 11
    Country: Number of subjects enrolled
    Colombia: 1
    Country: Number of subjects enrolled
    Czechia: 9
    Country: Number of subjects enrolled
    Denmark: 12
    Country: Number of subjects enrolled
    Estonia: 7
    Country: Number of subjects enrolled
    Finland: 5
    Country: Number of subjects enrolled
    France: 80
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Hong Kong: 5
    Country: Number of subjects enrolled
    Ireland: 3
    Country: Number of subjects enrolled
    Israel: 6
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Japan: 152
    Country: Number of subjects enrolled
    Korea, Republic of: 38
    Country: Number of subjects enrolled
    Malaysia: 4
    Country: Number of subjects enrolled
    Mexico: 2
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    Norway: 7
    Country: Number of subjects enrolled
    Peru: 2
    Country: Number of subjects enrolled
    Portugal: 13
    Country: Number of subjects enrolled
    Russian Federation: 7
    Country: Number of subjects enrolled
    Spain: 24
    Country: Number of subjects enrolled
    Sweden: 6
    Country: Number of subjects enrolled
    Taiwan: 23
    Country: Number of subjects enrolled
    Thailand: 10
    Country: Number of subjects enrolled
    Turkey: 19
    Country: Number of subjects enrolled
    United Kingdom: 27
    Country: Number of subjects enrolled
    United States: 76
    Worldwide total number of subjects
    628
    EEA total number of subjects
    189
    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)
    356
    From 65 to 84 years
    272
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 At the time of the primary analysis data cut-off of 15-Oct-2018, 67 participants were ongoing in the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pembrolizumab
    Arm description
    		 Participants received pembrolizumab 200 mg, intravenously (IV) on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 25 months).
    Arm type
    		 Experimental

    Investigational medicinal product name
    pembrolizumab
    Investigational medicinal product code
    Other name
    KEYTRUDA®, MK-3475
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg administered as IV infusion on Day 1 of every 21-day cycle

    Arm title
    		 Chemotherapy
    Arm description
    		 Participants received Investigator’s choice of paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle (up to approximately 19 months).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    paclitaxel
    Investigational medicinal product code
    Other name
    TAXOL®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80-100 mg/m^2 administered as IV infusion on Days 1, 8, and 15 of each 28-day cycle

    Investigational medicinal product name
    irinotecan
    Investigational medicinal product code
    Other name
    CAMPTOSAR®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    180 mg/m^2 administered as IV infusion on Day 1 of every 14-day cycle

    Investigational medicinal product name
    docetaxel
    Investigational medicinal product code
    Other name
    TAXOTERE®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    75 mg/m^2 administered as IV infusion on Day 1 of every 21-day cycle

    Number of subjects in period 1
    		Pembrolizumab Chemotherapy
    Started
    314
    314
    Treated
    314
    296
    Received Second Course of Pembrolizumab
    5
    0
    Completed
    0
    0
    Not completed
    314
    314
         Adverse event, serious fatal
    270
    262
         Sponsor's decision
    9
    4
         Consent withdrawn by subject
    4
    19
         Adverse event, non-fatal
    31
    29

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pembrolizumab
    Reporting group description
    		 Participants received pembrolizumab 200 mg, intravenously (IV) on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 25 months).

    Reporting group title
    Chemotherapy
    Reporting group description
    		 Participants received Investigator’s choice of paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle (up to approximately 19 months).

    Reporting group values
    		 Pembrolizumab Chemotherapy Total
    Number of subjects
    		 314 314 628
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 175 181 356
        From 65-84 years
    		 139 133 272
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 62.6 ( 9.4 ) 62.0 ( 9.6 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 41 43 84
        Male
    		 273 271 544
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1
        Asian
    		 126 122 248
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Black or African American
    		 3 3 6
        White
    		 179 172 351
        More than one race
    		 2 4 6
        Unknown or Not Reported
    		 4 11 15
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 19 25 44
        Not Hispanic or Latino
    		 288 273 561
        Unknown or Not Reported
    		 7 16 23
    Programmed Death-Ligand 1 (PD-L1) Status: Combined Positive Score (CPS)
    Participants were assessed for their PD-L1 tumor expression levels by immunohistochemistry assay on tumor tissue from a newly obtained biopsy. PD-L1 CPS was calculated as the number of PD-L1 positive cells (tumor cells, macrophages, lymphocytes) divided by the total tumor cells and is expressed as a percentage. Participants were classified based on their PD-L1 tumor status as being either PD-L1 CPS ≥10 or PD-L1 CPS <10.
    Units: Subjects
        PD-L1 CPS ≥10
    		 109 117 226
        PD-L1 CPS <10
    		 199 194 393
        Not Evaluable
    		 6 3 9
    Geographic Region
    Participants were classified based on their geographic region of enrollment as either being from Asia or from outside of Asia (Rest of World [RoW]).
    Units: Subjects
        Asia
    		 121 122 243
        RoW
    		 193 192 385
    Tumor Histology
    Participants were classified based on their tumor histology (cell type) as either having squamous cell carcinoma or having adenocarcinoma of esophagus and esophagogastric junction (EGJ) Siewert type I.
    Units: Subjects
        Squamous cell carcinoma
    		 199 204 403
        Adenocarcinoma of esophagus & EGJ Siewert type I
    		 115 110 225

    End points

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    End points reporting groups
    Reporting group title
    Pembrolizumab
    Reporting group description
    		 Participants received pembrolizumab 200 mg, intravenously (IV) on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 25 months).

