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    Clinical Trial Results:
    A Phase III, Open-label, Randomized, Multi-center, International Study of MEDI4736, Given as Monotherapy or in Combination with Tremelimumab, Determined by PD-L1 Expression, Versus Standard of Care in Patients with Locally Advanced or Metastatic Non-small Cell Lung Cancer (Stage IIIB-IV) Who Have Received At Least Two Prior Systemic Treatment Regimens Including One Platinum-based Chemotherapy Regimen and Do Not Have Known EGFR TK Activating Mutations or ALK Rearrangements (ARCTIC)

    Summary
    EudraCT number
    		 2014-000338-46
    Trial protocol
    		 DE   GB   ES   BE   GR   HU   NL   CZ   PL   IT  
    Global end of trial date
    30 Aug 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Aug 2024
    First version publication date
    10 Aug 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    D4191C00004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02352948
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Alderley Park, Macclesfield, Cheshire, United Kingdom, SK10 4TG
    Public contact
    Medical Science Director, AstraZeneca, +1 302 885 1180, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    Medical Science Director, AstraZeneca, +1 302 885 1180, ClinicalTrialTransparency@astrazeneca.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
    09 Feb 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Feb 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Aug 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Sub-study A [Programmed cell death ligand 1 (PD-L1) high population]: To assess the efficacy of durvalumab monotherapy compared with standard of care (SoC) in terms of overall survival (OS) and progression-free survival (PFS). Sub-study B (PD-L1 low/neg population): To assess the efficacy of durvalumab in combination with tremelimumab treatment compared with SoC in terms of OS and PFS.
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Conference on Harmonisation/Good Clinical Practice, applicable regulatory requirements, and the AstraZeneca policy on Bioethics and Human Biological Samples.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Jan 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Bulgaria: 7
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Chile: 6
    Country: Number of subjects enrolled
    Czechia: 1
    Country: Number of subjects enrolled
    France: 31
    Country: Number of subjects enrolled
    Germany: 53
    Country: Number of subjects enrolled
    Greece: 10
    Country: Number of subjects enrolled
    Hong Kong: 2
    Country: Number of subjects enrolled
    Hungary: 10
    Country: Number of subjects enrolled
    Italy: 48
    Country: Number of subjects enrolled
    Japan: 112
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Poland: 31
    Country: Number of subjects enrolled
    Korea, Republic of: 29
    Country: Number of subjects enrolled
    Romania: 11
    Country: Number of subjects enrolled
    Russian Federation: 32
    Country: Number of subjects enrolled
    Serbia: 18
    Country: Number of subjects enrolled
    Singapore: 14
    Country: Number of subjects enrolled
    Spain: 64
    Country: Number of subjects enrolled
    Taiwan: 6
    Country: Number of subjects enrolled
    Thailand: 11
    Country: Number of subjects enrolled
    United Kingdom: 19
    Country: Number of subjects enrolled
    United States: 55
    Worldwide total number of subjects
    595
    EEA total number of subjects
    282
    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)
    318
    From 65 to 84 years
    277
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was divided into 2 parts, sub-study A (82 centers across Europe, Asia, and North America) and sub-study B (149 centers across Europe, Asia, North America, and South America) conducted between 13 January 2015 and 09 February 2018 (data cut-off date).

    Pre-assignment
    Screening details
    		 The study had a pre-screening period to determine the programmed cell death ligand 1 (PD-L1) status, followed by a screening period and 12 month treatment period. A total of 595 participants were randomized to either sub-study A [PD-L1 high (>=25% of tumor cell (TC) expressing PD-L1)] or sub-study B [PD-L1 low/neg (<25% of TC expressing PD-L1)].

    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
    		 Sub-study A: Durvalumab
    Arm description
    		 Participants received durvalumab 10 milligrams per kilogram (mg/kg) intravenous (IV) infusion every 2 weeks (Q2W) for 12 months (up to 26 doses).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    MEDI4736
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Durvalumab 10 mg/kg IV infusion Q2W for 12 months.

    Arm title
    		 Sub-study A: SoC
    Arm description
    		 Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/meter square (m^2) IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until progression of disease (PD), initiation of alternative anti-cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Erlotinib 150 mg orally once daily.

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vinorelbine 30 mg/m^2 IV on Days 1, 8, 15, and 22 of a 28-day cycle.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle.

    Arm title
    		 Sub-study B: Durvalumab+Tremelimumab
    Arm description
    		 Participants received durvalumab 20 mg/kg plus tremelimumab 1 mg/kg IV infusion every 4 weeks (Q4W) for 12 weeks (4 doses) followed by durvalumab alone 10 mg/kg IV infusion Q2W for 34 weeks starting at Week 16 (up to 18 additional doses).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tremelimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tremelimumab 1 mg/kg IV infusion Q4W for 12 weeks.

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    MEDI4736
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Durvalumab 20 mg/kg IV infusion Q4W for 12 weeks followed by durvalumab 10 mg/kg IV infusion Q2W for 34 weeks starting at Week 16.

    Arm title
    		 Sub-study B: SoC
    Arm description
    		 Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until PD, initiation of alternative anti-cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Erlotinib 150 mg orally once daily.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle.

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vinorelbine 30 mg/m^2 IV on Days 1, 8, 15, and 22 of a 28-day cycle.

    Arm title
    		 Sub-study B: Durvalumab
    Arm description
    		 Participants received durvalumab 10 mg/kg IV infusion Q2W for 12 months (up to 26 doses).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    MEDI4736
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Durvalumab 10 mg/kg IV infusion Q2W for 12 months.

    Arm title
    		 Sub-study B: Tremelimumab
    Arm description
    		 Participants received tremelimumab 10 mg/kg IV infusion Q4W for 24 weeks followed by every 12 weeks (Q12W) for 24 weeks (up to 9 doses).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tremelimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tremelimumab 10 mg/kg IV infusion Q4W for 24 weeks followed by Q12W for 24 weeks.

    Number of subjects in period 1
    		Sub-study A: Durvalumab Sub-study A: SoC Sub-study B: Durvalumab+Tremelimumab Sub-study B: SoC Sub-study B: Durvalumab Sub-study B: Tremelimumab
    Started
    62
    64
    174
    118
    117
    60
    Received treatment
    62
    63
    173
    110
    117
    60
    Completed study treatment
    15
    0 [1]
    36 [2]
    0 [3]
    23 [4]
    4 [5]
    Completed
    13
    5
    45
    19
    29
    11
    Not completed
    49
    59
    129
    99
    88
    49
         Adverse event, serious fatal
    47
    48
    114
    74
    77
    44
         Consent withdrawn by subject
    1
    10
    11
    23
    9
    4
         Eligibility criteria not fulfilled
    -
    1
    -
    1
    -
    -
         Unspecified
    -
    -
    2
    -
    -
    -
         Lost to follow-up
    1
    -
    2
    1
    2
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It was not necessary for patients to complete the study treatment in order to complete the study
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It was not necessary for patients to complete the study treatment in order to complete the study
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It was not necessary for patients to complete the study treatment in order to complete the study
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It was not necessary for patients to complete the study treatment in order to complete the study
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It was not necessary for patients to complete the study treatment in order to complete the study

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sub-study A: Durvalumab
    Reporting group description
    		 Participants received durvalumab 10 milligrams per kilogram (mg/kg) intravenous (IV) infusion every 2 weeks (Q2W) for 12 months (up to 26 doses).

