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    Clinical Trial Results:
    A Phase III, Open-label, Multicenter Trial of Avelumab (MSB0010718C) Versus Platinum-based Doublet as a First-line Treatment of Recurrent or Stage IV PD-L1+NSCLC

    Summary
    EudraCT number
    		 2015-001537-24
    Trial protocol
    		 SK   DE   PT   LT   BE   CZ   GB   ES   HU   PL   NL   FR   DK   BG   HR   CY   GR   IT  
    Global end of trial date
    29 Jan 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Feb 2025
    First version publication date
    06 Feb 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    EMR 100070-005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02576574
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Healthcare KGaA
    Sponsor organisation address
    Frankfurter Strasse 250, Darmstadt, Germany, 64293
    Public contact
    Communication Center, Merck KGaA, Darmstadt, Germany, +49 6151725200, service@merckgroup.com
    Scientific contact
    Communication Center, Merck KGaA, Darmstadt, Germany, +49 6151725200, service@merckgroup.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
    29 Jan 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jan 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was to demonstrate superiority with regard to Overall Survival (OS) or Progression Free Survival (PFS) of avelumab versus platinum-based doublet, based on an Independent Review Committee assessment, in Non-small cell lung cancer (NSCLC) participants with Programmed death ligand 1+ (PD-L1+) tumors.
    Protection of trial subjects
    Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Oct 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    United States: 26
    Country: Number of subjects enrolled
    Brazil: 34
    Country: Number of subjects enrolled
    Chile: 15
    Country: Number of subjects enrolled
    Colombia: 1
    Country: Number of subjects enrolled
    Peru: 8
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Denmark: 9
    Country: Number of subjects enrolled
    Spain: 75
    Country: Number of subjects enrolled
    France: 44
    Country: Number of subjects enrolled
    Greece: 24
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Ireland: 1
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Netherlands: 8
    Country: Number of subjects enrolled
    Portugal: 19
    Country: Number of subjects enrolled
    Bulgaria: 7
    Country: Number of subjects enrolled
    Czechia: 6
    Country: Number of subjects enrolled
    Estonia: 1
    Country: Number of subjects enrolled
    Croatia: 6
    Country: Number of subjects enrolled
    Hungary: 54
    Country: Number of subjects enrolled
    Lithuania: 6
    Country: Number of subjects enrolled
    Poland: 58
    Country: Number of subjects enrolled
    Romania: 65
    Country: Number of subjects enrolled
    Russian Federation: 116
    Country: Number of subjects enrolled
    Serbia: 51
    Country: Number of subjects enrolled
    Slovakia: 2
    Country: Number of subjects enrolled
    Ukraine: 58
    Country: Number of subjects enrolled
    Australia: 49
    Country: Number of subjects enrolled
    New Zealand: 53
    Country: Number of subjects enrolled
    China: 28
    Country: Number of subjects enrolled
    Japan: 31
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 133
    Country: Number of subjects enrolled
    Singapore: 12
    Country: Number of subjects enrolled
    Thailand: 20
    Country: Number of subjects enrolled
    Taiwan: 13
    Country: Number of subjects enrolled
    South Africa: 2
    Country: Number of subjects enrolled
    Israel: 10
    Country: Number of subjects enrolled
    Lebanon: 7
    Country: Number of subjects enrolled
    Türkiye: 138
    Worldwide total number of subjects
    1214
    EEA total number of subjects
    403
    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)
    1214
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 3423 subjects were screened out of which 1214 subjects received the study treatments.

    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
    		 Avelumab Biweekly
    Arm description
    		 Subjects received Avelumab at a dose of 10 milligrams per kilogram (mg/kg) as a 1-hour (-10/+20 minutes) intravenous (IV) infusion once every 2 weeks until disease progression or unacceptable toxicities.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avelumab
    Investigational medicinal product code
    Other name
    MSB0010718C
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received Avelumab at a dose of 10 milligrams per kilogram (mg/kg) as a 1-hour (-10/+20 minutes) intravenous (IV) infusion once every 2 weeks until disease progression or unacceptable toxicities.

    Arm title
    		 Avelumab Weekly
    Arm description
    		 Subjects received Avelumab at a dose of 10 mg/kg as a 1-hour (-10/+20 minutes) IV infusion every week for 12 consecutive weeks, followed by Avelumab at a dose of 10 mg/kg once every 2 weeks until disease progression or unacceptable toxicities.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avelumab
    Investigational medicinal product code
    Other name
    MSB0010718C
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received Avelumab at a dose of 10 mg/kg as a 1-hour (-10/+20 minutes) IV infusion every week for 12 consecutive weeks.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received Cisplatin 75 mg/m^2 by IV infusion in 3-Week cycle up to a maximum of 6 cycles of IV injection until disease progression or unacceptable toxicities.

    Arm title
    		 Chemotherapy
    Arm description
    		 Subjects received Pemetrexed (500 milligrams per square meter [mg/m^2]) in combination with Cisplatin (75 mg/m^2) administered on Day1 of each cycle or pemetrexed (500 mg/m^2) in combination with carboplatin (area under the concentration curve [AUC] 6 milligrams per milliliter [mg/mL] * minutes administered on Day 1 of each cycle). Subjects assigned pemetrexed could continue to receive pemetrexed as a maintenance therapy after 4 cycles of platinum-based chemotherapy if their disease had not progressed. Subjects with tumor of squamous histology received Paclitaxel (200 mg/m^2) plus carboplatin (AUC 6 mg/mL * min administered on Day 1 of each cycle) or Gemcitabine (1250 mg/m^2 administered on Day 1 and Day 8 of each cycle) plus cisplatin (75 mg/m^2) or Gemcitabine (1000 mg/m^2 administered on Day 1 and Day 8 of each cycle) plus carboplatin (AUC 5 mg/mL * min) in 3-week cycles up to a maximum of 6 cycles of IV injection or until disease progression or unacceptable toxicities.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received Paclitaxel 200 mg/m^2 by IV infusion on Day 1 of 3-Week cycle up to a maximum of 6 cycles of IV injection until disease progression or unacceptable toxicities.

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion, Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received Pemetrexed 500 milligrams per square meter (mg/m^2) by IV infusion on Day 1 of 3-Week cycle up to a maximum of 6 cycles of IV injection until disease progression or unacceptable toxicities.

    Number of subjects in period 1
    		Avelumab Biweekly Avelumab Weekly Chemotherapy
    Started
    366
    322
    526
    Completed
    366
    322
    526

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Avelumab Biweekly
    Reporting group description
    		 Subjects received Avelumab at a dose of 10 milligrams per kilogram (mg/kg) as a 1-hour (-10/+20 minutes) intravenous (IV) infusion once every 2 weeks until disease progression or unacceptable toxicities.

    Reporting group title
    Avelumab Weekly
    Reporting group description
    		 Subjects received Avelumab at a dose of 10 mg/kg as a 1-hour (-10/+20 minutes) IV infusion every week for 12 consecutive weeks, followed by Avelumab at a dose of 10 mg/kg once every 2 weeks until disease progression or unacceptable toxicities.

    Reporting group title
    Chemotherapy
    Reporting group description
    		 Subjects received Pemetrexed (500 milligrams per square meter [mg/m^2]) in combination with Cisplatin (75 mg/m^2) administered on Day1 of each cycle or pemetrexed (500 mg/m^2) in combination with carboplatin (area under the concentration curve [AUC] 6 milligrams per milliliter [mg/mL] * minutes administered on Day 1 of each cycle). Subjects assigned pemetrexed could continue to receive pemetrexed as a maintenance therapy after 4 cycles of platinum-based chemotherapy if their disease had not progressed. Subjects with tumor of squamous histology received Paclitaxel (200 mg/m^2) plus carboplatin (AUC 6 mg/mL * min administered on Day 1 of each cycle) or Gemcitabine (1250 mg/m^2 administered on Day 1 and Day 8 of each cycle) plus cisplatin (75 mg/m^2) or Gemcitabine (1000 mg/m^2 administered on Day 1 and Day 8 of each cycle) plus carboplatin (AUC 5 mg/mL * min) in 3-week cycles up to a maximum of 6 cycles of IV injection or until disease progression or unacceptable toxicities.

    Reporting group values
    		 Avelumab Biweekly Avelumab Weekly Chemotherapy Total
    Number of subjects
    		 366 322 526 1214
    Age Categorical
    Units: subjects
        <=18 years
    		 0 0 0 0
        Between 18 and 65 years
    		 190 168 289 647
        >=65 years
    		 176 154 237 567
    Sex: Female, Male
    Units: subjects
        Female
    		 84 69 145 298
        Male
    		 282 253 381 916
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 85 53 104 242
        Native Hawaiian or Other Pacific Islander
    		 1 0 0 1
        Black or African American
    		 1 2 4 7
        White
    		 254 250 375 879
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 25 17 43 85
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 14 20 38 72
        Not Hispanic or Latino
    		 338 296 466 1100
        Unknown or Not Reported
    		 14 6 22 42

    End points

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    End points reporting groups
    Reporting group title
    Avelumab Biweekly
    Reporting group description
    		 Subjects received Avelumab at a dose of 10 milligrams per kilogram (mg/kg) as a 1-hour (-10/+20 minutes) intravenous (IV) infusion once every 2 weeks until disease progression or unacceptable toxicities.

    Reporting group title
    Avelumab Weekly
    Reporting group description
    		 Subjects received Avelumab at a dose of 10 mg/kg as a 1-hour (-10/+20 minutes) IV infusion every week for 12 consecutive weeks, followed by Avelumab at a dose of 10 mg/kg once every 2 weeks until disease progression or unacceptable toxicities.

    Reporting group title
    Chemotherapy
    Reporting group description
    		 Subjects received Pemetrexed (500 milligrams per square meter [mg/m^2]) in combination with Cisplatin (75 mg/m^2) administered on Day1 of each cycle or pemetrexed (500 mg/m^2) in combination with carboplatin (area under the concentration curve [AUC] 6 milligrams per milliliter [mg/mL] * minutes administered on Day 1 of each cycle). Subjects assigned pemetrexed could continue to receive pemetrexed as a maintenance therapy after 4 cycles of platinum-based chemotherapy if their disease had not progressed. Subjects with tumor of squamous histology received Paclitaxel (200 mg/m^2) plus carboplatin (AUC 6 mg/mL * min administered on Day 1 of each cycle) or Gemcitabine (1250 mg/m^2 administered on Day 1 and Day 8 of each cycle) plus cisplatin (75 mg/m^2) or Gemcitabine (1000 mg/m^2 administered on Day 1 and Day 8 of each cycle) plus carboplatin (AUC 5 mg/mL * min) in 3-week cycles up to a maximum of 6 cycles of IV injection or until disease progression or unacceptable toxicities.