    Reporting group title
    Chemotherapy
    Reporting group description
    		 Participants received Investigator’s choice of paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle (up to approximately 19 months).

    Primary: Overall Survival (OS) in Participants with Squamous Cell Carcinoma (SCC) of the Esophagus

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    End point title
    		 Overall Survival (OS) in Participants with Squamous Cell Carcinoma (SCC) of the Esophagus
    End point description
    OS was defined as the time from randomization to death due to any cause. The efficacy analysis population consisted of all randomized participants with SCC of the esophagus. Participants were included in the treatment group to which they were randomized. Median OS in participants with SCC of the esophagus is presented.
    End point type
    Primary
    End point timeframe
    Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
    End point values
    		 Pembrolizumab Chemotherapy
    Number of subjects analysed
    198
    203
    Units: Months
        median (confidence interval 95%)
    8.2 (6.7 to 10.3)
    7.1 (6.1 to 8.2)
    Statistical analysis title
    		 OS in Participants with SCC of the Esophagus
    Statistical analysis description
    Cox regression model with treatment as a covariate stratified by geographic region (Asia vs RoW)
    Comparison groups
    Pembrolizumab v Chemotherapy
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.00894 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 0.96
    Notes
    [1] - One-sided p-value based on stratified log-rank test

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

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    End point title
    		 Overall Survival (OS) in Participants with Programmed Death-Ligand 1 Combined Positive Score ≥10 (PD-L1 CPS ≥10)
    End point description
    OS was defined as the time from randomization to death due to any cause. The efficacy analysis population consisted of all randomized participants with a PD-L1 CPS ≥10. Participants were included in the treatment group to which they were randomized. Median OS in participants with a PD-L1 CPS ≥10 is presented.
    End point type
    Primary
    End point timeframe
    Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
    End point values
    		 Pembrolizumab Chemotherapy
    Number of subjects analysed
    107
    115
    Units: Months
        median (confidence interval 95%)
    9.3 (6.6 to 12.5)
    6.7 (5.1 to 8.2)
    Statistical analysis title
    		 OS in Participants with PD-L1 CPS ≥10
    Statistical analysis description
    Cox regression model with treatment as a covariate stratified by geographic region (Asia vs RoW) & tumor histology (SCC vs adenocarcinoma/Siewert type 1 adenocarcinoma of the esophagogastric junction [EGJ])
    Comparison groups
    Pembrolizumab v Chemotherapy
    Number of subjects included in analysis
    222
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.00855 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 0.94
    Notes
    [2] - One-sided p-value based on stratified log-rank test

    Primary: Overall Survival (OS) in All Participants

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    End point title
    		 Overall Survival (OS) in All Participants
    End point description
    OS was defined as the time from randomization to death due to any cause. The efficacy analysis population consisted of all randomized participants. Participants were included in the treatment group to which they were randomized. Median OS in all participants is presented.
    End point type
    Primary
    End point timeframe
    Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
    End point values
    		 Pembrolizumab Chemotherapy
    Number of subjects analysed
    314
    314
    Units: Months
        median (confidence interval 95%)
    7.1 (6.2 to 8.1)
    7.1 (6.3 to 8.0)
    Statistical analysis title
    		 OS in All Participants
    Statistical analysis description
    Cox regression model with treatment as a covariate stratified by geographic region (Asia vs RoW) & tumor histology (SCC vs adenocarcinoma/Siewert type 1 adenocarcinoma of the esophagogastric junction [EGJ])
    Comparison groups
    Pembrolizumab v Chemotherapy
    Number of subjects included in analysis
    628
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0531 [3]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.05
    Notes
    [3] - One-sided p-value based on stratified maximum weighted log rank test: the maximum of the log-rank test statistic & a weighted log-rank Fleming-Harrington (0,1) test statistic

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

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    End point title
    		 Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants
    End point description
    PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. The efficacy analysis population consisted of all randomized participants. Participants were included in the treatment group to which they were randomized. Median PFS as assessed by blinded independent central review per RECIST 1.1 in all participants is presented.
    End point type
    Secondary
    End point timeframe
    Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
    End point values
    		 Pembrolizumab Chemotherapy
    Number of subjects analysed
    314
    314
    Units: Months
        median (confidence interval 95%)
    2.1 (2.1 to 2.2)
    3.4 (2.8 to 3.9)
    Statistical analysis title
    		 PFS as Assessed by RECIST 1.1 in All Participants
    Statistical analysis description
    Cox regression model with treatment as a covariate stratified by geographic region (Asia vs RoW) & tumor histology (SCC vs adenocarcinoma/Siewert type 1 adenocarcinoma of the EGJ)
    Comparison groups
    Pembrolizumab v Chemotherapy
    Number of subjects included in analysis
    628
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.287 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.94
         upper limit
    		 1.31
    Notes
    [4] - One-sided p-value based on stratified maximum weighted log rank test: the maximum of the log-rank test statistic & a weighted log-rank Fleming-Harrington (0,1) test statistic