    Reporting group title
    Sub-study A: SoC
    Reporting group description
    		 Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/meter square (m^2) IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until progression of disease (PD), initiation of alternative anti-cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.

    Reporting group title
    Sub-study B: Durvalumab+Tremelimumab
    Reporting group description
    		 Participants received durvalumab 20 mg/kg plus tremelimumab 1 mg/kg IV infusion every 4 weeks (Q4W) for 12 weeks (4 doses) followed by durvalumab alone 10 mg/kg IV infusion Q2W for 34 weeks starting at Week 16 (up to 18 additional doses).

    Reporting group title
    Sub-study B: SoC
    Reporting group description
    		 Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until PD, initiation of alternative anti-cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.

    Reporting group title
    Sub-study B: Durvalumab
    Reporting group description
    		 Participants received durvalumab 10 mg/kg IV infusion Q2W for 12 months (up to 26 doses).

    Reporting group title
    Sub-study B: Tremelimumab
    Reporting group description
    		 Participants received tremelimumab 10 mg/kg IV infusion Q4W for 24 weeks followed by every 12 weeks (Q12W) for 24 weeks (up to 9 doses).

    Reporting group values
    		 Sub-study A: Durvalumab Sub-study A: SoC Sub-study B: Durvalumab+Tremelimumab Sub-study B: SoC Sub-study B: Durvalumab Sub-study B: Tremelimumab Total
    Number of subjects
    		 62 64 174 118 117 60 595
    Age, Customized
    Units: Subjects
        <50 years
    		 3 11 16 8 13 4 55
        >=50 to <65 years
    		 31 25 79 49 52 27 263
        >=65 to <75 years
    		 24 21 64 50 39 24 222
        >=75 years
    		 4 7 15 11 13 5 55
    Sex: Female, Male
    Units: Subjects
        Female
    		 20 16 59 37 44 21 197
        Male
    		 42 48 115 81 73 39 398
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0 0
        Asian
    		 22 23 41 41 34 16 177
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0 0
        Black or African American
    		 0 1 3 2 2 1 9
        White
    		 40 40 129 74 79 43 405
        Unknown or Not Reported
    		 0 0 0 0 1 0 1
        Other
    		 0 0 1 1 1 0 3

    End points

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    End points reporting groups
    Reporting group title
    Sub-study A: Durvalumab
    Reporting group description
    		 Participants received durvalumab 10 milligrams per kilogram (mg/kg) intravenous (IV) infusion every 2 weeks (Q2W) for 12 months (up to 26 doses).

    Reporting group title
    Sub-study A: SoC
    Reporting group description
    		 Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/meter square (m^2) IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until progression of disease (PD), initiation of alternative anti-cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.

    Reporting group title
    Sub-study B: Durvalumab+Tremelimumab
    Reporting group description
    		 Participants received durvalumab 20 mg/kg plus tremelimumab 1 mg/kg IV infusion every 4 weeks (Q4W) for 12 weeks (4 doses) followed by durvalumab alone 10 mg/kg IV infusion Q2W for 34 weeks starting at Week 16 (up to 18 additional doses).

    Reporting group title
    Sub-study B: SoC
    Reporting group description
    		 Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until PD, initiation of alternative anti-cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.

    Reporting group title
    Sub-study B: Durvalumab
    Reporting group description
    		 Participants received durvalumab 10 mg/kg IV infusion Q2W for 12 months (up to 26 doses).

    Reporting group title
    Sub-study B: Tremelimumab
    Reporting group description
    		 Participants received tremelimumab 10 mg/kg IV infusion Q4W for 24 weeks followed by every 12 weeks (Q12W) for 24 weeks (up to 9 doses).

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS) [1]
    End point description
    The OS was defined as the time from the date of randomization until death due to any cause. Sub-study A and B: Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.
    End point type
    Primary
    End point timeframe
    From randomization (Day 1) until death due to any cause, approximately 36 months
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: no statistical analyses performed
    End point values
    		 Sub-study A: Durvalumab Sub-study A: SoC Sub-study B: Durvalumab+Tremelimumab Sub-study B: SoC
    Number of subjects analysed
    62
    64
    174
    118
    Units: months
        median (confidence interval 95%)
    11.7 (8.2 to 17.4)
    6.8 (4.9 to 10.2)
    11.5 (8.7 to 14.1)
    8.7 (6.5 to 11.7)
    Statistical analysis title
    		 Sub-study A: Durvalumab Vs SoC
    Statistical analysis description
    For sub-study A: durvalumab monotherapy treatment arm was compared with SoC.
    Comparison groups
    Sub-study A: SoC v Sub-study A: Durvalumab
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 0.93
    Notes
    [2] - Sub-study A was not powered and thus no formal statistical comparisons were performed. Hazard ratio and confidence interval (CI) are estimated from a stratified Cox proportional hazards model with Breslow method to control for ties, stratification factors SoC therapy, and histology in strata statement, and CI is calculated using profile likelihood approach.
    Statistical analysis title
    		 Sub-study B: Durvalumab+Tremelimumab Vs SoC
    Statistical analysis description
    For sub-study B: durvalumab plus tremelimumab treatment arm was compared with SoC.
    Comparison groups
    Sub-study B: Durvalumab+Tremelimumab v Sub-study B: SoC
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.109 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 1.05
    Notes
    [3] - Hazard ratio and CI are estimated from a stratified Cox proportional hazards model with Breslow method to control for ties, stratification factors SoC therapy, and histology in strata statement, and CI is calculated using profile likelihood approach.
    [4] - The P-value arises from a stratified log-rank test adjusting for SoC therapy and histology, with ties handled by the Breslow approach.

    Primary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS) [5]
    End point description
    The PFS was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdrew from randomized therapy or received another anti-cancer therapy prior to progression. The PFS was determined by Investigator assessments according to response evaluation criteria in solid tumours (RECIST) version 1.1. PD was defined as at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 millimeter (mm) or progression of non-target lesions or the appearance of a new lesion. Sub-study A and B: FAS included all randomized participants analyzed on an ITT basis.
    End point type
    Primary
    End point timeframe
    Tumour scans performed at baseline then every ~8 weeks up to 48 weeks, then every ~12 weeks thereafter until confirmed disease progression. Assessed up to a maximum of approximately 3 years.
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: no statistical analyses performed
    End point values
    		 Sub-study A: Durvalumab Sub-study A: SoC Sub-study B: Durvalumab+Tremelimumab Sub-study B: SoC
    Number of subjects analysed
    62
    64
    174
    118
    Units: months
        median (confidence interval 95%)
    3.8 (1.9 to 5.6)
    2.2 (1.9 to 3.7)
    3.5 (2.3 to 4.6)
    3.5 (1.9 to 3.9)
    Statistical analysis title
    		 Sub-study B: Durvalumab+Tremelimumab Vs SoC
    Statistical analysis description
    For sub-study B: durvalumab plus tremelimumab treatment arm was compared with SoC.
    Comparison groups
    Sub-study B: Durvalumab+Tremelimumab v Sub-study B: SoC
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.056 [7]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 1.01
    Notes
    [6] - Hazard ratio and CI are estimated from a stratified Cox proportional hazards model with Breslow method to control for ties, stratification factors SoC therapy, and histology in strata statement, and CI is calculated using profile likelihood approach.
    [7] - The P-value arises from a stratified log-rank test adjusting for SoC therapy and histology, with ties handled by the Breslow approach.
    Statistical analysis title
    		 Sub-study A: Durvalumab Vs SoC
    Statistical analysis description
    For sub-study A: durvalumab monotherapy treatment arm was compared with SoC.
    Comparison groups
    Sub-study A: Durvalumab v Sub-study A: SoC
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 1.04
    Notes
    [8] - Sub-study A was not powered and thus no formal statistical comparisons were performed. Hazard ratio and CI are estimated from a stratified Cox proportional hazards model with Breslow method to control for ties, stratification factors SoC therapy, and histology in strata statement, and CI is calculated using profile likelihood approach.

