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    Clinical Trial Results:
    An Open-Label, Randomized, Phase IIIb Trial Evaluating the Efficacy and Safety of Standard of Care ± Continuous Bevacizumab Treatment Beyond Progression of Disease in Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer (NSCLC) after First-Line Treatment with Bevacizumab plus a Platinum Doublet-Containing Chemotherapy

    Summary
    EudraCT number
    		 2010-022645-14
    Trial protocol
    		 ES   AT   NL   FR   SK   DK   DE   GR   IT  
    Global end of trial date
    24 Jun 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Jul 2017
    First version publication date
    09 Jul 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MO22097
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01351415
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.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
    24 Jun 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to assess the efficacy of continuous bevacizumab treatment beyond first progression of disease (PD) as measured by overall survival (OS)
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Jun 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 12
    Country: Number of subjects enrolled
    Austria: 14
    Country: Number of subjects enrolled
    Brazil: 9
    Country: Number of subjects enrolled
    Denmark: 6
    Country: Number of subjects enrolled
    France: 112
    Country: Number of subjects enrolled
    Germany: 63
    Country: Number of subjects enrolled
    Greece: 28
    Country: Number of subjects enrolled
    Italy: 36
    Country: Number of subjects enrolled
    Japan: 52
    Country: Number of subjects enrolled
    Lebanon: 3
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    Netherlands: 26
    Country: Number of subjects enrolled
    Slovakia: 3
    Country: Number of subjects enrolled
    Spain: 60
    Country: Number of subjects enrolled
    United Arab Emirates: 3
    Country: Number of subjects enrolled
    United States: 54
    Worldwide total number of subjects
    485
    EEA total number of subjects
    348
    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)
    284
    From 65 to 84 years
    201
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This phase 3b study was conducted across 16 different countries and enrolled 485 subjects. Subjects were 18 years or older and had locally recurrent or metastatic non-squamous Non-Small Cell Lung Cancer (NSCLC)

    Pre-assignment
    Screening details
    		 A total of 485 subjects were enrolled and randomised into the study. Of these, 475 subjects were treated; 243 subjects received bevacizumab plus standard of care (SoC) and 232 subjects received SoC alone.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bevacizumab + Standard of Care
    Arm description
    		 Subjects received bevacizumab on Day 1 of every 21-days cycle along with standard of care, until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received bevacizumab 7.5 milligram per kilogram (mg/kg) intravenously (i.v.) or 15 mg/kg i.v. on Day 1 every 21 days (±3 days) from Cycle 1 until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurred first).

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Erlotinib 150 mg daily as SOC treatment until the occurrence of unacceptable toxicity or withdrawal of consent (whichever occurred first)

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received Docetaxel 60 or 75 milligram per square meter (mg/m^2) on Day 1 every 21 days (±3 days) as 2nd-line SoC treatment until the occurrence of unacceptable toxicity or withdrawal of consent (whichever occurred first)

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received Pemetrexed 500 mg/m^2 IV over 10 minutes on Day 1 every 21 days (±3 days) as 2nd-line SOC treatment until the occurrence of unacceptable toxicity or withdrawal of consent (whichever occurred first)

    Arm title
    		 Standard of Care
    Arm description
    		 Subjects received investigator's choice of standard of care (Erlotinib or Docetaxel or Pemetrexed) according to local practice until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Erlotinib 150 mg daily as SOC treatment until the occurrence of unacceptable toxicity or withdrawal of consent (whichever occurred first)

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received Pemetrexed 500 mg/m^2 IV over 10 minutes on Day 1 every 21 days (±3 days) as 2nd-line SOC treatment until the occurrence of unacceptable toxicity or withdrawal of consent (whichever occurred first)

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received Docetaxel 60 or 75 milligram per square meter (mg/m^2) on Day 1 every 21 days (±3 days) as 2nd-line SoC treatment until the occurrence of unacceptable toxicity or withdrawal of consent (whichever occurred first)

    Number of subjects in period 1
    		Bevacizumab + Standard of Care Standard of Care
    Started
    245
    240
    Completed
    0
    0
    Not completed
    245
    240
         Adverse event, serious fatal
    190
    187
         Consent withdrawn by subject
    15
    17
         Physician decision
    2
    3
         Never Started
    5
    5
         Trial termination by the Sponsor
    28
    19
         Reason unknown
    -
    2
         Lost to follow-up
    5
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bevacizumab + Standard of Care
    Reporting group description
    		 Subjects received bevacizumab on Day 1 of every 21-days cycle along with standard of care, until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).

    Reporting group title
    Standard of Care
    Reporting group description
    		 Subjects received investigator's choice of standard of care (Erlotinib or Docetaxel or Pemetrexed) according to local practice until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).

    Reporting group values
    		 Bevacizumab + Standard of Care Standard of Care Total
    Number of subjects
    		 245 240 485
    Age categorical
    Units: Subjects
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 61.5 ( 9.61 ) 61.8 ( 9.29 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 90 102 192
        Male
    		 155 138 293

    End points

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    End points reporting groups
    Reporting group title
    Bevacizumab + Standard of Care
    Reporting group description
    		 Subjects received bevacizumab on Day 1 of every 21-days cycle along with standard of care, until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).