    Secondary: Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants

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    End point title
    		 Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants
    End point description
    ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1. The efficacy analysis population consisted of all randomized participants. Participants were included in the treatment group to which they were randomized. The percentage of all participants who experienced a CR or PR is presented.
    End point type
    Secondary
    End point timeframe
    Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
    End point values
    		 Pembrolizumab Chemotherapy
    Number of subjects analysed
    314
    314
    Units: Percentage of Participants
        number (confidence interval 95%)
    13.1 (9.5 to 17.3)
    6.7 (4.2 to 10.0)
    Statistical analysis title
    		 ORR as Assessed by RECIST 1.1 in All Participants
    Statistical analysis description
    Miettinen & Nurminen method stratified by geographic region (Asia vs RoW) & tumor histology (SCC vs adenocarcinoma/Siewert type I adenocarcinoma of the EGJ)
    Comparison groups
    Pembrolizumab v Chemotherapy
    Number of subjects included in analysis
    628
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0037 [5]
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Difference in Percentages
    Point estimate
    6.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.7
         upper limit
    		 11.2
    Notes
    [5] - One-sided p-value for testing. H0: difference in %=0 versus; H1: difference in %>0.

    Secondary: Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants with Squamous Cell Carcinoma (SCC) of the Esophagus

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    End point title
    		 Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants with Squamous Cell Carcinoma (SCC) of the Esophagus
    End point description
    PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. The efficacy analysis population consisted of all randomized participants with SCC of the esophagus. Participants were included in the treatment group to which they were randomized. Median PFS as assessed by blinded independent central review per RECIST 1.1 is presented for participants with SCC of the esophagus.
    End point type
    Secondary
    End point timeframe
    Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
    End point values
    		 Pembrolizumab Chemotherapy
    Number of subjects analysed
    198
    203
    Units: Months
        median (confidence interval 95%)
    2.2 (2.1 to 3.2)
    3.1 (2.2 to 3.9)
    Statistical analysis title
    		 PFS in Participants with SCC of the Esophagus
    Statistical analysis description
    Cox regression model with treatment as a covariate stratified by geographic region (Asia vs RoW)
    Comparison groups
    Pembrolizumab v Chemotherapy
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.216 [6]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.13
    Notes
    [6] - One-sided p-value based on stratified log-rank test

    Secondary: Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants with Programmed Death-Ligand 1 Combined Positive Score ≥10 (PD-L1 CPS ≥10)

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    End point title
    		 Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants with Programmed Death-Ligand 1 Combined Positive Score ≥10 (PD-L1 CPS ≥10)
    End point description
    PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. The efficacy analysis population consisted of all randomized participants with a PD-L1 CPS ≥10. Participants were included in the treatment group to which they were randomized. Median PFS as assessed by blinded independent central review per RECIST 1.1 is presented for participants with a PD-L1 CPS ≥10.
    End point type
    Secondary
    End point timeframe
    Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
    End point values
    		 Pembrolizumab Chemotherapy
    Number of subjects analysed
    107
    115
    Units: Months
        median (confidence interval 95%)
    2.6 (2.1 to 4.1)
    3.0 (2.1 to 3.7)
    Statistical analysis title
    		 PFS in Participants with PD-L1 CPS ≥10
    Statistical analysis description
    Cox regression model with treatment as a covariate stratified by geographic region (Asia vs RoW) & tumor histology (SCC vs adenocarcinoma/Siewert type 1 adenocarcinoma of the EGJ)
    Comparison groups
    Pembrolizumab v Chemotherapy
    Number of subjects included in analysis
    222
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.015 [7]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 0.97
    Notes
    [7] - One-sided p-value based on stratified log-rank test

    Secondary: Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants with Squamous Cell Carcinoma (SCC) of the Esophagus

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    End point title
    		 Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants with Squamous Cell Carcinoma (SCC) of the Esophagus
    End point description
    ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1. The efficacy analysis population consisted of all randomized participants with SCC of the esophagus. Participants were included in the treatment group to which they were randomized. The percentage of participants with SCC of the esophagus who experienced a CR or PR is presented.
    End point type
    Secondary
    End point timeframe
    Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
    End point values
    		 Pembrolizumab Chemotherapy
    Number of subjects analysed
    198
    203
    Units: Percentage of Participants
        number (confidence interval 95%)
    16.7 (11.8 to 22.6)
    7.4 (4.2 to 11.9)
    Statistical analysis title
    		 ORR in Participants with SCC of the Esophagus
    Statistical analysis description
    Miettinen & Nurminen method stratified by geographic region (Asia vs RoW)
    Comparison groups
    Pembrolizumab v Chemotherapy
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0022 [8]
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Difference in Percentages
    Point estimate
    9.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3
         upper limit
    		 15.8
    Notes
    [8] - One-sided p-value for testing. H0: difference in %=0; H1: difference in %>0.