    Secondary: OS, Contribution of the Components Analysis of Sub-study B

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    End point title
    		 OS, Contribution of the Components Analysis of Sub-study B [9]
    End point description
    The OS was defined as the time from the date of randomization until death due to any cause. The FAS included all randomized participants analyzed on an ITT basis.
    End point type
    Secondary
    End point timeframe
    From randomization (Day 1) until death due to any cause, approximately 36 months
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: no statistical analyses performed
    End point values
    		 Sub-study B: Durvalumab+Tremelimumab Sub-study B: Durvalumab Sub-study B: Tremelimumab
    Number of subjects analysed
    174
    117
    60
    Units: months
        median (confidence interval 95%)
    11.5 (8.7 to 14.1)
    10.0 (7.1 to 13.2)
    6.9 (3.9 to 13.2)
    Statistical analysis title
    		 Sub-study B: Durvalumab+Tremelimumab Vs Durvalumab
    Statistical analysis description
    As part of the contribution of components analysis for sub-study B, durvalumab plus tremelimumab treatment arm was compared with durvalumab monotherapy.
    Comparison groups
    Sub-study B: Durvalumab+Tremelimumab v Sub-study B: Durvalumab
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.885 [11]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.3
    Notes
    [10] - Hazard ratio and CI are estimated from a stratified Cox proportional hazards model with Breslow method to control for ties, stratification factors SoC therapy, and histology in strata statement, and CI is calculated using profile likelihood approach.
    [11] - The P-value arises from a stratified log-rank test adjusting for SoC therapy and histology, with ties handled by the Breslow approach.
    Statistical analysis title
    		 Sub-study B: Durvalumab+TremelimumabVsTremelimumab
    Statistical analysis description
    As part of the contribution of components analysis for sub-study B, durvalumab plus tremelimumab treatment arm was compared with tremelimumab monotherapy.
    Comparison groups
    Sub-study B: Durvalumab+Tremelimumab v Sub-study B: Tremelimumab
    Number of subjects included in analysis
    234
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.153 [13]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 1.11
    Notes
    [12] - Hazard ratio and CI are estimated from a stratified Cox proportional hazards model with Breslow method to control for ties, stratification factors SoC therapy, and histology in strata statement, and CI is calculated using profile likelihood approach.
    [13] - The P-value arises from a stratified log-rank test adjusting for SoC therapy and histology, with ties handled by the Breslow approach.

    Secondary: Percentage of Participants Alive at 12 Months (OS12)

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    End point title
    		 Percentage of Participants Alive at 12 Months (OS12)
    End point description
    The OS12 was defined as the percentage of participants who were alive at 12 months after randomisation per Kaplan-Meier estimate of OS at 12 months. Sub-study A and B: FAS included all randomized participants analyzed on an ITT basis.
    End point type
    Secondary
    End point timeframe
    From randomization (Day 1) up to 12 months
    End point values
    		 Sub-study A: Durvalumab Sub-study A: SoC Sub-study B: Durvalumab+Tremelimumab Sub-study B: SoC Sub-study B: Durvalumab Sub-study B: Tremelimumab
    Number of subjects analysed
    62
    64
    174
    118
    117
    60
    Units: percentage of participants
        number (confidence interval 95%)
    49.3 (36.3 to 61.0)
    31.3 (20.2 to 43.0)
    49.5 (41.7 to 56.7)
    38.8 (29.9 to 47.7)
    43.6 (34.4 to 52.4)
    41.2 (28.7 to 53.3)
    Statistical analysis title
    		 Sub-study B: Durvalumab+Tremelimumab Vs SoC
    Statistical analysis description
    For sub-study B: durvalumab plus tremelimumab treatment arm was compared with SoC.
    Comparison groups
    Sub-study B: Durvalumab+Tremelimumab v Sub-study B: SoC
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.063 [15]
    Method
    		 z-test
    Confidence interval
    Notes
    [14] - The variance is estimated using the delta method and Greenwood's formula.
    [15] - The z-test statistic is the ratio of log-transformed ratio of the cumulative hazards in the 2 treatment arms divided by square root of the variance.

    Secondary: PFS, Contribution of the Components Analysis of Sub-study B

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    End point title
    		 PFS, Contribution of the Components Analysis of Sub-study B [16]
    End point description
    The PFS was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdrew from randomized therapy or received another anti-cancer therapy prior to progression. The PFS was determined by Investigator assessments according to RECIST v1.1. PD was defined as at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm or progression of non-target lesions or the appearance of a new lesion. FAS included all randomized participants analyzed on an ITT basis.
    End point type
    Secondary
    End point timeframe
    Tumour scans performed at baseline then every ~8 weeks up to 48 weeks, then every ~12 weeks thereafter until confirmed disease progression. Assessed up to a maximum of approximately 3 years.
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: no statistical analyses performed
    End point values
    		 Sub-study B: Durvalumab+Tremelimumab Sub-study B: Durvalumab Sub-study B: Tremelimumab
    Number of subjects analysed
    174
    117
    60
    Units: months
        median (confidence interval 95%)
    3.5 (2.3 to 4.6)
    3.1 (1.9 to 3.7)
    2.1 (1.8 to 3.2)
    Statistical analysis title
    		 Sub-study B: Durvalumab+TremelimumabVsTremelimumab
    Statistical analysis description
    As part of the contribution of components analysis for sub-study B, durvalumab plus tremelimumab treatment arm was compared with tremelimumab monotherapy.
    Comparison groups
    Sub-study B: Durvalumab+Tremelimumab v Sub-study B: Tremelimumab
    Number of subjects included in analysis
    234
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.011 [18]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.92
    Notes
    [17] - Hazard ratio and CI are estimated from a stratified Cox proportional hazards model with Breslow method to control for ties, stratification factors SoC therapy, and histology in strata statement, and CI is calculated using profile likelihood approach.
    [18] - The P-value arises from a stratified log-rank test adjusting for SoC therapy and histology, with ties handled by the Breslow approach.
    Statistical analysis title
    		 Sub-study B: Durvalumab+Tremelimumab Vs Durvalumab
    Statistical analysis description
    As part of the contribution of components analysis for sub-study B, durvalumab plus tremelimumab treatment arm was compared with durvalumab monotherapy.
    Comparison groups
    Sub-study B: Durvalumab+Tremelimumab v Sub-study B: Durvalumab
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.282 [20]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.12
    Notes
    [19] - Hazard ratio and CI are estimated from a stratified Cox proportional hazards model with Breslow method to control for ties, stratification factors SoC therapy, and histology in strata statement, and CI is calculated using profile likelihood approach.
    [20] - The P-value arises from a stratified log-rank test adjusting for SoC therapy and histology, with ties handled by the Breslow approach.

