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    Clinical Trial Results:
    A Phase III Open-Label, Multicenter Trial of Avelumab (MSB0010718C) Versus Docetaxel in Subjects With Non-Small Cell Lung Cancer That Has Progressed After a Platinum-Containing Doublet

    Summary
    EudraCT number
    2014-005060-15
    Trial protocol
    SK   DE   GB   BE   HU   DK   AT   ES   NL   FR   CZ   PL   HR   LV  
    Global end of trial date
    03 Dec 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    05 Aug 2020
    First version publication date
    05 Aug 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EMR100070-004
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02395172
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Merck KGaA, Darmstadt, Germany
    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
    03 Dec 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Dec 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main purpose of this study was to demonstrate superiority with regards to overall survival of Avelumab versus Docetaxel in subjects with programmed death ligand 1 (PD-L1) positive, non-small cell lung cancer (NSCLC) after failure of a platinum-based doublet.
    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
    24 Mar 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    South Africa: 3
    Country: Number of subjects enrolled
    Spain: 36
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    Taiwan: 12
    Country: Number of subjects enrolled
    Turkey: 100
    Country: Number of subjects enrolled
    United Kingdom: 31
    Country: Number of subjects enrolled
    United States: 18
    Country: Number of subjects enrolled
    Argentina: 23
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    Belgium: 26
    Country: Number of subjects enrolled
    Brazil: 26
    Country: Number of subjects enrolled
    Bulgaria: 18
    Country: Number of subjects enrolled
    Chile: 22
    Country: Number of subjects enrolled
    Colombia: 6
    Country: Number of subjects enrolled
    Croatia: 7
    Country: Number of subjects enrolled
    Czech Republic: 8
    Country: Number of subjects enrolled
    Denmark: 9
    Country: Number of subjects enrolled
    Estonia: 1
    Country: Number of subjects enrolled
    France: 38
    Country: Number of subjects enrolled
    Hungary: 16
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Italy: 57
    Country: Number of subjects enrolled
    Japan: 101
    Country: Number of subjects enrolled
    Korea, Republic of: 100
    Country: Number of subjects enrolled
    Latvia: 1
    Country: Number of subjects enrolled
    Mexico: 10
    Country: Number of subjects enrolled
    Peru: 13
    Country: Number of subjects enrolled
    Poland: 67
    Country: Number of subjects enrolled
    Romania: 20
    Country: Number of subjects enrolled
    Russian Federation: 16
    Worldwide total number of subjects
    792
    EEA total number of subjects
    335
    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)
    426
    From 65 to 84 years
    361
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    First subject signed informed consent: 24 Mar 2015, Clinical data cut-off: 04 March 2019.

    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
    Arm description
    Subjects received 10 milligram per kilogram (mg/kg) of avelumab as a 1-hour intravenous infusion once every 2 weeks until confirmed disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or Investigational Medicinal Product (IMP) as defined in the study protocol was fulfilled.
    Arm type
    Experimental

    Investigational medicinal product name
    Avelumab
    Investigational medicinal product code
    MSB0010718C
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Subjects received intravenous infusion of avelumab at a dose of 10 mg/kg over the duration of 1 hour once every 2 weeks until confirmed disease progression.

    Arm title
    Docetaxel
    Arm description
    Subjects received 75 mg per square meter (m^2) (per label) of docetaxel by intravenous infusion once every 3 weeks until confirmed disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or Investigational Medicinal Product (IMP) as defined in the study protocol was fulfilled.
    Arm type
    Experimental

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Subjects received 75 mg per square meter (m^2) (per label) of docetaxel by intravenous infusion once every 3 weeks until confirmed disease progression.

    Number of subjects in period 1
    Avelumab Docetaxel
    Started
    396
    396
    Treated
    393
    365
    Completed
    393
    365
    Not completed
    3
    31
         Subjects randomized but not treated
    3
    31

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Avelumab
    Reporting group description
    Subjects received 10 milligram per kilogram (mg/kg) of avelumab as a 1-hour intravenous infusion once every 2 weeks until confirmed disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or Investigational Medicinal Product (IMP) as defined in the study protocol was fulfilled.

    Reporting group title
    Docetaxel
    Reporting group description
    Subjects received 75 mg per square meter (m^2) (per label) of docetaxel by intravenous infusion once every 3 weeks until confirmed disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or Investigational Medicinal Product (IMP) as defined in the study protocol was fulfilled.