    Secondary: Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants with Programmed Death-Ligand 1 Combined Positive Score ≥10 (PD-L1 CPS ≥10)

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    End point title
    		 Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants with Programmed Death-Ligand 1 Combined Positive Score ≥10 (PD-L1 CPS ≥10)
    End point description
    ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1. The efficacy analysis population consisted of all randomized participants with a PD-L1 CPS ≥10. Participants were included in the treatment group to which they were randomized. The percentage of participants with a PD-L1 CPS ≥10 who experienced a CR or PR is presented.
    End point type
    Secondary
    End point timeframe
    Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
    End point values
    		 Pembrolizumab Chemotherapy
    Number of subjects analysed
    107
    115
    Units: Percentage of Participants
        number (confidence interval 95%)
    21.5 (14.1 to 30.5)
    6.1 (2.5 to 12.1)
    Statistical analysis title
    		 ORR in Participants with PD-L1 CPS ≥10
    Statistical analysis description
    Miettinen & Nurminen method stratified by geographic region (Asia vs RoW) & tumor histology (SCC vs adenocarcinoma/Siewert type I adenocarcinoma of the EGJ)
    Comparison groups
    Pembrolizumab v Chemotherapy
    Number of subjects included in analysis
    222
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0006 [9]
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Difference in Percentages
    Point estimate
    15.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.2
         upper limit
    		 24.7
    Notes
    [9] - One-sided p-value for testing. H0: difference in %=0; H1: difference in %>0.

    Secondary: Number of Participants Experiencing an Adverse Event (AE)

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    End point title
    		 Number of Participants Experiencing an Adverse Event (AE)
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable 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 medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor’s product was also an AE. The analysis population consisted of all randomized participants who received at least 1 dose of study treatment. Participants were included in the treatment group to which they were randomized. The number of participants who experienced ≥1 AE is presented.
    End point type
    Secondary
    End point timeframe
    Through End-of-Trial Analysis data cutoff date of 14-Mar-2022 (up to approximately 6 years)
    End point values
    		 Pembrolizumab Chemotherapy
    Number of subjects analysed
    314
    296
    Units: Participants
    301
    288
    No statistical analyses for this end point

    Secondary: Number of Participants Discontinuing Study Treatment Due an Adverse Event (AE)

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    End point title
    		 Number of Participants Discontinuing Study Treatment Due an Adverse Event (AE)
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable 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 medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor’s product was also an AE. The analysis population consisted of all randomized participants who received at least 1 dose of study treatment. Participants were included in the treatment group to which they were randomized. The number of participants who discontinued study treatment due to an AE is presented.
    End point type
    Secondary
    End point timeframe
    Through End-of-Trial Analysis data cutoff date of 14-Mar-2022 (up to approximately 6 years)
    End point values
    		 Pembrolizumab Chemotherapy
    Number of subjects analysed
    314
    296
    Units: Participants
    40
    42
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Through End-of-Trial Analysis data cutoff date of 14-Mar-2022 (up to approximately 6 years)
    Adverse event reporting additional description
    Deaths (all-causes) analysis population included all randomized participants (N=314, 314, 5). AE analysis population included all participants who received ≥1 dose of study treatment (N=314, 296, 5). 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
    24.1
    Reporting groups
    Reporting group title
    Pembrolizumab First Course
    Reporting group description
    		 Participants received pembrolizumab 200 mg, intravenously (IV) on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 25 months).

    Reporting group title
    Pembrolizumab Second Course
    Reporting group description
    		 Qualified participants who received pembrolizumab as a first course and stopped the first course of pembrolizumab due to complete response (CR) or completed the first course of pembrolizumab and had stable disease but progressed after discontinuation, initiated a second course of pembrolizumab at the investigator's discretion for up to 17 cycles (approximately 1 year additional).

    Reporting group title
    Chemotherapy
    Reporting group description
    		 Participants received Investigator’s choice of paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle (up to approximately 19 months).