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    The ORR was defined as the percentage of participants with at least 1 visit response of complete response (CR) or partial response (PR) among ITT participants who had measurable disease at baseline. CR was defined as disappearance of all target lesions (any pathological lymph nodes selected as target lesions must have a reduction in short axis to <10 mm) and PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum of diameters as long as criteria for PD are not met). The ORR was measured using Investigator assessments according to RECIST v1.1. Sub-study A and B: FAS included all randomized participants with measureable disease at baseline analyzed on an ITT basis.
    End point type
    Secondary
    End point timeframe
    Tumour scans performed at baseline then every ~8 weeks up to 48 weeks, then every ~12 weeks thereafter until confirmed disease progression. Assessed up to a maximum of approximately 3 years.
    End point values
    		 Sub-study A: Durvalumab Sub-study A: SoC Sub-study B: Durvalumab+Tremelimumab Sub-study B: SoC Sub-study B: Durvalumab Sub-study B: Tremelimumab
    Number of subjects analysed
    62
    64
    174
    118
    117
    60
    Units: percentage of participants
        number (not applicable)
    35.5
    12.5
    14.9
    6.8
    15.4
    6.7
    Statistical analysis title
    		 Sub-study A: Durvalumab Vs SoC
    Statistical analysis description
    For sub-study A: durvalumab monotherapy treatment arm was compared with SoC.
    Comparison groups
    Sub-study A: Durvalumab v Sub-study A: SoC
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.61
         upper limit
    		 10.1
    Notes
    [21] - Sub-study A was not powered and thus no formal statistical comparisons were performed. The analysis was performed using logistic regression adjusting for SoC therapy (gemcitabine/vinorelbine versus erlotinib) and histology (squamous versus all other histology types), with 95% CI calculated by profile likelihood.
    Statistical analysis title
    		 Sub-study B: Durvalumab+TremelimumabVsTremelimumab
    Statistical analysis description
    For sub-study B: durvalumab plus tremelimumab treatment arm was compared with tremelimumab monotherapy.
    Comparison groups
    Sub-study B: Durvalumab+Tremelimumab v Sub-study B: Tremelimumab
    Number of subjects included in analysis
    234
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [22]
    P-value
    		 = 0.109
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 8.61
    Notes
    [22] - The analysis was performed using logistic regression adjusting for SoC therapy (gemcitabine/vinorelbine versus erlotinib) and histology (squamous versus all other histology types), with 95% CI calculated by profile likelihood.
    Statistical analysis title
    		 Sub-study B: Durvalumab+Tremelimumab Vs Durvalumab
    Statistical analysis description
    For sub-study B: durvalumab plus tremelimumab treatment arm was compared with durvalumab monotherapy.
    Comparison groups
    Sub-study B: Durvalumab+Tremelimumab v Sub-study B: Durvalumab
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 = 0.923
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 1.89
    Notes
    [23] - The analysis was performed using logistic regression adjusting for SoC therapy (gemcitabine/vinorelbine versus erlotinib) and histology (squamous versus all other histology types), with 95% CI calculated by profile likelihood.
    Statistical analysis title
    		 Sub-study B: Durvalumab+Tremelimumab Vs SoC
    Statistical analysis description
    For sub-study B: durvalumab plus tremelimumab treatment arm was compared with SoC.
    Comparison groups
    Sub-study B: Durvalumab+Tremelimumab v Sub-study B: SoC
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [24]
    P-value
    		 = 0.037
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 5.94
    Notes
    [24] - The analysis was performed using logistic regression adjusting for SoC therapy (gemcitabine/vinorelbine versus erlotinib) and histology (squamous versus all other histology types), with 95% CI calculated by profile likelihood.

    Secondary: Duration of Response (DoR)

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    End point title
    		 Duration of Response (DoR)
    End point description
    The DoR was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression. The DoR was determined by Investigator assessments according to RECIST v1.1. PD was defined as at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm or progression of non-target lesions or the appearance of a new lesion. Sub-study A and B: FAS included all randomized participants with measureable disease at baseline analyzed on an ITT basis. Only participants with objective response were analyzed. Here, '99999' denotes 'upper limit of 75th percentile was not reached'.
    End point type
    Secondary
    End point timeframe
    Tumour scans performed at baseline then every ~8 weeks up to 48 weeks, then every ~12 weeks thereafter until confirmed disease progression. Assessed up to a maximum of approximately 3 years.
    End point values
    		 Sub-study A: Durvalumab Sub-study A: SoC Sub-study B: Durvalumab+Tremelimumab Sub-study B: SoC Sub-study B: Durvalumab Sub-study B: Tremelimumab
    Number of subjects analysed
    22
    8
    26
    8
    18
    4
    Units: months
        median (inter-quartile range (Q1-Q3))
    9.5 (3.0 to 17.8)
    4.8 (1.9 to 7.6)
    12.2 (6.5 to 99999)
    10.8 (5.6 to 12.2)
    10.0 (4.0 to 99999)
    4.7 (2.9 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Alive and Progression Free at 6 Months (APF6)

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    End point title
    		 Percentage of Participants Alive and Progression Free at 6 Months (APF6)
    End point description
    The APF6 was defined as the percentage of participants who were alive and progression free per RECIST v1.1 at 6 months after randomization per Kaplan-Meier estimate of PFS at 6 months. PD was defined as at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm or progression of non-target lesions or the appearance of a new lesion. Sub-study A and B: FAS included all randomized participants analyzed on an ITT basis.
    End point type
    Secondary
    End point timeframe
    Tumour scans performed at baseline then every ~8 weeks up to 6 months
    End point values
    		 Sub-study A: Durvalumab Sub-study A: SoC Sub-study B: Durvalumab+Tremelimumab Sub-study B: SoC Sub-study B: Durvalumab Sub-study B: Tremelimumab
    Number of subjects analysed
    62
    64
    174
    118
    117
    60
    Units: percentage of participants
        number (confidence interval 95%)
    35.5 (23.9 to 47.3)
    24.1 (14.1 to 35.6)
    31.5 (24.6 to 38.7)
    27.6 (19.0 to 36.7)
    27.2 (19.4 to 35.6)
    14.5 (6.9 to 24.9)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Alive and Progression Free at 12 Months (APF12)