    Primary: Progression Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) Assessed by Independent Review Committee (IRC) in High Programmed Death Ligand 1 (PD-L1) + Full Analysis Set (FAS)

    		 Close Top of page
    End point title
    		 Progression Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) Assessed by Independent Review Committee (IRC) in High Programmed Death Ligand 1 (PD-L1) + Full Analysis Set (FAS) [1]
    End point description
    PFS is defined as the time from date of randomization until date of the first documentation of progressive disease (PD) or death due to any cause in the absence of documented PD, whichever occurs first. PD is defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was measured using Kaplan-Meier (KM) estimates. High PD-L1+ FAS included all high expression PD-L1+ subjects who were randomized to study intervention. High expression PD-L1+ subjects with greater than or equal to (>=) 80 percent (%) of tumor cells deemed positive for PD-L1 expression at any staining intensity (1+, 2+, or 3+).
    End point type
    Primary
    End point timeframe
    Time from date of randomization up to data cutoff (assessed up to approximately 71.5 months)
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint only compares the data of Avelumab and Chemotherapy groups
    End point values
    		 Avelumab Biweekly Chemotherapy
    Number of subjects analysed
    151
    216
    Units: months
        median (confidence interval 95%)
    8.4 (5.4 to 12.6)
    5.6 (5.4 to 6.8)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Avelumab Biweekly v Chemotherapy
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.007
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 0.93

    Primary: Progression Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) Assessed by Independent Review Committee (IRC) in High Programmed Death Ligand 1 (PD-L1) + Modified Full Analysis Set (mFAS)

    		 Close Top of page
    End point title
    		 Progression Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) Assessed by Independent Review Committee (IRC) in High Programmed Death Ligand 1 (PD-L1) + Modified Full Analysis Set (mFAS) [2]
    End point description
    PFS is defined as the time from date of randomization until date of the first documentation of progressive disease (PD) or death due to any cause in the absence of documented PD, whichever occurs first. PD is defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was measured using Kaplan-Meier (KM) estimates. High PD-L1+ mFAS included all high expression PD-L1+ subjects who were randomized to study intervention after weekly Avelumab was included into the randomization allocation. The PDL1+ subjects with >= 80% of tumor cells deemed positive for PD-L1 expression at any staining intensity (1+, 2+, or 3+).
    End point type
    Primary
    End point timeframe
    Time from date of randomization up to data cutoff (assessed up to approximately 71.5 months)
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint only compares the data of Avelumab and Chemotherapy groups
    End point values
    		 Avelumab Weekly Chemotherapy
    Number of subjects analysed
    130
    129
    Units: months
        median (confidence interval 95%)
    7.5 (4.2 to 11.1)
    5.6 (5.0 to 6.8)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Avelumab Weekly v Chemotherapy
    Number of subjects included in analysis
    259
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0196
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 0.98

    Primary: Overall Survival (OS) in High Programmed Death Ligand 1 (PD-L1) + Full Analysis Set (FAS)

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    End point title
    		 Overall Survival (OS) in High Programmed Death Ligand 1 (PD-L1) + Full Analysis Set (FAS) [3]
    End point description
    OS is defined as the time from randomization to the date of death, regardless of the actual cause of the subjects death. The subjects who were still alive at the time of data analysis or who were lost to follow-up OS time was censored at the last recorded date that the participant was known to be alive before the data cutoff date. OS was measured using Kaplan-Meier (KM) estimates. High PD-L1+ FAS included all high expression PD-L1+ subjects who were randomized to study intervention. High expression PD-L1+ subjects with greater than or equal to (>=) 80 percent (%) of tumor cells deemed positive for PD-L1 expression at any staining intensity (1+, 2+, or 3+).
    End point type
    Primary
    End point timeframe
    Time from date of randomization up to data cutoff (assessed up to approximately 71.5 months)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint only compares the data of Avelumab and Chemotherapy groups
    End point values
    		 Avelumab Biweekly Chemotherapy
    Number of subjects analysed
    151
    216
    Units: months
        median (confidence interval 95%)
    20.1 (15.0 to 24.3)
    14.9 (11.8 to 18.6)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Avelumab Biweekly v Chemotherapy
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1032
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.09

    Primary: Overall Survival (OS) in High Programmed Death Ligand 1 (PD-L1)+ Modified Full Analysis Set (mFAS)

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    End point title
    		 Overall Survival (OS) in High Programmed Death Ligand 1 (PD-L1)+ Modified Full Analysis Set (mFAS) [4]
    End point description
    OS is defined as the time from randomization to the date of death, regardless of the actual cause of the subjects death. The subjects who were still alive at the time of data analysis or who were lost to follow-up OS time was censored at the last recorded date that the subject was known to be alive before the data cutoff date. OS was measured using Kaplan-Meier (KM) estimates. High PD-L1+ mFAS included all high expression PD-L1+ subjects who were randomized to study intervention after weekly Avelumab was included into the randomization allocation. The PDL1+ subjects with >= 80% of tumor cells deemed positive for PD-L1 expression at any staining intensity (1+, 2+, or 3+).
    End point type
    Primary
    End point timeframe
    Time from date of randomization up to data cutoff (assessed up to approximately 71.5 months)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint only compares the data of Avelumab and Chemotherapy groups
    End point values
    		 Avelumab Weekly Chemotherapy
    Number of subjects analysed
    130
    129
    Units: months
        median (confidence interval 95%)
    19.3 (14.0 to 28.1)
    15.3 (11.6 to 19.1)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Avelumab Weekly v Chemotherapy
    Number of subjects included in analysis
    259
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.063
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 1.07

    Secondary: Progression Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) Assessed by Independent Review Committee (IRC) in Moderate and High Programmed Death Ligand 1 (PD-L1)+ Full Analysis Set (FAS)

    		 Close Top of page
    End point title
    		 Progression Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) Assessed by Independent Review Committee (IRC) in Moderate and High Programmed Death Ligand 1 (PD-L1)+ Full Analysis Set (FAS) [5]
    End point description
    PFS is defined as the time from date of randomization until date of the first documentation of progressive disease (PD) or death due to any cause in the absence of documented PD, whichever occurs first. PD is defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was measured using Kaplan-Meier (KM) estimates. Moderate and High PD-L1+ FAS included all high expression PDL-L1+ subjects who were randomized to study intervention. The PD-L1+ subjects with >= 50% of tumor cells deemed positive for PD-L1 expression at any staining intensity (1+, 2+, or 3+).
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to data cutoff (assessed up to approximately 71.5 months)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint only compares the data of Avelumab and Chemotherapy groups
    End point values
    		 Avelumab Biweekly Chemotherapy
    Number of subjects analysed
    218
    304
    Units: months
        median (confidence interval 95%)
    6.9 (5.4 to 9.6)
    5.6 (5.5 to 6.6)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Avelumab Biweekly v Chemotherapy
    Number of subjects included in analysis
    522
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0147
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 0.98

    Secondary: Progression Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) Assessed by Independent Review Committee (IRC) in Moderate and High Programmed Death Ligand 1 (PD-L1)+ Modified Full Analysis Set (mFAS)

    		 Close Top of page
    End point title
    		 Progression Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) Assessed by Independent Review Committee (IRC) in Moderate and High Programmed Death Ligand 1 (PD-L1)+ Modified Full Analysis Set (mFAS) [6]
    End point description
    PFS is defined as the time from date of randomization until date of the first documentation of progressive disease (PD) or death due to any cause in the absence of documented PD, whichever occurs first. PD is defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was measured using Kaplan-Meier (KM) estimates. Moderate and High PD-L1+ mFAS included all high expression PD-L1+ subjects who were randomized to study intervention after weekly avelumab was included into the randomization allocation. The PD-L1+ subjects with >= 50% of tumor cells deemed positive for PD-L1 expression at any staining intensity (1+, 2+, or 3+).
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to data cutoff (assessed up to approximately 71.5 months)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint only compares the data of Avelumab and Chemotherapy groups
    End point values
    		 Avelumab Weekly Chemotherapy
    Number of subjects analysed
    183
    183
    Units: months
        median (confidence interval 95%)
    5.6 (2.8 to 8.2)
    5.6 (5.5 to 6.6)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Avelumab Weekly v Chemotherapy
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1753
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.15

    Secondary: Overall Survival (OS) in Moderate and High Programmed Death Ligand 1 (PD-L1)+ Full Analysis Set (FAS)

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    End point title
    		 Overall Survival (OS) in Moderate and High Programmed Death Ligand 1 (PD-L1)+ Full Analysis Set (FAS) [7]
    End point description
    OS is defined as the time from randomization to the date of death, regardless of the actual cause of the subjects death. The subjects who were still alive at the time of data analysis or who were lost to follow-up OS time was censored at the last recorded date that the subject was known to be alive before the data cutoff date. OS was measured using Kaplan-Meier (KM) estimates. Moderate and High PD-L1+ FAS included all high expression PD-L1+ subjects who were randomized to study intervention. The PD-L1+ subjects with >= 50% of tumor cells deemed positive for PD-L1 expression at any staining intensity (1+, 2+, or 3+).
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to data cutoff (assessed up to approximately 71.5 months)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint only compares the data of Avelumab and Chemotherapy groups
    End point values
    		 Avelumab Biweekly Chemotherapy
    Number of subjects analysed
    218
    304
    Units: months
        median (confidence interval 95%)
    18.7 (14.6 to 21.7)
    13.3 (11.4 to 16.6)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Avelumab Biweekly v Chemotherapy
    Number of subjects included in analysis
    522
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0257
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1

    Secondary: Overall Survival (OS) in Moderate and High Programmed Death Ligand 1 (PD-L1)+ Modified Full Analysis Set (mFAS)

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    End point title
    		 Overall Survival (OS) in Moderate and High Programmed Death Ligand 1 (PD-L1)+ Modified Full Analysis Set (mFAS) [8]
    End point description
    OS is defined as the time from randomization to the date of death, regardless of the actual cause of the subjects death. The subjects who were still alive at the time of data analysis or who were lost to follow-up OS time was censored at the last recorded date that the subject was known to be alive before the data cutoff date. OS was measured using Kaplan-Meier (KM) estimates. Moderate and High PD-L1+ mFAS included all high expression PD-L1+ subjects who were randomized to study intervention after weekly avelumab was included into the randomization allocation. The PD-L1+ subjects with >= 50% of tumor cells deemed positive for PD-L1 expression at any staining intensity (1+, 2+, or 3+).
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to data cutoff (assessed up to approximately 71.5 months)
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint only compares the data of Avelumab and Chemotherapy groups
    End point values
    		 Avelumab Weekly Chemotherapy
    Number of subjects analysed
    183
    183
    Units: months
        median (confidence interval 95%)
    16.8 (12.5 to 21.3)
    13.0 (11.1 to 17.0)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Avelumab Weekly v Chemotherapy
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0809
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.07

    Secondary: Overall Survival (OS) in Full Analysis Set (FAS)

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    End point title
    		 Overall Survival (OS) in Full Analysis Set (FAS) [9]
    End point description
    OS is defined as the time from randomization to the date of death, regardless of the actual cause of the subjects death. The subjects who were still alive at the time of data analysis or who were lost to follow-up OS time was censored at the last recorded date that the participant was known to be alive before the data cutoff date. OS was measured using Kaplan-Meier (KM) estimates. FAS included all subjects who were randomized to study intervention.
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to data cutoff (assessed up to approximately 71.5 months)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint only compares the data of Avelumab and Chemotherapy groups
    End point values
    		 Avelumab Biweekly Chemotherapy
    Number of subjects analysed
    366
    526
    Units: months
        median (confidence interval 95%)
    15.0 (12.5 to 19.1)
    14.3 (11.8 to 15.6)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Avelumab Biweekly v Chemotherapy
    Number of subjects included in analysis
    892
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1294
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.07

    Secondary: Overall Survival (OS) in Modified Full Analysis Set (mFAS)

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    End point title
    		 Overall Survival (OS) in Modified Full Analysis Set (mFAS) [10]
    End point description
    OS is defined as the time from randomization to the date of death, regardless of the actual cause of the subjects death. The subjects who were still alive at the time of data analysis or who were lost to follow-up OS time was censored at the last recorded date that the subject was known to be alive before the data cutoff date. OS was measured using Kaplan-Meier (KM) estimates. mFAS included all subjects who were randomized to study intervention after weekly avelumab was included into the randomization allocation.
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to data cutoff (assessed up to approximately 71.5 months)
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint only compares the data of Avelumab and Chemotherapy groups
    End point values
    		 Avelumab Weekly Chemotherapy
    Number of subjects analysed
    322
    321
    Units: months
        median (confidence interval 95%)
    15.4 (12.1 to 18.1)
    14.8 (11.6 to 16.4)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Avelumab Weekly v Chemotherapy
    Number of subjects included in analysis
    643
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2618
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 1.13

    Secondary: Percentage of Subjects With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC) in High PD-L1+ Full Analysis Set