    Serious adverse events
    		 Pembrolizumab First Course Pembrolizumab Second Course Chemotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    127 / 314 (40.45%)
    1 / 5 (20.00%)
    121 / 314 (38.54%)
         number of deaths (all causes)
    305
    3
    305
         number of deaths resulting from adverse events
    5
    0
    5
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed [1]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Cancer pain
         subjects affected / exposed [2]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Head and neck cancer
         subjects affected / exposed [3]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Metastases to bone
         subjects affected / exposed [4]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
         subjects affected / exposed [5]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed [6]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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 [7]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Shock haemorrhagic
         subjects affected / exposed [8]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed [9]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed [10]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Fatigue
         subjects affected / exposed [11]
    2 / 314 (0.64%)
    0 / 5 (0.00%)
    2 / 296 (0.68%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed [12]
    5 / 314 (1.59%)
    0 / 5 (0.00%)
    10 / 296 (3.38%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    0 / 10
         deaths causally related to treatment / all
    1 / 5
    0 / 0
    0 / 10
    Chest pain
         subjects affected / exposed [13]
    2 / 314 (0.64%)
    0 / 5 (0.00%)
    0 / 296 (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
    Strangulated hernia
         subjects affected / exposed [14]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed [15]
    4 / 314 (1.27%)
    0 / 5 (0.00%)
    4 / 296 (1.35%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed [16]
    0 / 314 (0.00%)
    1 / 5 (20.00%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed [17]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Acute respiratory distress syndrome
         subjects affected / exposed [18]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed [19]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed [20]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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 [21]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed [22]
    2 / 314 (0.64%)
    0 / 5 (0.00%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Hiccups
         subjects affected / exposed [23]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Interstitial lung disease
         subjects affected / exposed [24]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed [25]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Pleural effusion
         subjects affected / exposed [26]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    2 / 296 (0.68%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed [27]
    7 / 314 (2.23%)
    0 / 5 (0.00%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    7 / 7
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed [28]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheal fistula
         subjects affected / exposed [29]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Stridor
         subjects affected / exposed [30]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed [31]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pulmonary necrosis
         subjects affected / exposed [32]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Pulmonary embolism
         subjects affected / exposed [33]
    3 / 314 (0.96%)
    0 / 5 (0.00%)
    0 / 296 (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
    Upper airway obstruction
         subjects affected / exposed [34]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         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
    Completed suicide
         subjects affected / exposed [35]
    2 / 314 (0.64%)
    0 / 5 (0.00%)
    0 / 296 (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
    Confusional state
         subjects affected / exposed [36]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed [37]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Product issues
    Device occlusion
         subjects affected / exposed [38]
    2 / 314 (0.64%)
    0 / 5 (0.00%)
    0 / 296 (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
    Device dislocation
         subjects affected / exposed [39]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed [40]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed [41]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Neutrophil count decreased
         subjects affected / exposed [42]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    3 / 296 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    White blood cell count decreased
         subjects affected / exposed [43]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    2 / 296 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Weight decreased
         subjects affected / exposed [44]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    White blood cell count increased
         subjects affected / exposed [45]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anastomotic fistula
         subjects affected / exposed [46]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Anastomotic leak
         subjects affected / exposed [47]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed [48]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed [49]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrostomy failure
         subjects affected / exposed [50]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Foreign body in gastrointestinal tract
         subjects affected / exposed [51]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed [52]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Radiation pneumonitis
         subjects affected / exposed [53]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed [54]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Tracheal injury
         subjects affected / exposed [55]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Subdural haematoma
         subjects affected / exposed [56]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Tracheal obstruction
         subjects affected / exposed [57]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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 limb fracture
         subjects affected / exposed [58]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Congenital, familial and genetic disorders
    Tracheo-oesophageal fistula
         subjects affected / exposed [59]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Cardiac disorders
    Acute left ventricular failure
         subjects affected / exposed [60]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed [61]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed [62]
    2 / 314 (0.64%)
    0 / 5 (0.00%)
    2 / 296 (0.68%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed [63]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Myocarditis
         subjects affected / exposed [64]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Sinus tachycardia
         subjects affected / exposed [65]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed [66]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Dystonia
         subjects affected / exposed [67]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Cerebrovascular accident
         subjects affected / exposed [68]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Demyelination
         subjects affected / exposed [69]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Dyskinesia
         subjects affected / exposed [70]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebellar stroke
         subjects affected / exposed [71]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Bell's palsy
         subjects affected / exposed [72]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed [73]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Guillain-Barre syndrome
         subjects affected / exposed [74]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Facial paralysis