    Reporting group values
    Avelumab Docetaxel Total
    Number of subjects
    396 396 792
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    62.8 ± 9.99 62.5 ± 9.65 -
    Sex: Female, Male
    Units: Subjects
        Female
    127 123 250
        Male
    269 273 542
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    0 1 1
        Asian
    102 114 216
        Native Hawaiian or Other Pacific Islander
    1 0 1
        Black or African American
    5 1 6
        White
    273 262 535
        Not collected at the site
    14 14 28
        Other
    1 4 5
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    59 42 101
        Not Hispanic or Latino
    297 307 604
        Unknown or Not Reported
    40 47 87

    End points

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    End points reporting groups
    Reporting group title
    Avelumab
    Reporting group description
    Subjects received 10 milligram per kilogram (mg/kg) of avelumab as a 1-hour intravenous infusion once every 2 weeks until confirmed disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or Investigational Medicinal Product (IMP) as defined in the study protocol was fulfilled.

    Reporting group title
    Docetaxel
    Reporting group description
    Subjects received 75 mg per square meter (m^2) (per label) of docetaxel by intravenous infusion once every 3 weeks until confirmed disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or Investigational Medicinal Product (IMP) as defined in the study protocol was fulfilled.

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

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    End point title
    Overall Survival (OS) Time in Programmed Death Ligand 1 (PD-L1) + Full Analysis Set Population (FAS)
    End point description
    The OS time was defined as the time from randomization to the date of 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 subjects was known to be alive before the data cutoff date. OS was measured using Kaplan-Meier (KM) estimates. PD-L1+ FAS included all PD-L1+ tumor subjects who were randomly assigned to trial treatment. The PD-L1+ subjects were with greater than or equal to (>=) 1 percentage (%) of tumor cells with >=1+ positive membrane staining intensity for PD-L1 protein.
    End point type
    Primary
    End point timeframe
    Time from date of randomization up to 1420 days
    End point values
    Avelumab Docetaxel
    Number of subjects analysed
    264
    265
    Units: months
        median (confidence interval 95%)
    11.4 (9.4 to 13.8)
    10.6 (8.5 to 12.9)
    Statistical analysis title
    Statistical Analysis: OS in PD-L1 + FAS
    Comparison groups
    Avelumab v Docetaxel
    Number of subjects included in analysis
    529
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0721
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.71
         upper limit
    1.05

    Secondary: Overall Survival (OS) Time in Full Analysis Set Population

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    End point title
    Overall Survival (OS) Time in Full Analysis Set Population
    End point description
    The OS time was defined as the time from randomization to the date of 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 subjects was known to be alive before the data cutoff date. OS was measured using Kaplan-Meier (KM) estimates. Full analysis set (FAS) included all subjects who were randomized to study.
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to 1420 days
    End point values
    Avelumab Docetaxel
    Number of subjects analysed
    396
    396
    Units: months
        median (confidence interval 95%)
    10.6 (9.2 to 12.3)
    9.9 (8.1 to 11.9)
    Statistical analysis title
    Statistical Analysis: OS in FAS
    Comparison groups
    Avelumab v Docetaxel
    Number of subjects included in analysis
    792
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.77
         upper limit
    1.05

    Secondary: Progression-Free Survival (PFS) Time in PD-L1+ Full Analysis Set Population

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    End point title
    Progression-Free Survival (PFS) Time in PD-L1+ Full Analysis Set Population
    End point description
    PFS was 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. PFS was assessed as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) as adjudicated by independent endpoint review committee (IERC). PD was defined as at least a 20 percent (%) increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. PFS was measured using Kaplan-Meier (KM) estimates. PD-L1+ FAS included all PD-L1+ tumor subjects who were randomly assigned to trial treatment. PD-L1+ FAS included all PD-L1+ tumor subjects who were randomly assigned to trial treatment. The PD-L1+ subjects were with >= 1 percentage of tumor cells with >=1+ positive membrane staining intensity for PD-L1 protein.
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to 907 days
    End point values
    Avelumab Docetaxel
    Number of subjects analysed
    264
    265
    Units: months
        median (confidence interval 95%)
    3.4 (2.7 to 4.9)
    4.1 (3.0 to 5.3)
    Statistical analysis title
    Statistical Analysis: PFS in PD-L1 + FAS
    Comparison groups
    Avelumab v Docetaxel
    Number of subjects included in analysis
    529
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8
         upper limit
    1.27

    Secondary: Progression-Free Survival (PFS) Time in Full Analysis Set Population

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    End point title
    Progression-Free Survival (PFS) Time in Full Analysis Set Population
    End point description
    PFS was 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. PFS was assessed as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) as adjudicated by independent endpoint review committee (IERC). PD was defined as at least a 20 percent (%) increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. PFS was measured using Kaplan-Meier (KM) estimates. Full analysis set (FAS) included all subjects who were randomized to study.
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to 907 days
    End point values
    Avelumab Docetaxel
    Number of subjects analysed
    396
    396
    Units: months
        median (confidence interval 95%)
    2.8 (2.7 to 3.5)
    4.2 (3.3 to 5.2)
    Statistical analysis title
    Statistical Analysis of PFS in FAS
    Comparison groups
    Avelumab v Docetaxel
    Number of subjects included in analysis
    792
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.98
         upper limit
    1.41