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    End point title
    		 Percentage of Subjects With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC) in High PD-L1+ Full Analysis Set [11]
    End point description
    Confirmed objective response was defined as the percentage of subjects with a confirmed objective response of complete response (CR) or partial response (PR). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. High PD-L1+ FAS included all high expression PD-L1+ participants who were randomized to study intervention. High expression PD-L1+ subjects with greater than or equal to (>=) 80 percent (%) of tumor cells deemed positive for PD-L1 expression at any staining intensity (1+, 2+, or 3+).
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to data cutoff (assessed up to approximately 71.5 months)
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint only compares the data of Avelumab and Chemotherapy groups
    End point values
    		 Avelumab Biweekly Chemotherapy
    Number of subjects analysed
    151
    216
    Units: percentage of subjects
        number (confidence interval 95%)
    37.7 (30.0 to 46.0)
    30.1 (24.1 to 36.7)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Avelumab Biweekly v Chemotherapy
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.064
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 2.18

    Secondary: Percentage of Subjects With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC) in High PD-L1+ Modified Full Analysis Set

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    End point title
    		 Percentage of Subjects With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC) in High PD-L1+ Modified Full Analysis Set [12]
    End point description
    Confirmed objective response was defined as the percentage of subjects with a confirmed objective response of complete response (CR) or partial response (PR). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. High PD-L1+ mFAS included all high expression PD-L1+ subjects who were randomized to study intervention after weekly Avelumab was included into the randomization allocation. The PDL1+ subjects with >= 80% of tumor cells deemed positive for PD-L1 expression at any staining intensity (1+, 2+, or 3+).
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to data cutoff (assessed up to approximately 71.5 months)
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint only compares the data of Avelumab and Chemotherapy groups
    End point values
    		 Avelumab Weekly Chemotherapy
    Number of subjects analysed
    130
    129
    Units: percentage of subjects
        median (confidence interval 95%)
    34.6 (26.5 to 43.5)
    30.2 (22.5 to 38.9)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Avelumab Weekly v Chemotherapy
    Number of subjects included in analysis
    259
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2217
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 2.07

    Secondary: Percentage of Subjects With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC) in Moderate and High PD-L1+ Full Analysis Set

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    End point title
    		 Percentage of Subjects With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC) in Moderate and High PD-L1+ Full Analysis Set [13]
    End point description
    Confirmed objective response was defined as the percentage of subjects with a confirmed objective response of complete response (CR) or partial response (PR). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Moderate and High PD-L1+ FAS included all high expression PD-L1+ subjects who were randomized to study intervention. The PD-L1+ subjects with >= 50% of tumor cells deemed positive for PD-L1 expression at any staining intensity (1+, 2+, or 3+).
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to data cutoff (assessed up to approximately 71.5 months)
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint only compares the data of Avelumab and Chemotherapy groups
    End point values
    		 Avelumab Biweekly Chemotherapy
    Number of subjects analysed
    218
    304
    Units: percentage of subjects
        number (confidence interval 95%)
    33.5 (27.3 to 40.2)
    30.3 (25.1 to 35.8)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Avelumab Biweekly v Chemotherapy
    Number of subjects included in analysis
    522
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1912
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.72

    Secondary: Percentage of Subjects With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC) in Moderate and High PD-L1+ Modified Full Analysis Set

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    End point title
    		 Percentage of Subjects With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC) in Moderate and High PD-L1+ Modified Full Analysis Set [14]
    End point description
    Confirmed objective response was defined as the percentage of subjects with a confirmed objective response of complete response (CR) or partial response (PR). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Moderate and High PD-L1+ mFAS included all high expression PD-L1+ subjects who were randomized to study intervention after weekly avelumab was included into the randomization allocation. The PD-L1+ subjects with >= 50% of tumor cells deemed positive for PD-L1 expression at any staining intensity (1+, 2+, or 3+).
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to data cutoff (assessed up to approximately 71.5 months)
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint only compares the data of Avelumab and Chemotherapy groups
    End point values
    		 Avelumab Weekly Chemotherapy
    Number of subjects analysed
    183
    183
    Units: percentage of subjects
        number (confidence interval 95%)
    30.6 (24.0 to 37.8)
    30.6 (24.0 to 37.8)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Avelumab Weekly v Chemotherapy
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4951
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.57

    Secondary: Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC) in High Programmed Death Ligand 1 (PD-L1)+ Full Analysis Set (FAS)

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    End point title
    		 Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC) in High Programmed Death Ligand 1 (PD-L1)+ Full Analysis Set (FAS) [15]
    End point description
    DOR was defined for subjects with confirmed response, as the time from first documentation of objective response (Complete Response [CR] or Partial Response [PR]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. High PD-L1+ FAS was used. Here, "Overall Number of Subjects Analyzed" signifies those participants who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to data cutoff (assessed up to approximately 71.5 months)
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint only compares the data of Avelumab and Chemotherapy groups
    End point values
    		 Avelumab Biweekly Chemotherapy
    Number of subjects analysed
    57
    65
    Units: months
        median (full range (min-max))
    35.9 (1.4 to 60.8)
    8.4 (1.0 to 63.9)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC) in High Programmed Death Ligand 1 (PD-L1)+ Modified Full Analysis Set (mFAS)

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    End point title
    		 Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC) in High Programmed Death Ligand 1 (PD-L1)+ Modified Full Analysis Set (mFAS) [16]
    End point description
    DOR was defined for subjects with confirmed response, as the time from first documentation of objective response (Complete Response [CR] or Partial Response [PR]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. High PD-L1+ mFAS was used. Here, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to data cutoff (assessed up to approximately 71.5 months)
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint only compares the data of Avelumab and Chemotherapy groups
    End point values
    		 Avelumab Weekly Chemotherapy
    Number of subjects analysed
    45
    39
    Units: months
        median (full range (min-max))
    19.4 (3.8 to 43.9)
    8.4 (1.0 to 35.9)
    No statistical analyses for this end point

    Secondary: Change from Baseline in European Quality Of Life 5-dimensions (EQ-5D-5L) Visual Analog Scale (VAS) in High PD-L1+ Health-related Quality of Life (HRQoL) Analysis Set at End of Treatment

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    End point title
    		 Change from Baseline in European Quality Of Life 5-dimensions (EQ-5D-5L) Visual Analog Scale (VAS) in High PD-L1+ Health-related Quality of Life (HRQoL) Analysis Set at End of Treatment [17]
    End point description
    EQ-5D-5L is comprised of the following 5 subject-reported dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The responses are used to derive overall score using a visual analog scale (VAS) that ranged from 0 to 100 millimeter (mm), where 0 is the worst health you can imagine and 100 is the best health you can imagine. High PD-L1+HRQoL analysis set includes all high expression PD-L1+ FAS participants who have 1 baseline HRQoL assessment and have >=1 post-baseline HRQoL questionnaire complete. The high expression PDL1+ participants were with >= 80% of tumor cells deemed positive for PD-L1 expression at any staining intensity (1+, 2+, or 3+). Here, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, End of treatment (up to Week 283.9)
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint only compares the data of Avelumab and Chemotherapy groups
    End point values
    		 Avelumab Biweekly Chemotherapy
    Number of subjects analysed
    56
    107
    Units: millimeter (mm)
        arithmetic mean (standard deviation)
    -6.2 ( 23.61 )
    -5.2 ( 20.48 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in European Quality Of Life 5-dimensions (EQ-5D-5L) Visual Analog Scale (VAS) in High Programmed Death Ligand 1 (PD-L1)+ Modified HRQoL Analysis Set

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    End point title
    		 Change from Baseline in European Quality Of Life 5-dimensions (EQ-5D-5L) Visual Analog Scale (VAS) in High Programmed Death Ligand 1 (PD-L1)+ Modified HRQoL Analysis Set [18]
    End point description
    EQ-5D-5L is comprised of the following 5 subject-reported dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The responses are used to derive overall score using a visual analog scale (VAS) that ranged from 0 to 100 millimeter (mm), where 0 is the worst health you can imagine and 100 is the best health you can imagine. High PD-L1+ Modified HRQoL Analysis Set included all mFAS subjects who have 1 baseline HRQoL assessment and have >=1 post-baseline HRQoL questionnaire completed. The high expression PDL1+ subjects were with >= 80% of tumor cells deemed positive for PD-L1 expression at any staining intensity (1+, 2+, or 3+). Here, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, End of treatment (Week 283.9)
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint only compares the data of Avelumab and Chemotherapy groups
    End point values
    		 Avelumab Weekly Chemotherapy
    Number of subjects analysed
    53
    70
    Units: millimeter
        arithmetic mean (standard deviation)
    -10.3 ( 22.49 )
    -3.9 ( 20.21 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) Global Health Status at End of Treatment (EOT) in High Programmed Death Ligand 1 (PD-L1)+ HRQoL Analysis Set

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    End point title
    		 Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) Global Health Status at End of Treatment (EOT) in High Programmed Death Ligand 1 (PD-L1)+ HRQoL Analysis Set [19]
    End point description
    EORTC QLQ-C30 was a 30-question tool used to assess the overall quality of life (QoL) in cancer subjects. It consisted of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, role, cognitive, emotional, social), and 9 symptom scales/items (Fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, financial impact). The EORTC QLQ-C30 GHS/QoL score ranged from 0 to 100; High score indicated better GHS/QoL. Score 0 represents: very poor physical condition and QoL. Score 100 represents: excellent overall physical condition and QoL. High PD-L1+HRQoL analysis set includes all high expression PD-L1 FAS subjects who have 1 baseline HRQoL assessment and have >=1 post-baseline HRQoL questionnaire complete. The high expression PDL1+ subjects were with >= 80% of tumor cells deemed positive for PD-L1 expression at any staining intensity (1+, 2+, or 3+).
    End point type
    Secondary
    End point timeframe
    Baseline, End of treatment (up to Week 283.9)
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint only compares the data of Avelumab and Chemotherapy groups
    End point values
    		 Avelumab Biweekly Chemotherapy
    Number of subjects analysed
    56
    108
    Units: score on a scale
        arithmetic mean (standard deviation)
    -0.3 ( 22.30 )
    -6.1 ( 24.55 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer 13 (EORTC QLQ-LC13) at End of Treatment (EOT) in High Programmed Death Ligand 1 (PD-L1)+ HRQoL Analysis Set

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    End point title
    		 Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer 13 (EORTC QLQ-LC13) at End of Treatment (EOT) in High Programmed Death Ligand 1 (PD-L1)+ HRQoL Analysis Set [20]
    End point description
    EORTC QLQ-LC13 consists 13 questions relating to disease symptoms specific to lung cancer and treatment side effects typical of treatment with chemotherapy and radiotherapy. The EORTC QLQ-LC13 generated one multiple-item score assessing dyspnea and a series of single item scores assessing coughing, hemoptysis, sore mouth, dysphagia, peripheral neuropathy, alopecia, pain in chest, pain in arms or shoulder and pain in other parts. Score range: 0 (no burden of symptom domain or single symptom item) to 100 (highest burden of symptoms for symptom domains and single items). High PD-L1+ HRQoL analysis set includes all high expression PD-L1+ FAS subjects who have 1 baseline HRQoL assessment and have >=1 post-baseline HRQoL questionnaire complete. The high expression PDL1+ subjects were with >= 80% of tumor cells deemed positive for PD-L1 expression at any staining intensity (1+, 2+, or 3+).
    End point type
    Secondary
    End point timeframe
    Baseline, End of treatment (up to Week 283.9)
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint only compares the data of Avelumab and Chemotherapy groups
    End point values
    		 Avelumab Biweekly Chemotherapy
    Number of subjects analysed
    56
    108
    Units: score on a scale
    arithmetic mean (standard deviation)
        Dyspnea
    7.3 ( 24.10 )
    5.2 ( 19.66 )
        Coughing
    2.4 ( 29.04 )
    -4.3 ( 27.01 )
        Hemoptysis
    -1.8 ( 21.48 )
    1.5 ( 13.95 )
        Sore mouth
    3.0 ( 18.28 )
    1.9 ( 21.77 )
        Dysphagia
    3.0 ( 19.36 )
    -0.6 ( 21.36 )
        Peripheral neuropathy
    3.6 ( 17.60 )
    10.8 ( 24.46 )
        Alopecia
    0.0 ( 8.98 )
    14.2 ( 32.93 )
        Pain in chest
    -4.2 ( 22.96 )
    -1.5 ( 26.33 )
        Pain in arm or shoulder
    0.6 ( 32.71 )
    1.9 ( 26.50 )
        Pain in other parts
    1.8 ( 33.29 )
    1.5 ( 30.36 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) Global Health Status at End of Treatment (EOT) in High Programmed Death Ligand 1 (PD-L1)+ Modified HRQoL Analysis Set