         subjects affected / exposed [75]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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 intracranial
         subjects affected / exposed [76]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Neuralgia
         subjects affected / exposed [77]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Hemiparesis
         subjects affected / exposed [78]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Headache
         subjects affected / exposed [79]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Haemorrhagic stroke
         subjects affected / exposed [80]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed [81]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed [82]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Vocal cord paralysis
         subjects affected / exposed [83]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed [84]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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 [85]
    2 / 314 (0.64%)
    0 / 5 (0.00%)
    5 / 296 (1.69%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune thrombocytopenia
         subjects affected / exposed [86]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Febrile neutropenia
         subjects affected / exposed [87]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    22 / 296 (7.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    23 / 24
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed [88]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed [89]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    4 / 296 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed [90]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed [91]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Abdominal pain
         subjects affected / exposed [92]
    3 / 314 (0.96%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed [93]
    3 / 314 (0.96%)
    0 / 5 (0.00%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed [94]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed [95]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    4 / 296 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulum oesophageal
         subjects affected / exposed [96]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         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 [97]
    11 / 314 (3.50%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    1 / 12
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed [98]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         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 [99]
    2 / 314 (0.64%)
    0 / 5 (0.00%)
    4 / 296 (1.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    Gastrointestinal hypomotility
         subjects affected / exposed [100]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed [101]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Impaired gastric emptying
         subjects affected / exposed [102]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed [103]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         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 [104]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    3 / 296 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal fistula
         subjects affected / exposed [105]
    2 / 314 (0.64%)
    0 / 5 (0.00%)
    0 / 296 (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
    Oesophageal haemorrhage
         subjects affected / exposed [106]
    4 / 314 (1.27%)
    0 / 5 (0.00%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 4
    0 / 0
    0 / 0
    Oesophageal obstruction
         subjects affected / exposed [107]
    3 / 314 (0.96%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal perforation
         subjects affected / exposed [108]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed [109]
    2 / 314 (0.64%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal ulcer
         subjects affected / exposed [110]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed [111]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritoneal adhesions
         subjects affected / exposed [112]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed [113]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    3 / 296 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Vomiting
         subjects affected / exposed [114]
    2 / 314 (0.64%)
    0 / 5 (0.00%)
    5 / 296 (1.69%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed [115]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autoimmune hepatitis
         subjects affected / exposed [116]
    3 / 314 (0.96%)
    0 / 5 (0.00%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed [117]
    2 / 314 (0.64%)
    0 / 5 (0.00%)
    0 / 296 (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
    Hepatic failure
         subjects affected / exposed [118]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Hepatic function abnormal
         subjects affected / exposed [119]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Immune-mediated hepatitis
         subjects affected / exposed [120]
    2 / 314 (0.64%)
    0 / 5 (0.00%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed [121]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Skin and subcutaneous tissue disorders
    Dermal cyst
         subjects affected / exposed [122]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed [123]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed [124]
    2 / 314 (0.64%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypercalcaemia of malignancy
         subjects affected / exposed [125]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Hypophysitis
         subjects affected / exposed [126]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed [127]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed [128]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed [129]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Polymyositis
         subjects affected / exposed [130]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Neck pain
         subjects affected / exposed [131]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fistula inflammation
         subjects affected / exposed [132]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed [133]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    2 / 296 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Beta haemolytic streptococcal infection
         subjects affected / exposed [134]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Bacteraemia
         subjects affected / exposed [135]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Bronchitis
         subjects affected / exposed [136]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    2 / 296 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed [137]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Candida infection
         subjects affected / exposed [138]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         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 [139]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed [140]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Hepatic infection
         subjects affected / exposed [141]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Empyema
         subjects affected / exposed [142]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed [143]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    2 / 296 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed [144]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed [145]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    2 / 296 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection viral
         subjects affected / exposed [146]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Peritonitis
         subjects affected / exposed [147]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Mediastinitis
         subjects affected / exposed [148]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed [149]
    12 / 314 (3.82%)
    0 / 5 (0.00%)
    5 / 296 (1.69%)
         occurrences causally related to treatment / all
    1 / 13
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 5
    0 / 0
    1 / 1
    Pneumonia