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    End point title
    		 Percentage of Participants Alive and Progression Free at 12 Months (APF12)
    End point description
    The APF12 was defined as the percentage of participants who were alive and progression free per RECIST v1.1 at 12 months after randomization per Kaplan-Meier estimate of PFS at 12 months. PD was defined as at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm or progression of non-target lesions or the appearance of a new lesion. Sub-study A and B: FAS included all randomized participants analyzed on an ITT basis.
    End point type
    Secondary
    End point timeframe
    Tumour scans performed at baseline then every ~8 weeks up to 12 months.
    End point values
    		 Sub-study A: Durvalumab Sub-study A: SoC Sub-study B: Durvalumab+Tremelimumab Sub-study B: SoC Sub-study B: Durvalumab Sub-study B: Tremelimumab
    Number of subjects analysed
    62
    64
    174
    118
    117
    60
    Units: percentage of participants
        number (confidence interval 95%)
    19.4 (10.7 to 30.0)
    9.9 (3.8 to 19.3)
    20.6 (14.7 to 27.1)
    8.0 (3.4 to 15.2)
    15.0 (9.1 to 22.3)
    7.3 (2.4 to 16.0)
    No statistical analyses for this end point

    Secondary: Time From Randomisation to Second Progression (PFS2) of Sub-study B

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    End point title
    		 Time From Randomisation to Second Progression (PFS2) of Sub-study B [25]
    End point description
    The PFS2 was defined as the time from the date of randomization to the earliest of the progression event subsequent to that used for the PFS endpoint or death and determined by local standard clinical practice and have included any of the following: objective radiological, symptomatic progression, or death. PFS2 was reported for sub-study B only. The FAS included all randomized participants analyzed on an ITT basis.
    End point type
    Secondary
    End point timeframe
    Tumour scans performed at baseline then every ~8 weeks up to 48 weeks, then every ~12 weeks thereafter until first progression. Disease then assessed per local practice until 2nd progression. Assessed up to a maximum of approximately 3 years.
    Notes
    [25] - 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: no statistical analyses performed
    End point values
    		 Sub-study B: Durvalumab+Tremelimumab Sub-study B: SoC Sub-study B: Durvalumab Sub-study B: Tremelimumab
    Number of subjects analysed
    174
    118
    117
    60
    Units: months
        median (confidence interval 95%)
    9.1 (6.6 to 12.3)
    6.7 (4.7 to 8.9)
    8.0 (6.3 to 10.0)
    5.7 (3.2 to 10.0)
    Statistical analysis title
    		 Sub-study B: Durvalumab+Tremelimumab Vs SoC
    Statistical analysis description
    For sub-study B: durvalumab plus tremelimumab treatment arm was compared with SoC.
    Comparison groups
    Sub-study B: Durvalumab+Tremelimumab v Sub-study B: SoC
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [26]
    P-value
    		 = 0.002 [27]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.85
    Notes
    [26] - Hazard ratio and CI are estimated from a stratified Cox proportional hazards model with Breslow method to control for ties, stratification factors SoC therapy, and histology in strata statement, and CI is calculated using profile likelihood approach.
    [27] - The P-value arises from a stratified log-rank test adjusting for SoC therapy and histology, with ties handled by the Breslow approach.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signature of informed consent up to 90 days after the last dose of durvalumab and/or tremelimumab and 30 days after the last dose of SoC, approximately 15 months.
    Adverse event reporting additional description
    Sub-study A and B: Safety analysis set included all participants who received at least 1 dose of randomized treatment. Total # of deaths (all causes) was defined as death due to any cause (including disease progression) for the entire duration of the study assessed in all randomised participants.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Sub-study A: SoC
    Reporting group description
    		 Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.

    Reporting group title
    Sub-study B: Durvalumab+Tremelimumab
    Reporting group description
    		 Participants received durvalumab 20 mg/kg plus tremelimumab 1 mg/kg IV infusion Q4W for 12 weeks (4 doses) followed by durvalumab alone 10 mg/kg IV infusion Q2W for 34 weeks starting at Week 16 (up to 18 additional doses).

    Reporting group title
    Sub-study A: Durvalumab
    Reporting group description
    		 Participants received durvalumab 10 mg/kg IV infusion Q2W for 12 months (up to 26 doses).

    Reporting group title
    Sub-study B: SoC
    Reporting group description
    		 Participants received either erlotinib 150 mg tablet orally once daily; gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle; or vinorelbine 30 mg/m^2 IV infusion on Days 1, 8, 15, and 22 of a 28-day cycle until PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment criterion occurred.

    Reporting group title
    Sub-study B: Tremelimumab
    Reporting group description
    		 Participants received tremelimumab 10 mg/kg IV infusion Q4W for 24 weeks followed by Q12W for 24 weeks (up to 9 doses).

    Reporting group title
    Sub-study B: Durvalumab
    Reporting group description
    		 Participants received durvalumab 10 mg/kg IV infusion Q2W for 12 months (up to 26 doses).