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    End point title
    		 Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) Global Health Status at End of Treatment (EOT) in High Programmed Death Ligand 1 (PD-L1)+ Modified HRQoL Analysis Set [21]
    End point description
    EORTC QLQ-C30 a 30-question tool used to assess the QoL in cancer subjects. It consisted of 15 domains: 1 GHS scale, 5 functional scales (Physical, role, cognitive, emotional, social), and 9 symptom scales/items (Fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, financial impact). The EORTC QLQ-C30 GHS/QoL score ranged from 0 to 100; High score indicated better GHS/QoL. Score 0 represents: very poor physical condition and QoL. Score 100 represents: excellent overall physical condition and QoL. High PD-L1+modified HRQoL analysis set includes all high expression PD-l1+ mFAS subjects who have 1 baseline HRQoL assessment and have ≥1 post-baseline HRQoL questionnaire completed. The high expression PDL1+ subjects were with >= 80% of tumor cells deemed positive for PD-L1 expression at any staining intensity (1+, 2+, or 3+). Here, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, End of treatment (Week 283.9)
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint only compares the data of Avelumab and Chemotherapy groups
    End point values
    		 Avelumab Weekly Chemotherapy
    Number of subjects analysed
    53
    71
    Units: score on a scale
        arithmetic mean (standard deviation)
    -12.9 ( 21.03 )
    -4.5 ( 23.30 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer 13 (EORTC QLQ-LC13) at End of Treatment (EOT) in High Programmed Death Ligand 1 (PD-L1)+ Modified HRQoL Analysis Set

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    End point title
    		 Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer 13 (EORTC QLQ-LC13) at End of Treatment (EOT) in High Programmed Death Ligand 1 (PD-L1)+ Modified HRQoL Analysis Set [22]
    End point description
    EORTC QLQ-LC13 consisted of 13 questions relating to disease symptoms specific to lung cancer and treatment side effects typical of treatment with chemotherapy and radiotherapy. The EORTC QLQ-LC13 module generated one multiple-item score assessing dyspnea and a series of single item scores assessing coughing, hemoptysis, sore mouth, dysphagia, peripheral neuropathy, alopecia, pain in chest, pain in arms or shoulder and pain in other parts. Score range: 0 (no burden of symptom domain or single symptom item) to 100 (highest burden of symptoms for symptom domains and single items). High PD-L1+ modified HRQoL analysis set was used. Here, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure and "number analyzed" signifies those subjects who were evaluable for specified categories.
    End point type
    Secondary
    End point timeframe
    Baseline, End of treatment (up to Week 283.9)
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint only compares the data of Avelumab and Chemotherapy groups
    End point values
    		 Avelumab Weekly Chemotherapy
    Number of subjects analysed
    53
    71
    Units: score on a scale
    arithmetic mean (standard deviation)
        Dyspnea
    6.1 ( 27.19 )
    4.9 ( 18.77 )
        Coughing
    -0.6 ( 28.87 )
    -5.2 ( 24.34 )
        Hemoptysis
    -0.6 ( 17.89 )
    0.0 ( 12.59 )
        Sore mouth
    0.6 ( 13.97 )
    1.9 ( 17.71 )
        Dysphagia
    3.8 ( 14.10 )
    -0.5 ( 22.88 )
        Peripheral neuropathy
    0.6 ( 21.17 )
    9.9 ( 23.49 )
        Alopecia
    -2.5 ( 17.11 )
    15.0 ( 29.70 )
        Pain in chest
    2.5 ( 29.13 )
    -0.5 ( 25.50 )
        Pain in arm or shoulder
    4.4 ( 30.69 )
    1.4 ( 25.46 )
        Pain in other parts
    10.1 ( 28.93 )
    1.4 ( 28.97 )
    No statistical analyses for this end point

    Secondary: Number of Subjects with Shift From Baseline to Greater Than or Equal to (>=) Grade 3 in Laboratory Parameter Values Based on National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03

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    End point title
    		 Number of Subjects with Shift From Baseline to Greater Than or Equal to (>=) Grade 3 in Laboratory Parameter Values Based on National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03
    End point description
    Number of subjects with shifts from Baseline values (Grade 0/1/2/3) to abnormal post-baseline values (shift to >= Grade 4) were reported as per NCI-CTCAE, v4.03 graded from Grade 1 to 5. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Death. Shifts in laboratory parameter (anemia, lymphocyte count decreased, neutrophil count decreased, platelet count decreased, white blood cell count decreased, alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, creatine phosphokinase increased, creatinine increased and Hyperglycemia) were reported. The Safety analysis set (Safety-AS) included all randomized subjects who were administered at least one dose of the study medication, that is (i.e.) avelumab or chemotherapy.
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to data cutoff (assessed up to approximately 71.5 months)
    End point values
    		 Avelumab Biweekly Avelumab Weekly Chemotherapy
    Number of subjects analysed
    361
    318
    500
    Units: subjects
        Anemia: Grade 0 to Grade 3
    4
    2
    58
        Anemia: Grade 1 to Grade 3
    4
    5
    30
        Anemia: Grade 2 to Grade 3
    4
    6
    6
        Lymphocyte count decreased: Grade 0 to Grade 3
    16
    15
    31
        Lymphocyte count decreased: Grade 0 to Grade 4
    1
    2
    3
        Lymphocyte count decreased: Grade 1 to Grade 3
    2
    10
    12
        Lymphocyte count decreased: Grade 2 to Grade 3
    7
    6
    12
        Lymphocyte count decreased: Grade 2 to Grade 4
    0
    0
    1
        Lymphocyte count decreased: Grade 3 to Grade 4
    0
    0
    1
        Neutrophil count decreased: Grade 0 to Grade 3
    4
    4
    65
        Neutrophil count decreased: Grade 0 to Grade 4
    0
    3
    25
        Neutrophil count decreased: Grade 1 to Grade 3
    1
    0
    1
        Platelet count decreased: Grade 0 to Grade 3
    0
    1
    18
        Platelet count decreased: Grade 0 to Grade 4
    0
    3
    20
        Platelet count decreased: Grade 1 to Grade 3
    0
    1
    0
        WBC count decreased:Grade0 to Grade3
    0
    3
    24
        WBC count decreased: Grade 0 to Grade 4
    0
    1
    11
        Alanineaminotransferase increased:Grade0 to 3
    12
    8
    5
        Alanineaminotransferase increased: Grade0 to 4
    1
    1
    3
        Alanineaminotransferase increased: Grade 1 to 3
    1
    0
    2
        Alkaline phosphatase increased: Grade 0 to Grade 3
    0
    3
    1
        Alkaline phosphatase increased: Grade 1 to Grade 3
    1
    3
    1
        Alkaline phosphatase increased: Grade 1 to Grade 4
    0
    0
    1
        Alkaline phosphatase increased: Grade 2 to Grade 3
    0
    1
    0
        Aspartate aminotransferase increased: Grade 0 to 3
    7
    4
    3
        Aspartate aminotransferase increased: Grade 0 to 4
    1
    2
    2
        Aspartate aminotransferase increased: Grade 1 to 3
    0
    0
    1
        Blood bilirubin increased: Grade 0 to Grade 3
    0
    4
    3
        Blood bilirubin increased: Grade 0 to Grade 4
    0
    1
    0
        Creatine phosphokinase increased: Grade 0 to 3
    6
    5
    1
        Creatine phosphokinase increased: Grade 0 to 4
    5
    0
    0
        Creatine phosphokinase increased: Grade 1 to 4
    0
    1
    0
        Creatine phosphokinase increased: Grade 2 to 3
    0
    1
    0
        Creatinine increased: Grade 0 to Grade 3
    6
    4
    4
        Creatinine increased: Grade 1 to Grade 3
    0
    0
    1
        Hyperglycemia: Grade 0 to Grade 3
    21
    20
    35
        Hyperglycemia: Grade 0 to Grade 4
    0
    0
    3
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and AEs of Special Interest (AESIs)

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and AEs of Special Interest (AESIs)
    End point description
    Adverse event (AE) was defined as any untoward medical occurrence in a subject, which does not necessarily have causal relationship with treatment. A serious AE was defined as an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged in subject hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Any AE that was suspicious to be a potential Immune-related adverse event (irAE) including infusion related reactions were considered AESIs. Number of subjects with TEAEs and AESIs were reported. High PD-L1+ modified HRQoL analysis set was used. Here, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure and "number analyzed" signifies those subjects who were evaluable for specified categories.
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to data cutoff (assessed up to approximately 71.5 months)
    End point values
    		 Avelumab Biweekly Avelumab Weekly Chemotherapy
    Number of subjects analysed
    361
    318
    500
    Units: subjects
        TEAEs
    346
    308
    484
        AESIs
    158
    160
    173
    No statistical analyses for this end point

    Secondary: Number of Subjects with Maximal On-Treatment Changes From Baseline in Vital Signs - Maximal Body Temperature Increase

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    End point title
    		 Number of Subjects with Maximal On-Treatment Changes From Baseline in Vital Signs - Maximal Body Temperature Increase
    End point description
    The number of subjects with changes from baseline in increased Body Temperature (degree Celsius [°C]) were reported by using criteria: Baseline temperature (temp.) less than (<) 37°C, on treatment change <1°C, 1 - <2°C, 2 - <3°C, greater than or equal to (>=)3°C and missing; Baseline temp. 37 - <38°C, on treatment change <1°C, 1 - <2°C, 2 - <3°C, >=3°C and missing; Baseline temp. 38 - <39°C, on treatment change <1°C, 1 - <2°C, 2 - <3°C, >=3°C and missing; Baseline temp. 39-<40°C, on treatment change <1°C, 1 - <2°C, 2 - <3°C, >=3°C and missing; Baseline temp. >=40°C, on treatment change <1°C, 1 - <2°C, 2 - <3°C, >=3°C and missing; Baseline temp. missing, on treatment change missing. The Safety analysis set (Safety-AS) included all randomized subjects who were administered at least one dose of the study medication, that is (i.e.) avelumab or chemotherapy.
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to data cutoff (assessed up to approximately 71.5 months)
    End point values
    		 Avelumab Biweekly Avelumab Weekly Chemotherapy
    Number of subjects analysed
    361
    318
    500
    Units: subjects
        Baseline temp.<37°C, on treatment change<1°C
    271
    256
    403
        Baseline temp.<37°C, on treatment change 1 - <2°C
    45
    32
    33
        Baseline temp.<37°C, on treatment change2-<3°C
    3
    2
    0
        Baseline temp.<37°C,on treatment change>=3°C
    0
    1
    0
        Baseline temp.<37°C,on treatment change missing
    16
    6
    21
        Baseline temp.37-<38°C, on treatment change<1°C
    23
    19
    37
        Baseline temp.37-<38°C, on treatment change1-<2°C
    1
    2
    1
        Baseline temp.37-<38°C, on treatment change2-<3°C
    0
    0
    0
        Baseline temp.37-<38°C, on treatment change >=3°C
    0
    0
    0
        Baseline temp.37-<38°C,treatment change missing
    1
    0
    3
        Baseline temp.38-<39°C, on treatment change <1°C
    0
    0
    0
        Baseline temp.38-<39°C, on treatment change1<2°C
    0
    0
    0
        Baseline temp.38-<39°C, on treatment change2-<3°C
    0
    0
    0
        Baseline temp.38-<39°C,on treatment change>=3°C
    0
    0
    0
        Baseline temp.38-<39°C, treatment change missing
    0
    0
    0
        Baseline temp.39-<40°C, on treatment change<1°C
    1
    0
    0
        Baseline temp.39-<40°C, on treatment change1-<2°C
    0
    0
    0
        Baseline temp.39-<40°C, on treatment change2-<3°C
    0
    0
    0
        Baseline temp.39-<40°C, on treatment change>=3°C
    0
    0
    0
        Baseline temp.39-<40°C,treatment change missing
    0
    0
    0
        Baseline temp.>=40°C, on treatment change<1°C
    0
    0
    0
        Baseline temp.>=40°C, on treatment change1-<2°C
    0
    0
    0
        Baseline temp.>=40°C, on treatment change2-<3°C
    0
    0
    0
        Baseline temp.>=40°C, on treatment change>=3°C
    0
    0
    0
        Baseline temp.>=40°C, on treatment change missing
    0
    0
    0
        Baseline temp. missing, treatment change missing
    0
    0
    2
    No statistical analyses for this end point