         subjects affected / exposed [150]
    14 / 314 (4.46%)
    0 / 5 (0.00%)
    22 / 296 (7.43%)
         occurrences causally related to treatment / all
    3 / 15
    0 / 0
    12 / 26
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    1 / 5
    Pneumonia bacterial
         subjects affected / exposed [151]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    2 / 296 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia necrotising
         subjects affected / exposed [152]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed [153]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed [154]
    4 / 314 (1.27%)
    0 / 5 (0.00%)
    3 / 296 (1.01%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    Respiratory tract infection
         subjects affected / exposed [155]
    3 / 314 (0.96%)
    0 / 5 (0.00%)
    2 / 296 (0.68%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed [156]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Subcutaneous abscess
         subjects affected / exposed [157]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         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 infection
         subjects affected / exposed [158]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Tracheitis
         subjects affected / exposed [159]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Tracheostomy infection
         subjects affected / exposed [160]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed [161]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed [162]
    2 / 314 (0.64%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Varicella zoster virus infection
         subjects affected / exposed [163]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Vascular device infection
         subjects affected / exposed [164]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed [165]
    2 / 314 (0.64%)
    0 / 5 (0.00%)
    2 / 296 (0.68%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed [166]
    2 / 314 (0.64%)
    0 / 5 (0.00%)
    4 / 296 (1.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed [167]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed [168]
    3 / 314 (0.96%)
    0 / 5 (0.00%)
    0 / 296 (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
    Electrolyte imbalance
         subjects affected / exposed [169]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Hypoglycaemia
         subjects affected / exposed [170]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Hypokalaemia
         subjects affected / exposed [171]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    Hyponatraemia
         subjects affected / exposed [172]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    2 / 296 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed [173]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed [174]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    0 / 296 (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
    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.
    [151] - 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.
    [152] - 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.
    [153] - 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.
    [154] - 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.
    [155] - 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.
    [156] - 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.
    [157] - 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.
    [158] - 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.
    [159] - 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.
    [160] - 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.
    [161] - 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.
    [162] - 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.
    [163] - 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.
    [164] - 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.
    [165] - 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.
    [166] - 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.
    [167] - 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.
    [168] - 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.
    [169] - 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.
    [170] - 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.
    [171] - 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.
    [172] - 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.
    [173] - 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.
    [174] - 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 Chemotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    285 / 314 (90.76%)
    5 / 5 (100.00%)
    281 / 314 (89.49%)
    Investigations
    Blood creatinine increased
         subjects affected / exposed [175]
    8 / 314 (2.55%)
    1 / 5 (20.00%)
    3 / 296 (1.01%)
         occurrences all number
    11
    1
    4
    Aspartate aminotransferase increased
         subjects affected / exposed [176]
    26 / 314 (8.28%)
    1 / 5 (20.00%)
    14 / 296 (4.73%)
         occurrences all number
    33
    1
    16
    Alanine aminotransferase increased
         subjects affected / exposed [177]
    22 / 314 (7.01%)
    0 / 5 (0.00%)
    10 / 296 (3.38%)
         occurrences all number
    26
    0
    16
    Blood sodium decreased
         subjects affected / exposed [178]
    0 / 314 (0.00%)
    1 / 5 (20.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    1
    Blood thyroid stimulating hormone increased
         subjects affected / exposed [179]
    3 / 314 (0.96%)
    1 / 5 (20.00%)
    3 / 296 (1.01%)
         occurrences all number
    4
    1
    3
    Lymphocyte count decreased
         subjects affected / exposed [180]
    9 / 314 (2.87%)
    1 / 5 (20.00%)
    9 / 296 (3.04%)
         occurrences all number
    10
    1
    15
    Weight decreased
         subjects affected / exposed [181]
    39 / 314 (12.42%)
    1 / 5 (20.00%)
    34 / 296 (11.49%)
         occurrences all number
    39
    1
    43
    Neutrophil count decreased
         subjects affected / exposed [182]
    2 / 314 (0.64%)
    0 / 5 (0.00%)
    50 / 296 (16.89%)
         occurrences all number
    2
    0
    113
    White blood cell count decreased
         subjects affected / exposed [183]
    1 / 314 (0.32%)
    0 / 5 (0.00%)
    52 / 296 (17.57%)
         occurrences all number
    1
    0
    114
    Nervous system disorders
    Dementia Alzheimer's type
         subjects affected / exposed [184]
    0 / 314 (0.00%)
    1 / 5 (20.00%)
    0 / 296 (0.00%)
         occurrences all number
    0
    1
    0
    Neuropathy peripheral
         subjects affected / exposed [185]
    6 / 314 (1.91%)
    0 / 5 (0.00%)
    25 / 296 (8.45%)
         occurrences all number
    7
    0
    28
    Peripheral sensory neuropathy
         subjects affected / exposed [186]
    3 / 314 (0.96%)
    0 / 5 (0.00%)
    52 / 296 (17.57%)
         occurrences all number
    3
    0
    53
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed [187]
    52 / 314 (16.56%)
    1 / 5 (20.00%)
    83 / 296 (28.04%)
         occurrences all number
    60
    2
    110
    Neutropenia
         subjects affected / exposed [188]
    0 / 314 (0.00%)
    0 / 5 (0.00%)
    36 / 296 (12.16%)
         occurrences all number
    0
    0
    65
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed [189]
    67 / 314 (21.34%)
    0 / 5 (0.00%)
    87 / 296 (29.39%)
         occurrences all number
    70
    0
    121
    Asthenia
         subjects affected / exposed [190]
    45 / 314 (14.33%)
    0 / 5 (0.00%)
    43 / 296 (14.53%)
         occurrences all number
    48
    0
    58
    Malaise
         subjects affected / exposed [191]
    15 / 314 (4.78%)
    0 / 5 (0.00%)
    19 / 296 (6.42%)
         occurrences all number
    18
    0
    26
    Oedema peripheral
         subjects affected / exposed [192]
    19 / 314 (6.05%)
    0 / 5 (0.00%)
    19 / 296 (6.42%)
         occurrences all number
    20
    0
    19
    Pyrexia
         subjects affected / exposed [193]
    31 / 314 (9.87%)
    0 / 5 (0.00%)
    45 / 296 (15.20%)
         occurrences all number
    41
    0
    58
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed [194]
    7 / 314 (2.23%)
    1 / 5 (20.00%)
    2 / 296 (0.68%)
         occurrences all number
    7
    1
    2