    Secondary: Number of Subjects with Confirmed Best Overall Response (BOR) as Assessed by an Independent Endpoint Review Committee (IERC) in Full Analysis Set Population

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    End point title
    Number of Subjects with Confirmed Best Overall Response (BOR) as Assessed by an Independent Endpoint Review Committee (IERC) in Full Analysis Set Population
    End point description
    Confirmed BOR: best response of any of the complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from the date of randomization until disease progression or recurrence (taking the smallest measurement recorded since the start of treatment as reference). CR: Disappearance of all evidence of target & non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. SD: Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD: a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions & unequivocal progression of non-target lesions. Number of subjects with best overall response in each category (CR, PR, SD, PD) was reported. FAS was used.
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to 907 days
    End point values
    Avelumab Docetaxel
    Number of subjects analysed
    396
    396
    Units: subjects
        Complete Response
    5
    2
        Partial Response
    54
    42
        Stable Disease
    129
    158
        Non-complete Response/ Non-progressive Disease
    5
    13
        Progressive Disease
    150
    82
        Not Evaluable
    53
    99
    No statistical analyses for this end point

    Secondary: Number of Subjects with Confirmed Best Overall Response (BOR) as Assessed by Independent Endpoint Review Committee (IERC) in PD-L1+ Full Analysis Set Population

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    End point title
    Number of Subjects with Confirmed Best Overall Response (BOR) as Assessed by Independent Endpoint Review Committee (IERC) in PD-L1+ Full Analysis Set Population
    End point description
    Confirmed BOR: best response of any of the complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from the date of randomization until disease progression or recurrence (taking the smallest measurement recorded since the start of treatment as reference). CR: Disappearance of all evidence of target & non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. SD: Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD: a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions & unequivocal progression of non-target lesions. Number of subjects with best overall response in each category (CR, PR, SD, PD) was reported. PD-L1+FAS was used.
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to 907 days
    End point values
    Avelumab Docetaxel
    Number of subjects analysed
    264
    265
    Units: subjects
        Complete Response
    4
    1
        Partial Response
    46
    30
        Stable Disease
    86
    104
        Non-complete Response/ Non-progressive Disease
    4
    12
        Progressive Disease
    93
    57
        Not Evaluable
    31
    61
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Objective Response as Assessed by Independent Endpoint Review Committee (IERC) in Full Analysis Set Population

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    End point title
    Percentage of Subjects with Objective Response as Assessed by Independent Endpoint Review Committee (IERC) in Full Analysis Set Population
    End point description
    Percentage of subjects with objective response (CR plus PR) according to RECIST Version 1.1 was reported. 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. Full analysis set (FAS) included all subjects who were randomized to study.
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to 907 days
    End point values
    Avelumab Docetaxel
    Number of subjects analysed
    396
    396
    Units: percentage of subjects
        number (confidence interval 95%)
    14.9 (11.5 to 18.8)
    11.1 (8.2 to 14.6)
    Statistical analysis title
    Objective Response in FAS
    Comparison groups
    Avelumab v Docetaxel
    Number of subjects included in analysis
    792
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.92
         upper limit
    2.13

    Secondary: Percentage of Subjects with Objective Response as Assessed by Independent Endpoint Review Committee (IERC) in PD-L1+ Full Analysis Set Population

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    End point title
    Percentage of Subjects with Objective Response as Assessed by Independent Endpoint Review Committee (IERC) in PD-L1+ Full Analysis Set Population
    End point description
    Percentage of subjects with objective response (CR plus PR) according to RECIST Version 1.1 was reported. 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. PD-L1+ FAS included all PD-L1+ tumor subjects who were randomly assigned to trial treatment. The PD-L1+ subjects were with >= 1 percentage of tumor cells with >=1+ positive membrane staining intensity for PD-L1 protein.
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to 907 days
    End point values
    Avelumab Docetaxel
    Number of subjects analysed
    264
    265
    Units: percentage of subjects
        number (confidence interval 95%)
    18.9 (14.4 to 24.2)
    11.7 (8.1 to 16.2)
    Statistical analysis title
    Objective Response in PD-L1 + FAS
    Comparison groups
    Avelumab v Docetaxel
    Number of subjects included in analysis
    529
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.08
         upper limit
    2.86