    Secondary: Number of Subjects with Maximal On-Treatment Changes From Baseline in Vital Signs - Maximal Weight Increase/Decrease

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    End point title
    		 Number of Subjects with Maximal On-Treatment Changes From Baseline in Vital Signs - Maximal Weight Increase/Decrease
    End point description
    The number of subjects with maximal on-treatment changes from baseline in Increase (Ic.)/Decrease (Dc.) in maximal weight were reported by using criteria: Ic./Dc. From baseline, on treatment (TR) change <10 percentage (%), >=10% and missing. The Safety analysis set (Safety-AS) included all randomized subjects who were administered at least one dose of the study medication, that is (i.e.) avelumab or chemotherapy.
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to data cutoff (assessed up to approximately 71.5 months)
    End point values
    		 Avelumab Biweekly Avelumab Weekly Chemotherapy
    Number of subjects analysed
    361
    318
    500
    Units: subjects
        Ic. from baseline, on TR change <10%
    302
    280
    436
        Ic. from baseline, on TR change >=10%
    38
    28
    39
        Ic. from baseline, on TR change missing
    21
    10
    25
        Dc. from baseline, on TR change <10%
    296
    258
    423
        Dc. from baseline, on TR change >=10%
    44
    50
    52
        Dc. from baseline, on TR change missing
    21
    10
    25
    No statistical analyses for this end point

    Secondary: Number of Subjects With Maximal On-Treatment Changes From Baseline in Vital Signs - Maximal Heart Rate Increase/Decrease

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    End point title
    		 Number of Subjects With Maximal On-Treatment Changes From Baseline in Vital Signs - Maximal Heart Rate Increase/Decrease
    End point description
    The number of subjects with maximal on-treatment (TR) changes from baseline (BS) in Increase (Ic.)/Decrease (Dc.) heart rate (HR) (beats per minute [bpm]) were reported by using criteria: Ic./Dc. BS HR <100/>=100 bpm, on treatment change =<20 bpm, >20 - =<40 bpm, >40 bpm and missing; Ic./Dc. BS HR missing, on treatment change missing. The Safety analysis set (Safety-AS) included all randomized subjects who were administered at least one dose of the study medication, that is (i.e.) avelumab or chemotherapy.
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to data cutoff (assessed up to approximately 71.5 months)
    End point values
    		 Avelumab Biweekly Avelumab Weekly Chemotherapy
    Number of subjects analysed
    361
    318
    500
    Units: subjects
        Ic. BS HR <100 bpm, on TR change =<20 bpm
    206
    202
    332
        Ic. BS HR <100 bpm, on TR change >20 - =<40 bpm
    86
    66
    85
        Ic. BS HR <100 bpm, on TR change >40 bpm
    21
    12
    9
        Ic. BS HR <100 bpm, on TR change missing
    14
    5
    16
        Ic. BS HR >= 100 bpm, on TR change =<20 bpm
    31
    30
    46
        Ic. BS HR >= 100 bpm, on TR change >20 - =<40 bpm
    0
    2
    3
        Ic. BS HR >= 100 bpm, on TR change >40 bpm
    0
    0
    0
        Ic. BS HR >= 100 bpm, on TR change missing
    3
    1
    7
        Ic. BS HR missing, on TR change missing
    0
    0
    2
        Dc. BS HR <100 bpm, on TR change =<20 bpm
    267
    227
    385
        Dc. BS HR <100 bpm, on TR change >20 - =<40 bpm
    44
    52
    40
        Dc. BS HR <100 bpm, on TR change >40 bpm
    2
    1
    1
        Dc. BS HR <100 bpm, on TR change missing
    14
    5
    16
        Dc. BS HR >= 100 bpm, on TR change =<20 bpm
    14
    13
    20
        Dc. BS HR >= 100 bpm, on TR change >20 - =<40 bpm
    6
    12
    26
        Dc. BS HR >= 100 bpm, on TR change >40 bpm
    11
    7
    3
        Dc. BS HR >= 100 bpm, on TR change missing
    3
    1
    7
        Dc. BS HR missing, on TR change missing
    0
    0
    2
    No statistical analyses for this end point

    Secondary: Number of Subjects With Maximal On-Treatment Changes From Baseline in Vital Signs - Maximal Systolic Blood Pressure Increase/Decrease and Maximal Diastolic Blood Pressure Increase/Decrease

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    End point title
    		 Number of Subjects With Maximal On-Treatment Changes From Baseline in Vital Signs - Maximal Systolic Blood Pressure Increase/Decrease and Maximal Diastolic Blood Pressure Increase/Decrease
    End point description
    The number of subjects with maximal on-treatment changes from baseline (BS) in Increase (Ic.)/Decrease (Dc.) Systolic Blood Pressure (SBP) and diastolic blood pressure (DBP) (millimeter of mercury [mmHg]) were reported by using criteria: Ic./Dc. BS SBP <140 mmHg and >=140 mmHg, on maximal treatment (TR) change =<20 mmHg, >20 - =<40 mmHg, >40 mmHg and missing; Ic./Dc. BS SBP missing, on maximal treatment (TR) change missing; Ic./Dc. BS DBP <90 mmHg and >= 90 mmHg, on maximal TR change =<20 mmHg, >20 - =<40 mmHg, >40 mmHg and missing; Ic./Dc. BS DBP missing on maximal TR change missing. The Safety analysis set (Safety-AS) included all randomized subjects who were administered at least one dose of the study medication, that is (i.e.) avelumab or chemotherapy.
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to data cutoff (assessed up to approximately 71.5 months)
    End point values
    		 Avelumab Biweekly Avelumab Weekly Chemotherapy
    Number of subjects analysed
    361
    318
    500
    Units: subjects
        Ic. BS SBP <140 mmHg, on TR change =<20 mmHg
    219
    209
    278
        Ic. BS SBP <140 mmHg, on TR change >20 - =<40 mmHg
    61
    56
    104
        Ic. BS SBP <140 mmHg, on TR change >40 mmHg
    16
    16
    10
        Ic. BS SBP <140 mmHg, on TR change missing
    14
    4
    21
        Ic. BS SBP >=140 mmHg, on TR change =<20 mmHg
    41
    26
    78
        Ic. BS SBP>=140mmHg,onTR change>20-=<40mmHg
    7
    5
    5
        Ic. BS SBP >=140 mmHg, on TR change >40 mmHg
    0
    0
    1
        Ic. BS SBP > = 140 mmHg, on TR change missing
    3
    2
    2
        Ic. BS SBP missing, on TR change missing
    0
    0
    1
        Dc. BS SBP <140 mmHg, on TR change =<20 mmHg
    220
    204
    322
        Dc. BS SBP <140 mmHg, on TR change >20 - =<40 mmHg
    70
    70
    69
        Dc. BS SBP <140 mmHg, on TR change >40 mmHg
    6
    7
    1
        Dc. BS SBP <140 mmHg, on TR change missing
    14
    4
    21
        Dc. BS SBP >=140 mmHg, on TR change =<20 mmHg
    11
    6
    32
        Dc. BS SBP>=140 mmHg, on TR change>20-=<40mmHg
    25
    15
    34
        Dc. BS SBP >=140 mmHg, on TR change >40 mmHg
    12
    10
    18
        Dc. BS SBP > = 140 mmHg, on TR change missing
    3
    2
    2
        Dc. BS SBP missing, on TR change missing
    0
    0
    1
        Ic. BS DBP <90 mmHg, on TR change =<20 mmHg
    272
    260
    402
        Ic. BS DBP <90 mmHg, on TR change >20 - =<40 mmHg
    48
    37
    45
        Ic. BS DBP <90 mmHg, on TR change >40 mmHg
    0
    1
    1
        Ic. BS DBP <90 mmHg, on TR change missing
    17
    5
    23
        Ic. BS DBP missing, on TR change missing
    0
    0
    1
        Ic. BS DBP >=90 mmHg, on TR change =<20 mmHg
    24
    12
    28
        Ic. BS DBP >=90 mmHg, on TR change >20 - =<40 mmHg
    0
    1
    0
        Ic. BS DBP >=90 mmHg, on TR change >40 mmHg
    0
    1
    0
        Ic. BS DBP >=90 mmHg, on TR change missing
    0
    1
    0
        Dc. BS DBP <90 mmHg, on TR change =<20 mmHg
    279
    264
    415
        Dc. BS DBP <90 mmHg, on TR change >20 - =<40 mmHg
    38
    33
    32
        Dc. BS DBP <90 mmHg, on TR change >40 mmHg
    3
    1
    1
        Dc. BS DBP <90 mmHg, on TR change missing
    17
    5
    23
        Dc. BS DBP >=90 mmHg, on TR change =<20 mmHg
    11
    5
    18
        Dc. BS DBP >=90 mmHg,on TR change >20 - =<40 mmHg
    12
    9
    10
        Dc. BS DBP >=90 mmHg, on TR change >40 mmHg
    1
    0
    0
        Dc. BS DBP >=90 mmHg, on TR change missing
    0
    1
    0
        Dc. BS DBP missing, on TR change missing
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects With Maximal On-Treatment Changes From Baseline in Vital Signs - Maximal Respiration Rate Increase/Decrease

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    End point title
    		 Number of Subjects With Maximal On-Treatment Changes From Baseline in Vital Signs - Maximal Respiration Rate Increase/Decrease
    End point description
    The number of subjects with maximal on-treatment (TR) changes from baseline (BS) in Increase (Ic.)/Decrease (Dc.) maximal Respiration Rate (RR) were reported by using criteria: Ic./Dc. BS RR <20 breaths per minute (breaths/min), on TR change =<5 breaths/min, >5 - =<10 breaths/min, >10 breaths/min and missing. Ic./Dc. BS RR missing, on TR change missing. Ic./Dc. BS RR >=20 breaths/min, on TR change(chge) =<5 breaths/min, >5 - =<10 breaths/min, >10 breaths/min and missing. The Safety analysis set (Safety-AS) included all randomized subjects who were administered at least one dose of the study medication, that is (i.e.) avelumab or chemotherapy.
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to data cutoff (assessed up to 71.5 months)
    End point values
    		 Avelumab Biweekly Avelumab Weekly Chemotherapy
    Number of subjects analysed
    361
    318
    500
    Units: subjects
        Ic.BS RR<20breaths/min, onTRchge=<5breath/min
    221
    224
    306
        Ic.BS RR<20breaths/min, onTRchge>5-=<10breath/min
    18
    13
    26
        Ic.BS RR<20breaths/min, onTRchge>10breath/min
    1
    1
    2
        Ic.BS RR<20breaths/min, onTRchge missing
    11
    4
    14
        Ic.BS RR>=20breaths/min,onTRchge=<5breath/min
    89
    68
    124
        Ic.BS RR>=20breath/min,on TRchge>5-=<10breath/min
    5
    4
    2
        Ic.BS RR>=20breath/min,on TRchge >10breath/min
    3
    1
    0
        Ic. BS RR >=20 breath/min, on TR change missing
    7
    2
    15
        Ic. BS RR missing, on TR change missing
    6
    1
    11
        Dc.BS RR<20 breath/min,onTRchge=<5breaths/min
    232
    236
    325
        Dc.BSRR<20 breath/min,onTR chge>5-=<10breath/min
    8
    2
    8
        Dc.BSRR<20breath/min, onTRchge>10 breath/min
    0
    0
    1
        Dc.BSRR<20breaths/min,onTRchange missing
    11
    4
    14
        Dc.BSRR>=20breath/min,on TRch=<5 breath/min
    79
    58
    101
        Dc.BSRR>=20breath/min,onTRchge>5-=<10breath/min
    14
    13
    22
        Dc.BS RR>=20breath/min,onTRchge>10 breath/min
    4
    2
    3
        Dc.BS RR>=20breaths/min,onTRchange missing
    7
    2
    15
        Dc.BS RRmissing, onTR change missing
    6
    1
    11
    No statistical analyses for this end point