    Serious adverse events
    		 Sub-study A: SoC Sub-study B: Durvalumab+Tremelimumab Sub-study A: Durvalumab Sub-study B: SoC Sub-study B: Tremelimumab Sub-study B: Durvalumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 63 (25.40%)
    65 / 173 (37.57%)
    23 / 62 (37.10%)
    28 / 110 (25.45%)
    23 / 60 (38.33%)
    36 / 117 (30.77%)
         number of deaths (all causes)
    55
    118
    48
    90
    46
    83
         number of deaths resulting from adverse events
    0
    0
    0
    0
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colorectal cancer
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    1 / 60 (1.67%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour necrosis
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer stage IV
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphangiosis carcinomatosa
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic venous thrombosis
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Internal haemorrhage
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    1 / 62 (1.61%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    1 / 62 (1.61%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 63 (1.59%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    1 / 62 (1.61%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Perforation
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    2 / 117 (1.71%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 63 (0.00%)
    2 / 173 (1.16%)
    0 / 62 (0.00%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    2 / 117 (1.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    1 / 62 (1.61%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchial obstruction
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 63 (0.00%)
    7 / 173 (4.05%)
    1 / 62 (1.61%)
    2 / 110 (1.82%)
    0 / 60 (0.00%)
    2 / 117 (1.71%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 7
    0 / 1
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 63 (1.59%)
    2 / 173 (1.16%)
    1 / 62 (1.61%)
    0 / 110 (0.00%)
    1 / 60 (1.67%)
    2 / 117 (1.71%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    0 / 1
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    1 / 60 (1.67%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 63 (0.00%)
    5 / 173 (2.89%)
    2 / 62 (3.23%)
    1 / 110 (0.91%)
    1 / 60 (1.67%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 2
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    1 / 62 (1.61%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Bronchial fistula
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 63 (0.00%)
    2 / 173 (1.16%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 63 (0.00%)
    2 / 173 (1.16%)
    0 / 62 (0.00%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    2 / 62 (3.23%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 63 (0.00%)
    2 / 173 (1.16%)
    3 / 62 (4.84%)
    0 / 110 (0.00%)
    2 / 60 (3.33%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 3
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 63 (0.00%)
    5 / 173 (2.89%)
    0 / 62 (0.00%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    1 / 62 (1.61%)
    1 / 110 (0.91%)
    2 / 60 (3.33%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 1
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    1 / 1
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    1 / 62 (1.61%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Amylase increased
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    1 / 62 (1.61%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    1 / 62 (1.61%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fractured ischium
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 63 (0.00%)
    2 / 173 (1.16%)
    1 / 62 (1.61%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    1 / 62 (1.61%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vocal cord paralysis
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    1 / 60 (1.67%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    1 / 62 (1.61%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    1 / 62 (1.61%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    1 / 60 (1.67%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 63 (3.17%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    5 / 63 (7.94%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Enterocolitis
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 63 (0.00%)
    3 / 173 (1.73%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    7 / 60 (11.67%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
    0 / 0
    0 / 0
    7 / 8
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 63 (0.00%)
    3 / 173 (1.73%)
    1 / 62 (1.61%)
    0 / 110 (0.00%)
    5 / 60 (8.33%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
    1 / 1
    0 / 0
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    1 / 60 (1.67%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal toxicity
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    1 / 60 (1.67%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 63 (0.00%)
    3 / 173 (1.73%)
    1 / 62 (1.61%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    1 / 62 (1.61%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 63 (0.00%)
    3 / 173 (1.73%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    1 / 62 (1.61%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    1 / 62 (1.61%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    1 / 62 (1.61%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glucocorticoid deficiency
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    1 / 62 (1.61%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    1 / 62 (1.61%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroiditis
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    1 / 62 (1.61%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 63 (0.00%)
    2 / 173 (1.16%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    2 / 117 (1.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    2 / 60 (3.33%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis viral
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    1 / 60 (1.67%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Infection
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    1 / 60 (1.67%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    1 / 62 (1.61%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 63 (4.76%)
    7 / 173 (4.05%)
    4 / 62 (6.45%)
    2 / 110 (1.82%)
    2 / 60 (3.33%)
    2 / 117 (1.71%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 7
    1 / 5
    0 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 173 (0.00%)
    1 / 62 (1.61%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 63 (1.59%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    2 / 62 (3.23%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Varicella zoster virus infection
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    1 / 60 (1.67%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    1 / 62 (1.61%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 173 (0.58%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 173 (0.00%)
    0 / 62 (0.00%)
    0 / 110 (0.00%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Sub-study A: SoC Sub-study B: Durvalumab+Tremelimumab Sub-study A: Durvalumab Sub-study B: SoC Sub-study B: Tremelimumab Sub-study B: Durvalumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    59 / 63 (93.65%)
    139 / 173 (80.35%)
    52 / 62 (83.87%)
    100 / 110 (90.91%)
    48 / 60 (80.00%)
    99 / 117 (84.62%)
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    4 / 63 (6.35%)
    2 / 173 (1.16%)
    2 / 62 (3.23%)
    3 / 110 (2.73%)
    2 / 60 (3.33%)
    4 / 117 (3.42%)
         occurrences all number
    4
    3
    2
    6
    2
    5
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 63 (3.17%)
    11 / 173 (6.36%)
    1 / 62 (1.61%)
    8 / 110 (7.27%)
    5 / 60 (8.33%)
    2 / 117 (1.71%)
         occurrences all number
    2
    12
    2
    12
    6
    5