    Secondary: Change From Baseline in European Quality of Life 5-dimensions (EQ-5D-5L) Health Outcome Questionnaire Through Composite Index Score at End of Treatment (EOT)

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    End point title
    Change From Baseline in European Quality of Life 5-dimensions (EQ-5D-5L) Health Outcome Questionnaire Through Composite Index Score at End of Treatment (EOT)
    End point description
    The EQ-5D-5L health outcome questionnaire was a measure of health status that provides a simple descriptive profile and a single index value. The EQ-5D-5L defined health in terms of mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The 5 items were combined to generate health profiles. These profiles were converted to a continuous single index score. The lowest possible score was -0.59 (unable to walk, unable to self-care, unable to do usual activities, extreme pain or discomfort, extreme anxiety or depression) and the highest score was 1.00 (no problems in all 5 dimensions). Health-related quality of life (HRQoL) analysis set was a subset of the FAS and includes all FAS subjects who had 1 baseline HRQoL assessment and at least 1 post-baseline HRQoL questionnaire completed. Here, “number of subjects analyzed” signified the subjects analyzed in this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, End of treatment visit (up to Week 124)
    End point values
    Avelumab Docetaxel
    Number of subjects analysed
    172
    196
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.1245 ± 0.28021
    -0.0988 ± 0.26615
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Quality of Life 5-dimensions (EQ-5D-5L) Health Outcome Questionnaire Through Visual Analogue Scale (VAS) at End of Treatment (EOT)

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    End point title
    Change From Baseline in European Quality of Life 5-dimensions (EQ-5D-5L) Health Outcome Questionnaire Through Visual Analogue Scale (VAS) at End of Treatment (EOT)
    End point description
    EQ-5D-5L was comprised of the following 5 participant-reported dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension had 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The responses were used to derive overall score using a visual analog scale (VAS) that ranged from 0 to 100 millimeter (mm), where 0 (worst health you can imagine) and 100 (best health you can imagine). Health-related quality of life (HRQoL) analysis set was a subset of the FAS and includes all FAS subjects who had 1 baseline HRQoL assessment and at least 1 post-baseline HRQoL questionnaire completed. Here, “Number of subjects analyzed” signified the subjects analyzed in this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, End of treatment visit (up to Week 124)
    End point values
    Avelumab Docetaxel
    Number of subjects analysed
    171
    196
    Units: millimeter
        arithmetic mean (standard deviation)
    -8.1 ± 22.06
    -7.0 ± 21.12
    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)

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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)
    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, where 0 (very poor physical condition and QoL) and 100 (excellent overall physical condition and QoL). Health-related quality of life (HRQoL) analysis set was a subset of the FAS and includes all FAS subjects who had 1 baseline HRQoL assessment and at least 1 post-baseline HRQoL questionnaire completed. Here, “Number of subjects analyzed” signified the subjects analyzed in this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, End of treatment visit (up to Week 124)
    End point values
    Avelumab Docetaxel
    Number of subjects analysed
    172
    196
    Units: units on a scale
        arithmetic mean (standard deviation)
    -9.79 ± 24.506
    -9.44 ± 18.933
    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)

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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)
    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 scale assessing dyspnea, coughing, hemoptysis, sore mouth, dysphagia, 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). Health-related quality of life (HRQoL) analysis set was a subset of the FAS and includes all FAS subjects who had 1 baseline HRQoL assessment and at least 1 post-baseline HRQoL questionnaire completed. Here, "n" signified those subjects who were evaluable for the specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, End of treatment visit (up to Week 124)
    End point values
    Avelumab Docetaxel
    Number of subjects analysed
    348
    333
    Units: units on a scale
    arithmetic mean (standard deviation)
        Dyspnea: (n = 172, 197)
    9.95 ± 22.094
    8.52 ± 21.285
        Coughing: (n = 172, 197)
    -0.58 ± 30.263
    -2.03 ± 32.582
        Hemoptysis: (n = 172, 197)
    0.19 ± 14.191
    -0.34 ± 16.832
        Sore Mouth: (n = 172, 197)
    0.78 ± 17.643
    3.72 ± 24.920
        Dysphagia: (n = 172, 197)
    5.62 ± 18.401
    4.23 ± 21.538
        Peripheral Neuropathy: (n = 172, 197)
    0.19 ± 20.550
    9.81 ± 30.015
        Alopecia: (n = 172, 197)
    -3.10 ± 20.789
    30.80 ± 42.582
        Pain in Chest: (n = 172, 197)
    4.84 ± 28.993
    0.34 ± 26.935
        Pain in Arm or Shoulder: (n = 172, 197)
    5.62 ± 28.852
    0.85 ± 29.439
        Pain in Other Parts: (n = 171, 197)
    8.77 ± 34.410
    6.60 ± 30.978
    No statistical analyses for this end point