    Secondary: Number of Subjects With Potentially Clinically Significant Abnormalities (PCSA) in Electrocardiogram (ECG) Parameters

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    End point title
    		 Number of Subjects With Potentially Clinically Significant Abnormalities (PCSA) in Electrocardiogram (ECG) Parameters
    End point description
    ECG parameters included heart rate, PR interval, QRS interval, corrected QT interval using Bazett's formula (QTcB) and corrected QT interval using Fridericia's formula (QTcF). PCSA criteria for abnormal value of ECG parameters: any heart rate <= 50 bpm and decrease from baseline >=20 bpm , any hear rate >= 120 bpm and increase from baseline >= 20 bpm; PR interval: >= 220 milliseconds (ms) and increase from baseline >= 20 ms; QRS interval >= 120 ms; QTcF > 450 ms, > 480 ms, > 500 ms, QTcF increase from baseline > 30 ms and QTcF increase from baseline > 60 ms; QTcB > 450 ms, > 480 ms, > 500 ms, QTcB increase from baseline > 30 ms and QTcB increase from baseline > 60 ms. The Safety analysis set (Safety-AS) included all randomized subjects who were administered at least one dose of the study medication, that is (i.e.) avelumab or chemotherapy.
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to data cutoff (assessed up to approximately 71.5 months)
    End point values
    		 Avelumab Biweekly Avelumab Weekly Chemotherapy
    Number of subjects analysed
    264
    223
    399
    Units: subjects
        Heart Rate<=50bpm&decrease from baseline>=20bpm
    1
    1
    0
        Heart Rate>=120bpm&decrease from baseline>=20bpm
    10
    6
    7
        PRinterval>=220ms&increase from baseline >=20ms
    0
    5
    3
        QRS interval >= 120 ms
    18
    10
    15
        QTcF > 450 ms
    19
    13
    24
        QTcF > 480 ms
    5
    4
    11
        QTcF > 500 ms
    3
    1
    5
        QTcF increase from baseline > 30 ms
    20
    12
    39
        QTcF increase from baseline > 60 ms
    6
    1
    13
        QTcB > 450 ms
    49
    31
    70
        QTcB > 480 ms
    13
    11
    24
        QTcB > 500 ms
    6
    5
    16
        QTcB increase from baseline > 30 ms
    32
    25
    49
        QTcB increase from baseline > 60 ms
    11
    7
    19
    No statistical analyses for this end point

    Secondary: Number of Subjects With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score

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    End point title
    		 Number of Subjects With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score
    End point description
    ECOG performance status measured to assess subjects performance status on a scale of 0 to 5, where 0 = Fully active, able to carry on all pre-disease activities without restriction; 1 = Restricted in physically strenuous activity, ambulatory and able to carry out light or sedentary work; 2 = Ambulatory and capable of all selfcare but unable to carry out any work activities; 3 = Capable of only limited self-care, confined to bed/chair for more than 50 percent of waking hours; 4 = Completely disabled, cannot carry on any self-care, totally confined to bed/chair; 5 = dead. ECOG performance status was reported in terms of number of participants with baseline value vs worst post-baseline value (that is [i.e.] highest score). The Safety analysis set (Safety-AS) included all randomized subjects who were administered at least one dose of the study medication, that is (i.e.) avelumab or chemotherapy.
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to data cutoff (assessed up to approximately 71.5 months)
    End point values
    		 Avelumab Biweekly Avelumab Weekly Chemotherapy
    Number of subjects analysed
    361
    318
    500
    Units: subjects
        Baseline score0,worst post-baseline score0
    50
    35
    84
        Baseline score0,worst post-baseline score1
    56
    49
    83
        Baseline score0,worst post-baseline score2
    8
    9
    11
        Baseline score0,worst post-baseline score3
    1
    7
    4
        Baseline score0,worst post-baseline score4
    1
    0
    0
        Baseline score0,worst post-baseline score5
    0
    0
    1
        Baseline score0,worst post-baseline scoreMissing
    6
    4
    4
        Baseline score1,worst post-baselinescore0
    1
    2
    4
        Baseline score1,worst post-baseline score1
    168
    153
    233
        Baseline score1,worst post-baseline score2
    35
    32
    46
        Baseline score1,worst post-baseline score3
    16
    18
    6
        Baseline score1,worst post-baseline score4
    3
    1
    4
        Baseline score1,worst post-baseline score5
    5
    1
    3
        Baseline score1, worst post-baselinescoreMissing
    10
    6
    16
        Baseline score>=2,worst post-baseline score0
    0
    0
    0
        Baseline score>=2,worst post-baseline score1
    0
    0
    0
        Baseline score>=2,worst post-baseline score2
    0
    0
    0
        Baseline score>=2,worst post-baseline score3
    1
    0
    0
        Baseline score>=2,worst post-baseline score4
    0
    0
    0
        Baseline score>=2,worst post-baseline score5
    0
    1
    0
        Baseline score>=2,worst post-baseline scoremissing
    0
    0
    0
        Baseline score missing,worst post-baseline score0
    0
    0
    0
        Baseline score missing,worst post-baseline score1
    0
    0
    1
        Baseline score missing,worst post-baseline score2
    0
    0
    0
        Baseline score missing,worst post-baseline score3
    0
    0
    0
        Baseline score missing,worst post-baseline score4
    0
    0
    0
        Baseline score missing,worst post-baseline score5
    0
    0
    0
        Baseline score&worst post-baselinescoremissing
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With At Least One Positive Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Avelumab

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    End point title
    		 Number of Subjects With At Least One Positive Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Avelumab [23]
    End point description
    Serum samples were analyzed by a validated electrochemiluminesce immunoassay to detect the presence of antidrug antibodies (ADA). Samples that screened positive were subsequently tested in a confirmatory assay were tested for neutralizing antibodies (nAb). Number of subjects with ADA or nAb positive results for Avelumab were reported. The Safety analysis set (Safety-AS) included all randomized subjects who were administered at least one dose of the study medication, that is (i.e.) avelumab or chemotherapy.
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to data cutoff (assessed up to approximately 71.5 months)
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint only compares the data of Avelumab and Chemotherapy groups
    End point values
    		 Avelumab Biweekly Avelumab Weekly
    Number of subjects analysed
    360
    318
    Units: subjects
        ADAs to Avelumab
    66
    38
        NAbs to Avelumab
    43
    18
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Time from date of randomization up to data cutoff (assessed up to approximately 71.5 months)
    Adverse event reporting additional description
    Only subjects who received study medication were included in the analysis of adverse events. All randomized subjects were included in the analysis of all-cause mortality.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Avelumab Biweekly
    Reporting group description
    		 Subjects received Avelumab at a dose of 10 milligrams per kilogram (mg/kg) as a 1-hour (-10/+20 minutes) intravenous (IV) infusion once every 2 weeks until disease progression or unacceptable toxicities.

    Reporting group title
    Chemotherapy
    Reporting group description
    		 Subjects with tumor of nonsquamous histology received Pemetrexed in combination with Cisplatin (75 mg/m^2) administered on Day 1 of each cycle or pemetrexed (500 mg/m^2) in combination with carboplatin AUC 6 milligrams per milliliter minutes administered on Day 1 of each cycle. Subjects who were assigned pemetrexed could continue to receive pemetrexed as a maintenance therapy after 4 cycles of platinum-based chemotherapy if their disease had not progressed.Subjects with tumor of squamous histology received Paclitaxel (200 mg/m^2) plus carboplatin (AUC 6 mg/mL * min administered on Day 1 of each cycle) or Gemcitabine (1250 mg/m^2 administered on Day 1 and Day 8 of each cycle) plus cisplatin (75 mg/m^2) or Gemcitabine (1000 mg/m^2 administered on Day 1 and Day 8 of each cycle) plus carboplatin (AUC 5 mg/mL * min) in 3-week cycles up to a maximum of 6 cycles of IV injection or until disease progression or unacceptable toxicities.

    Reporting group title
    Avelumab Weekly
    Reporting group description
    		 Subjects received Avelumab at a dose of 10 mg/kg as a 1-hour (-10/+20 minutes) IV infusion every week for 12 consecutive weeks, followed by Avelumab at a dose of 10 mg/kg once every 2 weeks until disease progression or unacceptable toxicities.