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 63 (4.76%)
    10 / 173 (5.78%)
    1 / 62 (1.61%)
    10 / 110 (9.09%)
    5 / 60 (8.33%)
    5 / 117 (4.27%)
         occurrences all number
    3
    11
    2
    15
    6
    9
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 63 (3.17%)
    4 / 173 (2.31%)
    4 / 62 (6.45%)
    1 / 110 (0.91%)
    1 / 60 (1.67%)
    1 / 117 (0.85%)
         occurrences all number
    3
    4
    5
    1
    1
    2
    Neutrophil count decreased
         subjects affected / exposed
    9 / 63 (14.29%)
    2 / 173 (1.16%)
    2 / 62 (3.23%)
    18 / 110 (16.36%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    33
    2
    2
    43
    0
    1
    Platelet count decreased
         subjects affected / exposed
    6 / 63 (9.52%)
    1 / 173 (0.58%)
    1 / 62 (1.61%)
    8 / 110 (7.27%)
    0 / 60 (0.00%)
    0 / 117 (0.00%)
         occurrences all number
    8
    1
    1
    27
    0
    0
    Weight decreased
         subjects affected / exposed
    4 / 63 (6.35%)
    14 / 173 (8.09%)
    6 / 62 (9.68%)
    4 / 110 (3.64%)
    4 / 60 (6.67%)
    8 / 117 (6.84%)
         occurrences all number
    4
    14
    7
    4
    4
    8
    White blood cell count decreased
         subjects affected / exposed
    6 / 63 (9.52%)
    2 / 173 (1.16%)
    1 / 62 (1.61%)
    11 / 110 (10.00%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    21
    2
    1
    32
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 63 (7.94%)
    9 / 173 (5.20%)
    6 / 62 (9.68%)
    5 / 110 (4.55%)
    3 / 60 (5.00%)
    8 / 117 (6.84%)
         occurrences all number
    5
    10
    6
    6
    3
    8
    Headache
         subjects affected / exposed
    7 / 63 (11.11%)
    17 / 173 (9.83%)
    9 / 62 (14.52%)
    6 / 110 (5.45%)
    5 / 60 (8.33%)
    8 / 117 (6.84%)
         occurrences all number
    8
    19
    11
    8
    6
    8
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    4 / 63 (6.35%)
    2 / 173 (1.16%)
    0 / 62 (0.00%)
    7 / 110 (6.36%)
    1 / 60 (1.67%)
    0 / 117 (0.00%)
         occurrences all number
    8
    3
    0
    15
    1
    0
    Neutropenia
         subjects affected / exposed
    7 / 63 (11.11%)
    3 / 173 (1.73%)
    0 / 62 (0.00%)
    18 / 110 (16.36%)
    1 / 60 (1.67%)
    0 / 117 (0.00%)
         occurrences all number
    40
    7
    0
    48
    3
    0
    Anaemia
         subjects affected / exposed
    17 / 63 (26.98%)
    17 / 173 (9.83%)
    5 / 62 (8.06%)
    27 / 110 (24.55%)
    5 / 60 (8.33%)
    11 / 117 (9.40%)
         occurrences all number
    22
    18
    5
    49
    5
    13
    Thrombocytopenia
         subjects affected / exposed
    5 / 63 (7.94%)
    3 / 173 (1.73%)
    1 / 62 (1.61%)
    11 / 110 (10.00%)
    2 / 60 (3.33%)
    4 / 117 (3.42%)
         occurrences all number
    10
    6
    2
    15
    2
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    8 / 63 (12.70%)
    31 / 173 (17.92%)
    6 / 62 (9.68%)
    17 / 110 (15.45%)
    9 / 60 (15.00%)
    16 / 117 (13.68%)
         occurrences all number
    17
    39
    6
    19
    9
    21
    Fatigue
         subjects affected / exposed
    10 / 63 (15.87%)
    25 / 173 (14.45%)
    10 / 62 (16.13%)
    24 / 110 (21.82%)
    4 / 60 (6.67%)
    22 / 117 (18.80%)
         occurrences all number
    16
    27
    10
    30
    4
    24
    Pyrexia
         subjects affected / exposed
    6 / 63 (9.52%)
    20 / 173 (11.56%)
    9 / 62 (14.52%)
    23 / 110 (20.91%)
    6 / 60 (10.00%)
    12 / 117 (10.26%)
         occurrences all number
    8
    27
    14
    33
    7
    15
    Oedema peripheral
         subjects affected / exposed
    3 / 63 (4.76%)
    16 / 173 (9.25%)
    6 / 62 (9.68%)
    9 / 110 (8.18%)
    2 / 60 (3.33%)
    8 / 117 (6.84%)
         occurrences all number
    5
    17
    8
    10
    3
    10
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 63 (3.17%)
    4 / 173 (2.31%)
    4 / 62 (6.45%)
    4 / 110 (3.64%)
    1 / 60 (1.67%)
    2 / 117 (1.71%)
         occurrences all number
    3
    4
    4
    4
    1
    2
    Malaise
         subjects affected / exposed
    4 / 63 (6.35%)
    3 / 173 (1.73%)
    1 / 62 (1.61%)
    5 / 110 (4.55%)
    1 / 60 (1.67%)
    8 / 117 (6.84%)
         occurrences all number
    8
    3
    1
    5
    1
    8
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    8 / 63 (12.70%)
    36 / 173 (20.81%)
    9 / 62 (14.52%)
    18 / 110 (16.36%)
    16 / 60 (26.67%)
    25 / 117 (21.37%)
         occurrences all number
    8
    45
    13
    26
    20
    33
    Nausea
         subjects affected / exposed
    15 / 63 (23.81%)
    28 / 173 (16.18%)
    11 / 62 (17.74%)
    22 / 110 (20.00%)
    11 / 60 (18.33%)
    20 / 117 (17.09%)
         occurrences all number
    20
    33
    12
    32
    16
    25
    Stomatitis
         subjects affected / exposed
    5 / 63 (7.94%)
    10 / 173 (5.78%)
    5 / 62 (8.06%)
    5 / 110 (4.55%)
    1 / 60 (1.67%)
    3 / 117 (2.56%)
         occurrences all number
    5
    11
    6
    6
    3
    3
    Vomiting
         subjects affected / exposed
    4 / 63 (6.35%)
    17 / 173 (9.83%)
    8 / 62 (12.90%)
    8 / 110 (7.27%)
    7 / 60 (11.67%)
    18 / 117 (15.38%)
         occurrences all number
    5
    17
    8
    13
    10
    22
    Abdominal pain
         subjects affected / exposed
    4 / 63 (6.35%)
    5 / 173 (2.89%)
    4 / 62 (6.45%)
    2 / 110 (1.82%)
    2 / 60 (3.33%)
    2 / 117 (1.71%)
         occurrences all number
    4
    5
    4
    5
    2
    2
    Constipation
         subjects affected / exposed
    15 / 63 (23.81%)
    14 / 173 (8.09%)
    13 / 62 (20.97%)
    11 / 110 (10.00%)
    4 / 60 (6.67%)
    15 / 117 (12.82%)
         occurrences all number
    16
    15
    15
    12
    4
    16
    Abdominal pain upper
         subjects affected / exposed
    1 / 63 (1.59%)
    2 / 173 (1.16%)
    1 / 62 (1.61%)
    4 / 110 (3.64%)
    2 / 60 (3.33%)
    7 / 117 (5.98%)
         occurrences all number
    1
    2
    1
    6
    2
    7
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    9 / 63 (14.29%)
    25 / 173 (14.45%)
    11 / 62 (17.74%)
    15 / 110 (13.64%)
    6 / 60 (10.00%)
    16 / 117 (13.68%)
         occurrences all number
    11
    26
    12
    16
    6
    17
    Rhinorrhoea
         subjects affected / exposed
    1 / 63 (1.59%)
    4 / 173 (2.31%)
    6 / 62 (9.68%)
    2 / 110 (1.82%)
    1 / 60 (1.67%)
    1 / 117 (0.85%)
         occurrences all number
    1
    4
    6
    2
    1
    1
    Haemoptysis
         subjects affected / exposed
    2 / 63 (3.17%)
    6 / 173 (3.47%)
    4 / 62 (6.45%)
    4 / 110 (3.64%)
    1 / 60 (1.67%)
    7 / 117 (5.98%)
         occurrences all number
    2
    7
    8
    4
    1
    7
    Cough
         subjects affected / exposed
    5 / 63 (7.94%)
    24 / 173 (13.87%)
    11 / 62 (17.74%)
    14 / 110 (12.73%)
    5 / 60 (8.33%)
    15 / 117 (12.82%)
         occurrences all number
    5
    29
    13
    15
    5
    20
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    4 / 63 (6.35%)
    4 / 173 (2.31%)
    0 / 62 (0.00%)
    5 / 110 (4.55%)
    3 / 60 (5.00%)
    4 / 117 (3.42%)
         occurrences all number
    4
    4
    0
    5
    3
    6
    Rash
         subjects affected / exposed
    9 / 63 (14.29%)
    14 / 173 (8.09%)
    3 / 62 (4.84%)
    17 / 110 (15.45%)
    9 / 60 (15.00%)
    7 / 117 (5.98%)
         occurrences all number
    9
    15
    4
    17
    11
    9
    Pruritus
         subjects affected / exposed
    2 / 63 (3.17%)
    28 / 173 (16.18%)
    7 / 62 (11.29%)
    5 / 110 (4.55%)
    14 / 60 (23.33%)
    11 / 117 (9.40%)
         occurrences all number
    2
    36
    8
    5
    17
    12
    Dermatitis acneiform
         subjects affected / exposed
    6 / 63 (9.52%)
    6 / 173 (3.47%)
    3 / 62 (4.84%)
    4 / 110 (3.64%)
    0 / 60 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    6
    11
    4
    4
    0
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 63 (6.35%)
    6 / 173 (3.47%)
    7 / 62 (11.29%)
    5 / 110 (4.55%)
    5 / 60 (8.33%)
    7 / 117 (5.98%)
         occurrences all number
    4
    6