    Secondary: Number of Subjects with Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Drug Related Treatment Emergent Adverse Events and Treatment Emergent Adverse Events Leading to Death

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    End point title
    Number of Subjects with Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Drug Related Treatment Emergent Adverse Events and Treatment Emergent Adverse Events Leading to Death
    End point description
    An Adverse event (AE) was defined as any unfavorable and unintended sign (including clinically significant abnormal laboratory, vital signs and 12-lead Electrocardiogram findings), symptom, or disease temporally associated with the use of study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was 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. Treatment-emergent events between first dose of study drug that were absent before treatment or that worsened relative to pre-treatment state up to 30 days after last administration. TEAEs included both Serious TEAEs and non-serious TEAEs. Safety analysis set included all subjects who were administered at least 1 dose of the Investigational Medicinal Product.
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to 1420 days
    End point values
    Avelumab Docetaxel
    Number of subjects analysed
    393
    365
    Units: subjects
        TEAEs
    375
    346
        TESAEs
    167
    145
        Drug Related TEAEs
    252
    313
        TEAEs Leading to Death
    64
    51
    No statistical analyses for this end point

    Secondary: Number of Subjects with Treatment Emergent Adverse Events (TEAEs) by Severity

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    End point title
    Number of Subjects with Treatment Emergent Adverse Events (TEAEs) by Severity
    End point description
    Treatment Emergent Adverse Events were graded as per National Cancer Institute Common Terminology Criteria for Adverse Experience version 4.03 (NCI-CTCAE v 4.03). Grade 3 refers to severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care and Activity of daily living (ADL), Grade 4 refers to Life-threatening consequences; where urgent intervention indicated, Grade 5 refers to the death related to adverse event. Safety analysis set included all subjects who were administered at least 1 dose of the Investigational Medicinal Product.
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to 1420 days
    End point values
    Avelumab Docetaxel
    Number of subjects analysed
    393
    365
    Units: subjects
        Grade 3 or Higher
    209
    247
        Grade 4 or Higher
    87
    122
        Grade 5
    63
    51
    No statistical analyses for this end point

    Secondary: Number of Subjects with Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score vs. Worst Post-baseline Score

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    End point title
    Number of Subjects with Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score vs. Worst Post-baseline Score
    End point description
    ECOG performance status measured to assess subject’s 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. The subjects with missing worst post baseline score were also reported. ECOG performance status was reported in terms of number of subjects with Baseline value vs. worst post-baseline value (i.e. highest score) combination. Safety analysis set included all subjects who were administered at least 1 dose of the Investigational Medicinal Product.
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to 1420 days
    End point values
    Avelumab Docetaxel
    Number of subjects analysed
    393
    365
    Units: subjects
        Baseline score 0, worst post-baseline score 0
    52
    55
        Baseline score 0, worst post-baseline score 1
    67
    41
        Baseline score 0, worst post-baseline score 2
    19
    12
        Baseline score 0, worst post-baseline score 3
    5
    2
        Baseline score 0, worst post-baseline score 4
    0
    1
        Baseline score 0, worst post-baseline score 5
    1
    0
        Baseline score 0, worst post-baseline Missing
    0
    6
        Baseline score 1, worst post-baseline score 0
    6
    1
        Baseline score 1, worst post-baseline score 1
    157
    172
        Baseline score 1, worst post-baseline score 2
    47
    41
        Baseline score 1, worst post-baseline score 3
    23
    8
        Baseline score 1, worst post-baseline score 4
    3
    2
        Baseline score 1, worst post-baseline score 5
    1
    1
        Baseline score 1, worst post-baseline Missing
    12
    23
    No statistical analyses for this end point

    Secondary: Number of Subjects with Positive Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Avelumab

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    End point title
    Number of Subjects with Positive Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) for Avelumab [1]
    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. Full analysis set (FAS) included all subjects who were randomized to study. Here, "Number of Subjects Analyzed" signified subjects with at least on valid ADA result at any time point.
    End point type
    Secondary
    End point timeframe
    Time from date of randomization up to 1420 days
    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: This endpoint was evaluated for Avelumab arm only.
    End point values
    Avelumab
    Number of subjects analysed
    388
    Units: subjects
        ADAs to Avelumab
    58
        NAbs to Avelumab
    14
    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 1420 days
    Adverse event reporting additional description
    Safety analysis set included all subjects who were administered at least 1 dose of the Investigational Medicinal Product.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Docetaxel
    Reporting group description
    Subjects received 75 mg per square meter (m^2) (per label) of docetaxel by intravenous infusion once every 3 weeks until confirmed disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or Investigational Medicinal Product (IMP) as defined in the study protocol was fulfilled.