    Serious adverse events
    		 Avelumab Biweekly Chemotherapy Avelumab Weekly
    Total subjects affected by serious adverse events
         subjects affected / exposed
    181 / 361 (50.14%)
    195 / 500 (39.00%)
    143 / 318 (44.97%)
         number of deaths (all causes)
    279
    405
    237
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lymphangiosis carcinomatosa
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Laryngeal cancer
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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 central nervous system
         subjects affected / exposed
    2 / 361 (0.55%)
    2 / 500 (0.40%)
    2 / 318 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    Cancer pain
         subjects affected / exposed
    3 / 361 (0.83%)
    3 / 500 (0.60%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Metastases to bone
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of the oral cavity
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    2 / 318 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumor compression
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seborrhoeic keratosis
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Metastases to meninges
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Metastases to lymph nodes
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Malignant ascites
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Duodenal neoplasm
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Tumor hemorrhage
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Tumor pain
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Superior vena cava syndrome
         subjects affected / exposed
    3 / 361 (0.83%)
    0 / 500 (0.00%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Shock hemorrhagic
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 500 (0.20%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    Peripheral ischemia
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 500 (0.20%)
    2 / 318 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Inferior vena caval occlusion
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Arterial thrombosis
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Venous thrombosis limb
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Orthostatic hypotension
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 361 (0.28%)
    8 / 500 (1.60%)
    3 / 318 (0.94%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 8
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    33 / 361 (9.14%)
    22 / 500 (4.40%)
    18 / 318 (5.66%)
         occurrences causally related to treatment / all
    0 / 33
    0 / 22
    1 / 18
         deaths causally related to treatment / all
    0 / 26
    0 / 21
    0 / 17
    Fatigue
         subjects affected / exposed
    4 / 361 (1.11%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    2 / 361 (0.55%)
    5 / 500 (1.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 361 (0.55%)
    2 / 500 (0.40%)
    2 / 318 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
    Sudden death
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 500 (0.20%)
    3 / 318 (0.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
    General physical health deterioration
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    3 / 318 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Mucosal inflammation
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 361 (0.00%)
    2 / 500 (0.40%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Peripheral swelling
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    3 / 361 (0.83%)
    0 / 500 (0.00%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Anaphylactic shock
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Anaphylactic reaction
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Contrast media allergy
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    3 / 318 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    11 / 361 (3.05%)
    7 / 500 (1.40%)
    3 / 318 (0.94%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnea
         subjects affected / exposed
    9 / 361 (2.49%)
    8 / 500 (1.60%)
    5 / 318 (1.57%)
         occurrences causally related to treatment / all
    0 / 9
    1 / 8
    1 / 5
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    1 / 1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    5 / 361 (1.39%)
    3 / 500 (0.60%)
    6 / 318 (1.89%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    6 / 361 (1.66%)
    6 / 500 (1.20%)
    5 / 318 (1.57%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    8 / 361 (2.22%)
    0 / 500 (0.00%)
    5 / 318 (1.57%)
         occurrences causally related to treatment / all
    8 / 8
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    5 / 361 (1.39%)
    4 / 500 (0.80%)
    2 / 318 (0.63%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 4
    0 / 3
    0 / 2
    Pulmonary haemorrhage
         subjects affected / exposed
    2 / 361 (0.55%)
    2 / 500 (0.40%)
    4 / 318 (1.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    Haemoptysis
         subjects affected / exposed
    3 / 361 (0.83%)
    3 / 500 (0.60%)
    4 / 318 (1.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 361 (0.55%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Stridor
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Pleurisy
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Pneumothorax
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 500 (0.20%)
    2 / 318 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    Pulmonary congestion
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Dysphonia
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Dyspnoea exertional
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         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 oedema
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Haemothorax
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Hypoxia
         subjects affected / exposed
    0 / 361 (0.00%)
    2 / 500 (0.40%)
    2 / 318 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Interstitial lung disease
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    2 / 318 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Epistaxis
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory depression
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    2 / 361 (0.55%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Anxiety
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Breath holding
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Investigations
    Platelet count decreased
         subjects affected / exposed
    0 / 361 (0.00%)
    7 / 500 (1.40%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    7 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 361 (0.83%)
    0 / 500 (0.00%)
    2 / 318 (0.63%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood sodium decreased
         subjects affected / exposed
    2 / 361 (0.55%)
    0 / 500 (0.00%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    White blood cell count decreased
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 361 (0.00%)
    2 / 500 (0.40%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Transaminases increased
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Troponin T increased
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    11 / 361 (3.05%)
    0 / 500 (0.00%)
    7 / 318 (2.20%)
         occurrences causally related to treatment / all
    11 / 11
    0 / 0
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    2 / 318 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    2 / 361 (0.55%)
    0 / 500 (0.00%)
    0 / 318 (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
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural discomfort
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Rib fracture
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord injury
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Toxicity to various agents
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Wrist fracture
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Femoral neck fracture
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Fibula fracture
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radiation necrosis
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         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 compression fracture
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Soft tissue injury
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Congenital, familial and genetic disorders
    Aplasia
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    2 / 361 (0.55%)
    3 / 500 (0.60%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
    Cardiac failure
         subjects affected / exposed
    2 / 361 (0.55%)
    4 / 500 (0.80%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Myocarditis
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 500 (0.20%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Cardiac tamponade
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 500 (0.20%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Atrial flutter
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Pericardial effusion
         subjects affected / exposed
    2 / 361 (0.55%)
    1 / 500 (0.20%)
    3 / 318 (0.94%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 500 (0.20%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricle rupture
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Angina pectoris
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Atrial fibrillation
         subjects affected / exposed
    0 / 361 (0.00%)
    4 / 500 (0.80%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiac hypertrophy
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    0 / 361 (0.00%)
    2 / 500 (0.40%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Pericarditis
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Right ventricular failure
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Tachycardia
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Toxic cardiomyopathy
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    4 / 361 (1.11%)
    1 / 500 (0.20%)
    3 / 318 (0.94%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    Epilepsy
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Brain oedema
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 500 (0.20%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Coma
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Dysarthria
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Brachial plexopathy
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Ischaemic stroke
         subjects affected / exposed
    1 / 361 (0.28%)
    2 / 500 (0.40%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Cognitive disorder
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Radiculopathy
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Carotid artery stenosis
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Myasthenic syndrome
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Lethargy
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 361 (0.00%)
    13 / 500 (2.60%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    12 / 13
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    Anaemia
         subjects affected / exposed
    4 / 361 (1.11%)
    19 / 500 (3.80%)
    2 / 318 (0.63%)
         occurrences causally related to treatment / all
    1 / 4
    19 / 19
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 361 (0.00%)
    6 / 500 (1.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 361 (0.00%)
    7 / 500 (1.40%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    7 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 361 (0.00%)
    5 / 500 (1.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Haematotoxicity
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myelosuppression
         subjects affected / exposed
    0 / 361 (0.00%)
    2 / 500 (0.40%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 361 (0.55%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Macular fibrosis
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Swelling of eyelid
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    4 / 361 (1.11%)
    0 / 500 (0.00%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    4 / 361 (1.11%)
    3 / 500 (0.60%)
    4 / 318 (1.26%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 3
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 361 (0.55%)
    9 / 500 (1.80%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Dysphagia
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 361 (0.55%)
    2 / 500 (0.40%)
    2 / 318 (0.63%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 361 (0.28%)
    2 / 500 (0.40%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 361 (0.00%)
    3 / 500 (0.60%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 361 (0.00%)
    2 / 500 (0.40%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autoimmune colitis
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Mechanical ileus
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestinal ulcer
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Ileus
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inflammatory bowel disease
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         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
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         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 obstruction
         subjects affected / exposed
    0 / 361 (0.00%)
    2 / 500 (0.40%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Large intestine polyp
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intussusception
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Small intestinal obstruction
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    3 / 361 (0.83%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biliary obstruction
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis toxic
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Hepatic cytolysis
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 361 (0.55%)
    0 / 500 (0.00%)
    0 / 318 (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
    Urticaria
         subjects affected / exposed
    0 / 361 (0.00%)
    2 / 500 (0.40%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angioedema
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Rash maculo-papular
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Rash macular
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Dermatitis exfoliative generalized
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Lichenoid keratosis
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 361 (0.00%)
    2 / 500 (0.40%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Nephropathy
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephritis
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Acute kidney injury
         subjects affected / exposed
    2 / 361 (0.55%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypopituitarism
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Thyroiditis
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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 hypothyroidism
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Hyperthyroidism
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Goiter
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Hypothyroidism
         subjects affected / exposed
    2 / 361 (0.55%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Groin pain
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    1 / 361 (0.28%)
    2 / 500 (0.40%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    2 / 318 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Crystal arthropathy
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 500 (0.20%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle twitching
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    28 / 361 (7.76%)
    28 / 500 (5.60%)
    13 / 318 (4.09%)
         occurrences causally related to treatment / all
    2 / 28
    8 / 28
    0 / 13
         deaths causally related to treatment / all
    1 / 7
    1 / 6
    0 / 1
    Respiratory tract infection
         subjects affected / exposed
    4 / 361 (1.11%)
    3 / 500 (0.60%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    1 / 4
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 361 (1.11%)
    4 / 500 (0.80%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 4
    3 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 361 (0.55%)
    1 / 500 (0.20%)
    5 / 318 (1.57%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 361 (0.00%)
    6 / 500 (1.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 5
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 361 (0.83%)
    2 / 500 (0.40%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    2 / 361 (0.55%)
    0 / 500 (0.00%)
    0 / 318 (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
    Amoebiasis
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    Oral candidiasis
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 361 (0.28%)
    2 / 500 (0.40%)
    2 / 318 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    COVID-19
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    2 / 318 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 500 (0.20%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Bacterial sepsis
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 361 (0.00%)