    7
    5
    5
    7
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 63 (0.00%)
    14 / 173 (8.09%)
    6 / 62 (9.68%)
    1 / 110 (0.91%)
    3 / 60 (5.00%)
    10 / 117 (8.55%)
         occurrences all number
    0
    15
    6
    1
    4
    11
    Hyperthyroidism
         subjects affected / exposed
    1 / 63 (1.59%)
    17 / 173 (9.83%)
    2 / 62 (3.23%)
    0 / 110 (0.00%)
    1 / 60 (1.67%)
    6 / 117 (5.13%)
         occurrences all number
    1
    17
    2
    0
    1
    7
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    2 / 63 (3.17%)
    9 / 173 (5.20%)
    2 / 62 (3.23%)
    5 / 110 (4.55%)
    6 / 60 (10.00%)
    9 / 117 (7.69%)
         occurrences all number
    2
    11
    2
    5
    7
    11
    Myalgia
         subjects affected / exposed
    3 / 63 (4.76%)
    9 / 173 (5.20%)
    2 / 62 (3.23%)
    4 / 110 (3.64%)
    1 / 60 (1.67%)
    5 / 117 (4.27%)
         occurrences all number
    4
    9
    2
    4
    1
    5
    Musculoskeletal pain
         subjects affected / exposed
    4 / 63 (6.35%)
    7 / 173 (4.05%)
    6 / 62 (9.68%)
    5 / 110 (4.55%)
    1 / 60 (1.67%)
    12 / 117 (10.26%)
         occurrences all number
    4
    10
    8
    5
    1
    12
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 63 (3.17%)
    7 / 173 (4.05%)
    3 / 62 (4.84%)
    2 / 110 (1.82%)
    2 / 60 (3.33%)
    7 / 117 (5.98%)
         occurrences all number
    2
    7
    5
    2
    2
    7
    Back pain
         subjects affected / exposed
    6 / 63 (9.52%)
    11 / 173 (6.36%)
    7 / 62 (11.29%)
    4 / 110 (3.64%)
    4 / 60 (6.67%)
    14 / 117 (11.97%)
         occurrences all number
    7
    13
    7
    4
    4
    15
    Arthralgia
         subjects affected / exposed
    3 / 63 (4.76%)
    16 / 173 (9.25%)
    7 / 62 (11.29%)
    2 / 110 (1.82%)
    4 / 60 (6.67%)
    10 / 117 (8.55%)
         occurrences all number
    3
    19
    8
    4
    5
    10
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 63 (1.59%)
    15 / 173 (8.67%)
    3 / 62 (4.84%)
    5 / 110 (4.55%)
    1 / 60 (1.67%)
    7 / 117 (5.98%)
         occurrences all number
    1
    18
    5
    5
    1
    8
    Influenza
         subjects affected / exposed
    0 / 63 (0.00%)
    3 / 173 (1.73%)
    2 / 62 (3.23%)
    0 / 110 (0.00%)
    1 / 60 (1.67%)
    6 / 117 (5.13%)
         occurrences all number
    0
    3
    3
    0
    1
    6
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    3 / 63 (4.76%)
    3 / 173 (1.73%)
    5 / 62 (8.06%)
    2 / 110 (1.82%)
    9 / 60 (15.00%)
    8 / 117 (6.84%)
         occurrences all number
    3
    3
    6
    2
    10
    10
    Hyperkalaemia
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 173 (0.00%)
    5 / 62 (8.06%)
    1 / 110 (0.91%)
    0 / 60 (0.00%)
    4 / 117 (3.42%)
         occurrences all number
    2
    0
    5
    1
    0
    5
    Decreased appetite
         subjects affected / exposed
    20 / 63 (31.75%)
    34 / 173 (19.65%)
    16 / 62 (25.81%)
    23 / 110 (20.91%)
    12 / 60 (20.00%)
    27 / 117 (23.08%)
         occurrences all number
    24
    39
    19
    24
    12
    28
    Dehydration
         subjects affected / exposed
    1 / 63 (1.59%)
    1 / 173 (0.58%)
    1 / 62 (1.61%)
    1 / 110 (0.91%)
    4 / 60 (6.67%)
    0 / 117 (0.00%)
         occurrences all number
    3
    1
    1
    1
    6
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jun 2014
    Key changes from this amendment are listed under Amendment 3.
    28 Jul 2014
    Key changes from this amendment are listed under Amendment 3.
    08 Oct 2014
    The study design was updated to include 2 independent sub-studies as follows: Sub-study A was designed to enroll PD-L1 high non-small cell lung cancer (NSCLC) participants into either the durvalumab monotherapy arm or SoC treatment arm in a 1:1 ratio. Sub-study B was designed to enroll PD-L1 low/neg NSCLC participants into either durvalumab in combination with tremelimumab treatment arm, durvalumab monotherapy arm, tremelimumab monotherapy arm, or SoC treatment arm in a 1:1:1:1 ratio. PD-L1 tumor status was assessed as part of the pre-screening process. The study objectives were updated to include the additional treatment arms. Participants selection criteria were updated to include new treatment arms, PD-L1 tumor status (including requirements for archival tumor sample), retreatment criteria, additional exclusion criteria for sub-study B, and restrictions during the study. Descriptions of study treatments, treatment regimens, management of toxicity and adverse event of special interest (AESI), treatment compliance, and discontinuation of study treatment were updated. The evaluation and calculation of study variables, and statistical methods were updated.
    27 Mar 2015
    Deep sustained response was removed from the secondary objectives and endpoints. The dose regimen for sub-study B durvalumab in combination with tremelimumab treatment arm was updated to durvalumab 20 mg/kg plus tremelimumab 1 mg/kg Q4W IV for up to 12 weeks (4 doses) then durvalumab alone (10 mg/kg Q2W IV, starting at Week 16, for 34 weeks [18 doses]). Randomization to treatment arms for sub-study B was changed to a 3:2:2:1 ratio (durvalumab in combination with tremelimumab: SoC: durvalumab monotherapy: tremelimumab monotherapy, respectively). Language was updated to allow participants enrolled in the durvalumab in combination with tremelimumab treatment arm of sub-study B who progress while in the durvalumab monotherapy period to be retreated with the combination. Clarification of the process of treatment and retreatment in each sub-study was also provided. The exclusion criterion regarding participants with known epidermal growth factor receptor (EGFR) tyrosine kinase (TK) activating mutations was updated to allow participants with EGFR TK inactivating mutations (eg, exon 20) to enroll.
    30 Dec 2015
    Language regarding treatment through disease progression and retreatment within the inclusion criteria was updated and moved to a separate section of the protocol. New safety data were added, including an updated list of AESIs and a new appendix containing dose modification and toxicity management guidelines. Inclusion criteria 6 and 7 were updated with new parameters for both mandatory and optional archival tumor samples. Exclusion criterion 2 was updated to exclude participants from other durvalumab studies, and the language regarding participants with tuberculosis in exclusion criterion 25 was updated.
    31 Aug 2016
    The number of participants planned, determination of sample size, and statistics were updated. The outcome measures using blinded independent central review (BICR) assessments according to RECIST v1.1 were removed and replaced with Investigator assessments according to RECIST v1.1. The exploratory objective and outcome utilizing BICR assessments according to immune-related response criteria were also removed. Language was updated to clarify that the interim analysis will be conducted for Sub-study B only. The retreatment exclusion criteria were updated to remove the 28-day wash-out period before retreatment. The text regarding immunosuppressive medication was updated, and 3 additional criteria for concomitant medication use were included.
    19 Sep 2017
    The maximum period of retreatment was updated for all immunotherapy arms from a maximum of 12 months to as long as the participant gained clinical benefit, as judged by the Investigator. The dose modification and toxicity management guidelines for immune-mediated, infusion-related, and non immune-mediated reactions were updated, and language was updated on AESIs, including the list of AESIs. Language was added regarding timing of final PFS and OS analyses.
    08 Jan 2018
    The toxicity management guidelines for immune-mediated, infusion-related, and non-immune-mediated reactions and list of AESIs were updated.
    07 Feb 2020
    Toxicity management guidelines will be a separate annex to the protocol. Administrative changes.

    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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