    Reporting group title
    Avelumab
    Reporting group description
    Subjects received 10 milligram per kilogram (mg/kg) of avelumab as a 1-hour intravenous infusion once every 2 weeks until confirmed disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or Investigational Medicinal Product (IMP) as defined in the study protocol was fulfilled.

    Serious adverse events
    Docetaxel Avelumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    145 / 365 (39.73%)
    167 / 393 (42.49%)
         number of deaths (all causes)
    297
    316
         number of deaths resulting from adverse events
    Vascular disorders
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 365 (0.27%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic aneurysm
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intermittent claudication
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 365 (0.55%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to central nervous system
         subjects affected / exposed
    1 / 365 (0.27%)
    5 / 393 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    0 / 365 (0.00%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 365 (0.00%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal cancer
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 365 (0.27%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to liver
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tumour pain
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 365 (0.00%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    26 / 365 (7.12%)
    41 / 393 (10.43%)
         occurrences causally related to treatment / all
    0 / 26
    0 / 41
         deaths causally related to treatment / all
    0 / 20
    0 / 32
    Asthenia
         subjects affected / exposed
    3 / 365 (0.82%)
    6 / 393 (1.53%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    4 / 365 (1.10%)
    6 / 393 (1.53%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 6
         deaths causally related to treatment / all
    1 / 4
    0 / 6
    Pain
         subjects affected / exposed
    1 / 365 (0.27%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 365 (0.27%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 365 (0.27%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 365 (0.27%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    3 / 365 (0.82%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    2 / 365 (0.55%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 365 (0.55%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 365 (0.27%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 365 (0.00%)
    10 / 393 (2.54%)
         occurrences causally related to treatment / all
    0 / 0
    10 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 365 (0.00%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    4 / 365 (1.10%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 365 (0.00%)
    3 / 393 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 365 (0.00%)
    3 / 393 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 365 (0.27%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Acute coronary syndrome
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune myocarditis
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cardiac tamponade
         subjects affected / exposed
    0 / 365 (0.00%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 365 (0.27%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Acute myocardial infarction
         subjects affected / exposed
    1 / 365 (0.27%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia supraventricular
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    7 / 365 (1.92%)
    11 / 393 (2.80%)
         occurrences causally related to treatment / all
    2 / 7
    0 / 11
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Pleural effusion
         subjects affected / exposed
    3 / 365 (0.82%)
    10 / 393 (2.54%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    3 / 365 (0.82%)
    6 / 393 (1.53%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonitis
         subjects affected / exposed
    1 / 365 (0.27%)
    5 / 393 (1.27%)
         occurrences causally related to treatment / all
    1 / 1
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 365 (0.82%)
    4 / 393 (1.02%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Haemoptysis
         subjects affected / exposed
    4 / 365 (1.10%)
    3 / 393 (0.76%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Interstitial lung disease
         subjects affected / exposed
    3 / 365 (0.82%)
    3 / 393 (0.76%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Respiratory failure
         subjects affected / exposed
    3 / 365 (0.82%)
    3 / 393 (0.76%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 2
    1 / 2
    Acute respiratory failure
         subjects affected / exposed
    2 / 365 (0.55%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Hypoxia
         subjects affected / exposed
    1 / 365 (0.27%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 365 (0.27%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Asphyxia
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atelectasis
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hydrothorax
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oesophagobronchial fistula
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 365 (0.27%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchial obstruction
         subjects affected / exposed
    2 / 365 (0.55%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphonia
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 365 (0.27%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cystic lung cancer
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 365 (0.82%)
    4 / 393 (1.02%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    22 / 365 (6.03%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    21 / 22
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    Leukopenia
         subjects affected / exposed
    3 / 365 (0.82%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Neutropenia
         subjects affected / exposed
    10 / 365 (2.74%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    10 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Depressed level of consciousness
         subjects affected / exposed
    0 / 365 (0.00%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Balance disorder
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiplegia
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurotoxicity
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post herpetic neuralgia
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Syncope
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic cerebral infarction
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 365 (0.27%)
    3 / 393 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 365 (0.00%)
    3 / 393 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 365 (0.27%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    5 / 365 (1.37%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal pain
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    2 / 365 (0.55%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 365 (0.55%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 365 (0.55%)
    3 / 393 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Nephrolithiasis
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 365 (0.27%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Henoch-Schonlein purpura