    3 / 500 (0.60%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Bacteraemia
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine infection
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nosocomial infection
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Oral fungal infection
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Infection
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Diverticulitis
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Enterobacter infection
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Erysipelas
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Peritonitis
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pseudomembranous colitis
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 361 (0.00%)
    2 / 500 (0.40%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 361 (0.00%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic candida
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Tuberculosis
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis syndrome
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 361 (0.55%)
    2 / 500 (0.40%)
    6 / 318 (1.89%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 2
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 500 (0.20%)
    2 / 318 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (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
    2 / 361 (0.55%)
    0 / 500 (0.00%)
    0 / 318 (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
    Hypercalcaemia
         subjects affected / exposed
    2 / 361 (0.55%)
    0 / 500 (0.00%)
    3 / 318 (0.94%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 361 (0.55%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 361 (0.00%)
    2 / 500 (0.40%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Fluid overload
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 500 (0.20%)
    0 / 318 (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
    Malnutrition
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 361 (0.00%)
    2 / 500 (0.40%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 361 (0.00%)
    2 / 500 (0.40%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Avelumab Biweekly Chemotherapy Avelumab Weekly
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    331 / 361 (91.69%)
    474 / 500 (94.80%)
    298 / 318 (93.71%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumor pain
         subjects affected / exposed
    2 / 361 (0.55%)
    0 / 500 (0.00%)
    5 / 318 (1.57%)
         occurrences all number
    2
    0
    5
    Vascular disorders
    Hot flush
         subjects affected / exposed
    1 / 361 (0.28%)
    2 / 500 (0.40%)
    1 / 318 (0.31%)
         occurrences all number
    1
    2
    1
    Hypotension
         subjects affected / exposed
    11 / 361 (3.05%)
    8 / 500 (1.60%)
    1 / 318 (0.31%)
         occurrences all number
    11
    8
    1
    Hypertension
         subjects affected / exposed
    22 / 361 (6.09%)
    20 / 500 (4.00%)
    13 / 318 (4.09%)
         occurrences all number
    22
    20
    13
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    15 / 361 (4.16%)
    16 / 500 (3.20%)
    12 / 318 (3.77%)
         occurrences all number
    15
    16
    12
    Fatigue
         subjects affected / exposed
    58 / 361 (16.07%)
    99 / 500 (19.80%)
    56 / 318 (17.61%)
         occurrences all number
    58
    99
    56
    Pyrexia
         subjects affected / exposed
    51 / 361 (14.13%)
    32 / 500 (6.40%)
    50 / 318 (15.72%)
         occurrences all number
    51
    32
    50
    Chills
         subjects affected / exposed
    28 / 361 (7.76%)
    2 / 500 (0.40%)
    20 / 318 (6.29%)
         occurrences all number
    28
    2
    20
    Asthenia
         subjects affected / exposed
    58 / 361 (16.07%)
    74 / 500 (14.80%)
    54 / 318 (16.98%)
         occurrences all number
    58
    74
    54
    Oedema peripheral
         subjects affected / exposed
    14 / 361 (3.88%)
    48 / 500 (9.60%)
    9 / 318 (2.83%)
         occurrences all number
    14
    48
    9
    Chest pain
         subjects affected / exposed
    13 / 361 (3.60%)
    10 / 500 (2.00%)
    15 / 318 (4.72%)
         occurrences all number
    13
    10
    15
    Influenza like illness
         subjects affected / exposed
    10 / 361 (2.77%)
    5 / 500 (1.00%)
    1 / 318 (0.31%)
         occurrences all number
    10
    5
    1
    Immune system disorders
    Contrast media allergy
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    50 / 361 (13.85%)
    49 / 500 (9.80%)
    50 / 318 (15.72%)
         occurrences all number
    50
    49
    50
    Hypoxia
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 500 (0.20%)
    2 / 318 (0.63%)
         occurrences all number
    1
    1
    2
    Rhinitis allergic
         subjects affected / exposed
    2 / 361 (0.55%)
    5 / 500 (1.00%)
    1 / 318 (0.31%)
         occurrences all number
    2
    5
    1
    Pleural effusion
         subjects affected / exposed
    7 / 361 (1.94%)
    11 / 500 (2.20%)
    6 / 318 (1.89%)
         occurrences all number
    7
    11
    6
    Productive cough
         subjects affected / exposed
    14 / 361 (3.88%)
    14 / 500 (2.80%)
    8 / 318 (2.52%)
         occurrences all number
    14
    14
    8
    Haemoptysis
         subjects affected / exposed
    25 / 361 (6.93%)
    23 / 500 (4.60%)
    23 / 318 (7.23%)
         occurrences all number
    25
    23
    23
    Cough
         subjects affected / exposed
    48 / 361 (13.30%)
    45 / 500 (9.00%)
    41 / 318 (12.89%)
         occurrences all number
    48
    45
    41
    Psychiatric disorders
    Depression
         subjects affected / exposed
    6 / 361 (1.66%)
    8 / 500 (1.60%)
    2 / 318 (0.63%)
         occurrences all number
    6
    8
    2
    Insomnia
         subjects affected / exposed
    29 / 361 (8.03%)
    33 / 500 (6.60%)
    13 / 318 (4.09%)
         occurrences all number
    29
    33
    13
    Confusional state
         subjects affected / exposed
    2 / 361 (0.55%)
    2 / 500 (0.40%)
    2 / 318 (0.63%)
         occurrences all number
    2
    2
    2
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    24 / 361 (6.65%)
    30 / 500 (6.00%)
    22 / 318 (6.92%)
         occurrences all number
    24
    30
    22
    Alanine aminotransferase increased
         subjects affected / exposed
    31 / 361 (8.59%)
    37 / 500 (7.40%)
    37 / 318 (11.64%)
         occurrences all number
    31
    37
    37
    Weight decreased
         subjects affected / exposed
    37 / 361 (10.25%)
    41 / 500 (8.20%)
    32 / 318 (10.06%)
         occurrences all number
    37
    41
    32
    Lipase increased
         subjects affected / exposed
    20 / 361 (5.54%)
    11 / 500 (2.20%)
    17 / 318 (5.35%)
         occurrences all number
    20
    11
    17
    Weight increased
         subjects affected / exposed
    15 / 361 (4.16%)
    8 / 500 (1.60%)
    12 / 318 (3.77%)
         occurrences all number
    15
    8
    12
    Amylase increased
         subjects affected / exposed
    15 / 361 (4.16%)
    17 / 500 (3.40%)
    17 / 318 (5.35%)
         occurrences all number
    15
    17
    17
    Blood creatinine increased
         subjects affected / exposed
    16 / 361 (4.43%)
    30 / 500 (6.00%)
    12 / 318 (3.77%)
         occurrences all number
    16
    30
    12
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    19 / 361 (5.26%)
    22 / 500 (4.40%)
    20 / 318 (6.29%)
         occurrences all number
    19
    22
    20
    Blood creatine phosphokinase increased
         subjects affected / exposed
    8 / 361 (2.22%)
    4 / 500 (0.80%)
    10 / 318 (3.14%)
         occurrences all number
    8
    1
    10
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    5 / 361 (1.39%)
    4 / 500 (0.80%)
    3 / 318 (0.94%)
         occurrences all number
    5
    4
    3
    Neutrophil count decreased
         subjects affected / exposed
    2 / 361 (0.55%)
    62 / 500 (12.40%)
    2 / 318 (0.63%)
         occurrences all number
    2
    62
    2
    Blood calcium decreased
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences all number
    1
    1
    0
    C-reactive protein increased
         subjects affected / exposed
    1 / 361 (0.28%)
    4 / 500 (0.80%)
    6 / 318 (1.89%)
         occurrences all number
    1
    4
    6
    White blood cell count decreased
         subjects affected / exposed
    1 / 361 (0.28%)
    39 / 500 (7.80%)
    1 / 318 (0.31%)
         occurrences all number
    1
    39
    1
    White blood cell count increased
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 500 (0.20%)
    2 / 318 (0.63%)
         occurrences all number
    1
    1
    2
    Platelet count decreased
         subjects affected / exposed
    6 / 361 (1.66%)
    43 / 500 (8.60%)
    2 / 318 (0.63%)
         occurrences all number
    6
    43
    2
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    52 / 361 (14.40%)
    2 / 500 (0.40%)
    28 / 318 (8.81%)
         occurrences all number
    52
    2
    28
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    10 / 361 (2.77%)
    3 / 500 (0.60%)
    4 / 318 (1.26%)
         occurrences all number
    10
    3
    4
    Tachycardia
         subjects affected / exposed
    5 / 361 (1.39%)
    7 / 500 (1.40%)
    9 / 318 (2.83%)
         occurrences all number
    5
    7
    9
    Nervous system disorders
    Headache
         subjects affected / exposed
    24 / 361 (6.65%)
    24 / 500 (4.80%)
    21 / 318 (6.60%)
         occurrences all number
    24
    24
    21
    Paraesthesia
         subjects affected / exposed
    5 / 361 (1.39%)
    14 / 500 (2.80%)
    5 / 318 (1.57%)
         occurrences all number
    5
    14
    5
    Hypoaesthesia
         subjects affected / exposed
    5 / 361 (1.39%)
    5 / 500 (1.00%)
    2 / 318 (0.63%)
         occurrences all number
    5
    5
    2
    Dizziness
         subjects affected / exposed
    20 / 361 (5.54%)
    29 / 500 (5.80%)
    12 / 318 (3.77%)
         occurrences all number
    20
    29
    12
    Taste disorder
         subjects affected / exposed
    0 / 361 (0.00%)
    3 / 500 (0.60%)
    0 / 318 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    3 / 318 (0.94%)
         occurrences all number
    1
    0
    3
    Thrombocytopenia
         subjects affected / exposed
    5 / 361 (1.39%)
    60 / 500 (12.00%)
    8 / 318 (2.52%)
         occurrences all number
    5
    60
    8
    Anaemia
         subjects affected / exposed
    37 / 361 (10.25%)
    232 / 500 (46.40%)
    57 / 318 (17.92%)
         occurrences all number
    37
    232
    57
    Leukopenia
         subjects affected / exposed
    6 / 361 (1.66%)
    42 / 500 (8.40%)
    2 / 318 (0.63%)
         occurrences all number
    6
    42
    2
    Neutropenia
         subjects affected / exposed
    6 / 361 (1.66%)
    113 / 500 (22.60%)
    3 / 318 (0.94%)
         occurrences all number
    6
    113
    3
    Eye disorders
    Vitreous floaters
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 500 (0.00%)
    0 / 318 (0.00%)
         occurrences all number
    1
    0
    0
    Vision blurred
         subjects affected / exposed
    3 / 361 (0.83%)
    2 / 500 (0.40%)
    0 / 318 (0.00%)
         occurrences all number
    3
    2
    0
    Gastrointestinal disorders
    Gastrooesophageal reflux disease
         subjects affected / exposed
    4 / 361 (1.11%)
    7 / 500 (1.40%)
    1 / 318 (0.31%)
         occurrences all number
    4
    7
    1
    Constipation
         subjects affected / exposed
    59 / 361 (16.34%)
    87 / 500 (17.40%)
    21 / 318 (6.60%)
         occurrences all number
    59
    87
    21
    Nausea
         subjects affected / exposed
    41 / 361 (11.36%)
    164 / 500 (32.80%)
    33 / 318 (10.38%)
         occurrences all number
    41
    164
    33
    Dysphagia
         subjects affected / exposed
    5 / 361 (1.39%)
    4 / 500 (0.80%)
    6 / 318 (1.89%)
         occurrences all number
    5
    4
    6
    Dyspepsia
         subjects affected / exposed
    12 / 361 (3.32%)
    16 / 500 (3.20%)
    2 / 318 (0.63%)
         occurrences all number
    12
    16
    2
    Vomiting
         subjects affected / exposed
    19 / 361 (5.26%)
    73 / 500 (14.60%)
    24 / 318 (7.55%)
         occurrences all number
    19
    73
    24
    Diarrhoea
         subjects affected / exposed
    37 / 361 (10.25%)
    47 / 500 (9.40%)
    39 / 318 (12.26%)
         occurrences all number
    37
    47
    39
    Haemorrhoids
         subjects affected / exposed
    2 / 361 (0.55%)
    4 / 500 (0.80%)
    3 / 318 (0.94%)
         occurrences all number
    2
    4
    3
    Odynophagia
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 500 (0.20%)
    3 / 318 (0.94%)
         occurrences all number
    1
    1
    3
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    30 / 361 (8.31%)
    36 / 500 (7.20%)
    27 / 318 (8.49%)
         occurrences all number
    30
    36
    27
    Pruritus
         subjects affected / exposed
    26 / 361 (7.20%)
    15 / 500 (3.00%)
    28 / 318 (8.81%)
         occurrences all number
    26
    15
    28
    Dry skin
         subjects affected / exposed
    19 / 361 (5.26%)
    4 / 500 (0.80%)
    12 / 318 (3.77%)
         occurrences all number
    19
    4
    12
    Alopecia
         subjects affected / exposed
    4 / 361 (1.11%)
    30 / 500 (6.00%)
    3 / 318 (0.94%)
         occurrences all number
    4
    30
    3
    Rash maculo-papular
         subjects affected / exposed
    4 / 361 (1.11%)
    1 / 500 (0.20%)
    3 / 318 (0.94%)
         occurrences all number
    4
    1
    3
    Night sweats
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 500 (0.20%)
    0 / 318 (0.00%)
         occurrences all number
    1
    1
    0
    Photosensitivity reaction
         subjects affected / exposed
    0 / 361 (0.00%)
    3 / 500 (0.60%)
    0 / 318 (0.00%)
         occurrences all number
    0
    3
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    24 / 361 (6.65%)
    8 / 500 (1.60%)
    21 / 318 (6.60%)
         occurrences all number
    24
    8
    21
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    15 / 361 (4.16%)
    11 / 500 (2.20%)
    15 / 318 (4.72%)
         occurrences all number
    15
    11
    15
    Arthralgia
         subjects affected / exposed
    50 / 361 (13.85%)
    31 / 500 (6.20%)
    31 / 318 (9.75%)
         occurrences all number
    50
    31
    31
    Pain in extremity
         subjects affected / exposed
    15 / 361 (4.16%)
    20 / 500 (4.00%)
    12 / 318 (3.77%)
         occurrences all number
    15
    20
    12
    Musculoskeletal chest pain
         subjects affected / exposed
    14 / 361 (3.88%)
    15 / 500 (3.00%)
    12 / 318 (3.77%)
         occurrences all number
    14
    15
    12
    Bone pain
         subjects affected / exposed
    10 / 361 (2.77%)
    9 / 500 (1.80%)
    6 / 318 (1.89%)
         occurrences all number
    10
    9
    6
    Flank pain
         subjects affected / exposed
    6 / 361 (1.66%)
    0 / 500 (0.00%)
    0 / 318 (0.00%)
         occurrences all number
    6
    0
    0
    Neck pain
         subjects affected / exposed
    4 / 361 (1.11%)
    12 / 500 (2.40%)
    5 / 318 (1.57%)
         occurrences all number
    4
    12
    5
    Back pain
         subjects affected / exposed
    39 / 361 (10.80%)
    34 / 500 (6.80%)
    29 / 318 (9.12%)
         occurrences all number
    39
    34
    29
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    25 / 361 (6.93%)
    21 / 500 (4.20%)
    21 / 318 (6.60%)
         occurrences all number
    25
    21
    21
    Nasopharyngitis
         subjects affected / exposed
    23 / 361 (6.37%)
    16 / 500 (3.20%)
    11 / 318 (3.46%)
         occurrences all number
    23
    16
    11
    Pneumonia
         subjects affected / exposed
    23 / 361 (6.37%)
    28 / 500 (5.60%)
    24 / 318 (7.55%)
         occurrences all number
    23
    28
    24
    Respiratory tract infection
         subjects affected / exposed
    13 / 361 (3.60%)
    12 / 500 (2.40%)
    6 / 318 (1.89%)
         occurrences all number
    13
    12
    6
    Bronchitis
         subjects affected / exposed
    12 / 361 (3.32%)
    12 / 500 (2.40%)
    9 / 318 (2.83%)
         occurrences all number
    12
    12
    9
    Urinary tract infection
         subjects affected / exposed
    12 / 361 (3.32%)
    17 / 500 (3.40%)
    14 / 318 (4.40%)
         occurrences all number
    12
    17
    14
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    65 / 361 (18.01%)
    90 / 500 (18.00%)
    61 / 318 (19.18%)
         occurrences all number
    65
    90
    61
    Hypoalbuminaemia
         subjects affected / exposed
    14 / 361 (3.88%)
    12 / 500 (2.40%)
    20 / 318 (6.29%)
         occurrences all number
    14
    12
    20
    Hyponatraemia
         subjects affected / exposed
    12 / 361 (3.32%)
    15 / 500 (3.00%)
    16 / 318 (5.03%)
         occurrences all number
    12
    15
    16
    Hyperglycaemia
         subjects affected / exposed
    9 / 361 (2.49%)
    21 / 500 (4.20%)
    10 / 318 (3.14%)
         occurrences all number
    9
    21
    10
    Hypomagnesaemia
         subjects affected / exposed
    5 / 361 (1.39%)
    26 / 500 (5.20%)
    5 / 318 (1.57%)
         occurrences all number
    5
    26
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jan 2019
    Assumptions on PFS drop-out rate were revised.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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