    Abdominal pain
         subjects affected / exposed [195]
    34 / 314 (10.83%)
    0 / 5 (0.00%)
    27 / 296 (9.12%)
         occurrences all number
    36
    0
    32
    Abdominal pain upper
         subjects affected / exposed [196]
    14 / 314 (4.46%)
    0 / 5 (0.00%)
    17 / 296 (5.74%)
         occurrences all number
    16
    0
    19
    Diarrhoea
         subjects affected / exposed [197]
    38 / 314 (12.10%)
    1 / 5 (20.00%)
    79 / 296 (26.69%)
         occurrences all number
    65
    1
    120
    Constipation
         subjects affected / exposed [198]
    56 / 314 (17.83%)
    0 / 5 (0.00%)
    56 / 296 (18.92%)
         occurrences all number
    63
    0
    63
    Dyspepsia
         subjects affected / exposed [199]
    6 / 314 (1.91%)
    1 / 5 (20.00%)
    11 / 296 (3.72%)
         occurrences all number
    7
    1
    13
    Dysphagia
         subjects affected / exposed [200]
    40 / 314 (12.74%)
    1 / 5 (20.00%)
    26 / 296 (8.78%)
         occurrences all number
    44
    1
    27
    Nausea
         subjects affected / exposed [201]
    59 / 314 (18.79%)
    0 / 5 (0.00%)
    83 / 296 (28.04%)
         occurrences all number
    66
    0
    110
    Stomatitis
         subjects affected / exposed [202]
    9 / 314 (2.87%)
    0 / 5 (0.00%)
    28 / 296 (9.46%)
         occurrences all number
    9
    0
    30
    Vomiting
         subjects affected / exposed [203]
    37 / 314 (11.78%)
    0 / 5 (0.00%)
    53 / 296 (17.91%)
         occurrences all number
    45
    0
    74
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed [204]
    31 / 314 (9.87%)
    0 / 5 (0.00%)
    17 / 296 (5.74%)
         occurrences all number
    36
    0
    21
    Cough
         subjects affected / exposed [205]
    40 / 314 (12.74%)
    0 / 5 (0.00%)
    30 / 296 (10.14%)
         occurrences all number
    46
    0
    33
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed [206]
    4 / 314 (1.27%)
    0 / 5 (0.00%)
    88 / 296 (29.73%)
         occurrences all number
    4
    0
    88
    Pruritus
         subjects affected / exposed [207]
    23 / 314 (7.32%)
    1 / 5 (20.00%)
    8 / 296 (2.70%)
         occurrences all number
    27
    1
    8
    Rash
         subjects affected / exposed [208]
    20 / 314 (6.37%)
    0 / 5 (0.00%)
    25 / 296 (8.45%)
         occurrences all number
    24
    0
    27
    Psychiatric disorders
    Insomnia
         subjects affected / exposed [209]
    25 / 314 (7.96%)
    0 / 5 (0.00%)
    16 / 296 (5.41%)
         occurrences all number
    25
    0
    42
    Irritability
         subjects affected / exposed [210]
    0 / 314 (0.00%)
    1 / 5 (20.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed [211]
    37 / 314 (11.78%)
    1 / 5 (20.00%)
    7 / 296 (2.36%)
         occurrences all number
    40
    1
    7
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed [212]
    24 / 314 (7.64%)
    0 / 5 (0.00%)
    19 / 296 (6.42%)
         occurrences all number
    26
    0
    22
    Back pain
         subjects affected / exposed [213]
    38 / 314 (12.10%)
    0 / 5 (0.00%)
    24 / 296 (8.11%)
         occurrences all number
    40
    0
    27
    Myalgia
         subjects affected / exposed [214]
    8 / 314 (2.55%)
    0 / 5 (0.00%)
    25 / 296 (8.45%)
         occurrences all number
    10
    0
    31
    Pain in extremity
         subjects affected / exposed [215]
    8 / 314 (2.55%)
    1 / 5 (20.00%)
    8 / 296 (2.70%)
         occurrences all number
    10
    1
    9
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed [216]
    12 / 314 (3.82%)
    1 / 5 (20.00%)
    13 / 296 (4.39%)
         occurrences all number
    17
    2
    15
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed [217]
    76 / 314 (24.20%)
    1 / 5 (20.00%)
    76 / 296 (25.68%)
         occurrences all number
    82
    1
    97
    Gout
         subjects affected / exposed [218]
    1 / 314 (0.32%)
    1 / 5 (20.00%)
    0 / 296 (0.00%)
         occurrences all number
    1
    1
    0
    Hyperglycaemia
         subjects affected / exposed [219]
    16 / 314 (5.10%)
    0 / 5 (0.00%)
    14 / 296 (4.73%)
         occurrences all number
    21
    0
    14
    Hyperkalaemia
         subjects affected / exposed [220]
    8 / 314 (2.55%)
    1 / 5 (20.00%)
    6 / 296 (2.03%)
         occurrences all number
    13
    1
    7
    Hypoalbuminaemia
         subjects affected / exposed [221]
    17 / 314 (5.41%)
    0 / 5 (0.00%)
    15 / 296 (5.07%)
         occurrences all number
    23
    0
    16
    Hypokalaemia
         subjects affected / exposed [222]
    15 / 314 (4.78%)
    0 / 5 (0.00%)
    29 / 296 (9.80%)
         occurrences all number
    15
    0
    40
    Hyponatraemia
         subjects affected / exposed [223]
    19 / 314 (6.05%)
    0 / 5 (0.00%)
    17 / 296 (5.74%)
         occurrences all number
    27
    0
    24
    Iron deficiency
         subjects affected / exposed [224]
    1 / 314 (0.32%)
    1 / 5 (20.00%)
    1 / 296 (0.34%)
         occurrences all number
    1
    1
    1
    Notes
    [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.
    [193] - 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.
    [194] - 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.
    [195] - 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.
    [196] - 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.
    [197] - 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.
    [198] - 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.
    [199] - 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.
    [200] - 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.
    [201] - 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.
    [202] - 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.
    [203] - 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.
    [204] - 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.
    [205] - 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.
    [206] - 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.
    [207] - 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.
    [208] - 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.
    [209] - 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.
    [210] - 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.
    [211] - 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.
    [212] - 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.
    [213] - 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.
    [214] - 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.
    [215] - 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.
    [216] - 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.
    [217] - 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.
    [218] - 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.
    [219] - 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.
    [220] - 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.
    [221] - 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.
    [222] - 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.
    [223] - 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.
    [224] - 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.

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Dec 2016
    Amendment 02: Primary reason for amendment was to incorporate revisions to descriptions of gene expression profile (GEP) cut-off and how objectives and endpoints would be met and analyzed, respectively.
    07 Apr 2017
    Amendment 03: Primary reason for amendment was to incorporate revisions to the enrollment period to achieve the required sample size of the China Cohort.
    30 Aug 2017
    Amendment 04: Primary reason for amendment was to incorporate revisions to primary objectives, based on recommendations from emerging data.
    09 Mar 2018
    Amendment 05: Primary reason for amendment was to incorporate revisions to statistical tests for testing the OS and PFS hypotheses in all subjects.
    26 Aug 2021
    Amendment 06: Primary reason for amendment was to incorporate revisions to update the dose modification and toxicity management guidelines for immune-related AEs and to clarify the concomitant use of COVID-19 vaccines.

    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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