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 365 (0.55%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 365 (0.27%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoporotic fracture
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 365 (0.27%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    2 / 365 (0.55%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 365 (0.27%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune thyroiditis
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    1 / 365 (0.27%)
    3 / 393 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 365 (0.00%)
    3 / 393 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 365 (0.00%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 365 (0.27%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 365 (0.55%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    19 / 365 (5.21%)
    9 / 393 (2.29%)
         occurrences causally related to treatment / all
    9 / 19
    0 / 9
         deaths causally related to treatment / all
    3 / 5
    0 / 3
    Respiratory tract infection
         subjects affected / exposed
    5 / 365 (1.37%)
    4 / 393 (1.02%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    2 / 365 (0.55%)
    3 / 393 (0.76%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 365 (0.55%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Appendicitis
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural infection
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia streptococcal
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    4 / 365 (1.10%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic gangrene
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 365 (0.55%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    4 / 365 (1.10%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    2 / 365 (0.55%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    5 / 365 (1.37%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 0
         deaths causally related to treatment / all
    2 / 4
    0 / 0
    Serratia infection
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal infection
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 365 (0.55%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Docetaxel Avelumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    307 / 365 (84.11%)
    320 / 393 (81.42%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    66 / 365 (18.08%)
    70 / 393 (17.81%)
         occurrences all number
    66
    70
    Asthenia
         subjects affected / exposed
    64 / 365 (17.53%)
    55 / 393 (13.99%)
         occurrences all number
    64
    55
    Pyrexia
         subjects affected / exposed
    33 / 365 (9.04%)
    50 / 393 (12.72%)
         occurrences all number
    33
    50
    Chills
         subjects affected / exposed
    3 / 365 (0.82%)
    29 / 393 (7.38%)
         occurrences all number
    3
    29
    Oedema peripheral
         subjects affected / exposed
    37 / 365 (10.14%)
    21 / 393 (5.34%)
         occurrences all number
    37
    21
    Malaise
         subjects affected / exposed
    26 / 365 (7.12%)
    9 / 393 (2.29%)
         occurrences all number
    26
    9
    Mucosal inflammation
         subjects affected / exposed
    22 / 365 (6.03%)
    5 / 393 (1.27%)
         occurrences all number
    22
    5
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    22 / 365 (6.03%)
    19 / 393 (4.83%)
         occurrences all number
    22
    19
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    8 / 365 (2.19%)
    56 / 393 (14.25%)
         occurrences all number
    8
    56
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    34 / 365 (9.32%)
    3 / 393 (0.76%)
         occurrences all number
    34
    3
    Weight decreased
         subjects affected / exposed
    30 / 365 (8.22%)
    50 / 393 (12.72%)
         occurrences all number
    30
    50
    White blood cell count decreased
         subjects affected / exposed
    21 / 365 (5.75%)
    2 / 393 (0.51%)
         occurrences all number
    21
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    46 / 365 (12.60%)
    77 / 393 (19.59%)
         occurrences all number
    46
    77
    Dyspnoea
         subjects affected / exposed
    54 / 365 (14.79%)
    75 / 393 (19.08%)
         occurrences all number
    54
    75
    Haemoptysis
         subjects affected / exposed
    15 / 365 (4.11%)
    25 / 393 (6.36%)
         occurrences all number
    15
    25
    Productive cough
         subjects affected / exposed
    8 / 365 (2.19%)
    25 / 393 (6.36%)
         occurrences all number
    8
    25
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    81 / 365 (22.19%)
    50 / 393 (12.72%)
         occurrences all number
    81
    50
    Neutropenia
         subjects affected / exposed
    48 / 365 (13.15%)
    2 / 393 (0.51%)
         occurrences all number
    48
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    19 / 365 (5.21%)
    30 / 393 (7.63%)
         occurrences all number
    19
    30
    Neuropathy peripheral
         subjects affected / exposed
    33 / 365 (9.04%)
    6 / 393 (1.53%)
         occurrences all number
    33
    6
    Peripheral sensory neuropathy
         subjects affected / exposed
    27 / 365 (7.40%)
    3 / 393 (0.76%)
         occurrences all number
    27
    3
    Dysgeusia
         subjects affected / exposed
    23 / 365 (6.30%)
    1 / 393 (0.25%)
         occurrences all number
    23
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    57 / 365 (15.62%)
    56 / 393 (14.25%)
         occurrences all number
    57
    56
    Constipation
         subjects affected / exposed
    43 / 365 (11.78%)
    45 / 393 (11.45%)
         occurrences all number
    43
    45
    Diarrhoea
         subjects affected / exposed
    67 / 365 (18.36%)
    44 / 393 (11.20%)
         occurrences all number
    67
    44
    Vomiting
         subjects affected / exposed
    28 / 365 (7.67%)
    38 / 393 (9.67%)
         occurrences all number
    28
    38
    Stomatitis
         subjects affected / exposed
    42 / 365 (11.51%)
    9 / 393 (2.29%)
         occurrences all number
    42
    9
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    17 / 365 (4.66%)
    33 / 393 (8.40%)
         occurrences all number
    17
    33
    Pruritus
         subjects affected / exposed
    13 / 365 (3.56%)
    26 / 393 (6.62%)
         occurrences all number
    13
    26
    Alopecia
         subjects affected / exposed
    97 / 365 (26.58%)
    3 / 393 (0.76%)
         occurrences all number
    97
    3
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    17 / 365 (4.66%)
    47 / 393 (11.96%)
         occurrences all number
    17
    47
    Arthralgia
         subjects affected / exposed
    30 / 365 (8.22%)
    27 / 393 (6.87%)
         occurrences all number
    30
    27
    Pain in extremity
         subjects affected / exposed
    12 / 365 (3.29%)
    23 / 393 (5.85%)
         occurrences all number
    12
    23
    Musculoskeletal pain
         subjects affected / exposed
    15 / 365 (4.11%)
    25 / 393 (6.36%)
         occurrences all number
    15
    25
    Myalgia
         subjects affected / exposed
    43 / 365 (11.78%)
    17 / 393 (4.33%)
         occurrences all number
    43
    17
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 365 (0.27%)
    24 / 393 (6.11%)
         occurrences all number
    1
    24
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    76 / 365 (20.82%)
    79 / 393 (20.10%)
         occurrences all number
    76
    79
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    12 / 365 (3.29%)
    28 / 393 (7.12%)
         occurrences all number
    12
    28

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 May 2015
    - Added language regarding the predicted number of deaths due to NSCLC in the EU in 2014. - Added language to inclusion criterion 13 for subjects being treated with docetaxel to use effective contraception for up to 3 months after docetaxel treatment and to advise male subjects not to father a child during the 3 months after treatment with docetaxel and to seek advice on conservation of sperm prior to treatment.
    10 Jul 2015
    − Excluded further enrollment of NSCLC subjects with EGFR mutations. − Modified language in Exclusion criterion 4 such that prior therapy with cancer vaccine was no longer allowed. − Changed the duration of treatment for subjects with a confirmed CR to a maximum of 24 months. − Modified AE and SAE follow-up language such that subjects with an AE ongoing at the time of the End-of-Treatment visit must be followed up until the Safety follow-up visit and subjects with a SAE ongoing at the Long term follow-up visit must be followed up by the Investigator until stabilization or until outcome was known, unless the subject was documented as “lost to follow-up. − Changed the bilirubin inclusion criterion from 1.0 x ULN to 1.5 x ULN. − Modified hepatitis testing to include type of test. − Modified mandatory chest CT to allow MRI of the chest to account for regions where CT may be prohibited. − Added language stipulating that complete blood count and core chemistry samples must be drawn and results reviewed within 48 hours prior to IMP administration. − Deleted patient-reported outcome / quality-of-life assessments from the Safety Follow-up and Long-term Follow-up visits. − Added language allowing corticosteroid use in subjects randomized to docetaxel. − Added vaccines to the list of prohibited medications. − Added PK sampling at the End-of-Treatment visit and ADA sampling at the Safety Follow-up visit.
    15 Nov 2016
    − Increased the number of subject to be randomized in the study by 100 due to the new (lower) estimation of the proportion of subjects with PD-L1+ tumors and updated the proportion expected to have PD-L1+ tumors from 80% to 70%. − Updated language regarding tumor assessments so that after 1 year (Week 55) from the start of treatment, assessments would be every 12 weeks (rather than every 6 weeks). − Changed Human Antihuman Antibody (HAHA) to ADA throughout the protocol. − Corrected discrepancies in PK sampling between the text and the Schedule of Assessments − Updated contraception language in the Inclusion Criteria to harmonize with the rest of the avelumab program. − Deleted requirement for subjects with repeated Grade 2 IRRs and ADRs to be withdrawn from treatment. − Updated language on timing of when weight should be determined for dose calculation in order to give more flexibility to Investigators − Deleted bisphosphonate and denosumab from list of nonpermissible medications. − Added language to allow subjects with brain metastases to continue treatment if they fulfilled outlined criteria. − Added guidelines for the management of suspected cardiac-related Immune-related adverse event (irAEs). − Changed definition of overdose from >= 5% to >= 10% of calculated dose. − Deleted blood sample collection for Adrenocorticotropic hormone (ACTH), Antinuclear antibody (ANA), Antineutrophil cytoplasmic antibody (ANCA) and rheumatoid factor from End of Treatment and Safety Follow-up visits − Deleted the PP analysis set and any associated analyses − Replaced the ITT population with the FAS

    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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