    Reporting group title
    Standard of Care
    Reporting group description
    		 Subjects received investigator's choice of standard of care (Erlotinib or Docetaxel or Pemetrexed) according to local practice until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival (OS) was defined as the time from the date of randomisation at first progression of disease to the date of death, regardless of the cause of death. Intent to treat population included all randomised subjects.
    End point type
    Primary
    End point timeframe
    Up to data cut-off date 24 June 2016 (approximately 5 years)
    End point values
    		 Bevacizumab + Standard of Care Standard of Care
    Number of subjects analysed
    245
    240
    Units: Months
        median (confidence interval 90%)
    11.86 (10.22 to 13.67)
    10.22 (8.61 to 11.93)
    Statistical analysis title
    		 Overall Survival (OS)
    Statistical analysis description
    The stratification factors for Log-Rank test and Hazard Ratio (HR) are the type of planned 2nd-line SoC treatment, the number of cycles of bevacizumab maintenance treatment prior to first PD and smoking status.
    Comparison groups
    Bevacizumab + Standard of Care v Standard of Care
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1044
    Method
    		 Stratified Log-Rank test
    Parameter type
    		 Stratified Hazard Ratio
    Point estimate
    0.84
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1

    Secondary: Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)

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    End point title
    		 Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
    End point description
    PFS was defined as the time from start of treatment to the first event of death or PD. Tumor response was assessed by the IRF according to RECIST v1.1. Progression of disease (PD) was defined as ≥20% increase in sum longest diameter (LD) in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. PFS2 is defined as the time between randomisation at PD1 and the date of PD2 or death, whichever occurs first. PFS3 is defined as the time between PD2 and the date of PD3 or death, whichever occurs first. Intent to treat population included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Up to data cut-off date 24 June 2016 (approximately 5 years)
    End point values
    		 Bevacizumab + Standard of Care Standard of Care
    Number of subjects analysed
    245
    240
    Units: Months
    median (confidence interval 90%)
        PFS 2
    5.45 (4.21 to 5.68)
    3.98 (3.38 to 4.3)
        PFS 3
    4.01 (2.86 to 4.47)
    2.6 (2.33 to 2.92)
    Statistical analysis title
    		 PFS2
    Statistical analysis description
    PFS2: The stratification factors for Log-Rank test are the type of planned 2nd-line SoC treatment, the number of cycles of bevacizumab maintenance treatment prior to PD1 and the smoking status.
    Comparison groups
    Bevacizumab + Standard of Care v Standard of Care
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0573
    Method
    		 Stratified Log-Rank test
    Parameter type
    		 Stratified Hazard Ratio
    Point estimate
    0.83
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 0.98
    Statistical analysis title
    		 PFS3
    Statistical analysis description
    PFS3: The stratification factors for Log Rank test and Hazard Ratio (HR) are the type of planned 2nd-line SOC treatment, the number of cycles of bevacizumab maintenance treatment prior to first PD and smoking status.
    Comparison groups
    Bevacizumab + Standard of Care v Standard of Care
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0045
    Method
    		 Stratified Log-Rank test
    Parameter type
    		 Stratified Hazard Ratio
    Point estimate
    0.63
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.83

    Secondary: Percentage of Subjects with Objective Response According to RECIST v1.1

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    End point title
    		 Percentage of Subjects with Objective Response According to RECIST v1.1
    End point description
    The objective response is defined as complete response (CR) or partial response (PR) assessed according to the RECIST v.1.1 criteria with baseline tumour assessment as the reference. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumour marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR was defined ≥ 30 percent (%) decrease in sum of longest diameter of target lesions in reference to Baseline sum longest diameter. Response was to be confirmed ≥4 weeks after the initial assessment of CR or PR. Intent to treat population included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Up to data cut-off date 24 June 2016 (approximately 5 years)
    End point values
    		 Bevacizumab + Standard of Care Standard of Care
    Number of subjects analysed
    245
    240
    Units: Percentage of Subjects
        number (confidence interval 90%)
    8.6 (5.86 to 12.21)
    6.3 (3.91 to 9.5)
    Statistical analysis title
    		 Objective Response
    Statistical analysis description
    The stratification factors for Cochran-Mantel-Haenszel test are the type of planned 2nd-line SoC treatment, the number of cycles of Bevacizumab maintenance treatment prior to PD1 and the smoking status.
    Comparison groups
    Bevacizumab + Standard of Care v Standard of Care
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.081
    Method
    		 Stratified Cochran-Mantel-Haenszel test
    Parameter type
    		 Estimated difference in response rate
    Point estimate
    0.0237
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.0156
         upper limit
    		 0.063

    Secondary: Percentage of Subjects With Disease Control According to RECIST v1.1

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    End point title
    		 Percentage of Subjects With Disease Control According to RECIST v1.1
    End point description
    The disease control rate is defined as CR or PR or stable disease (SD) assessed according to the RECIST v.1.1 criteria with baseline tumour assessment as the reference. SD was defined as neither sufficient shrinkage to qualify for a PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameter since treatment started for target lesions and the persistence of 1 or more non-target lesions. Intent to treat population included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Up to data cut-off date 24 June 2016 (approximately 5 years)
    End point values
    		 Bevacizumab + Standard of Care Standard of Care
    Number of subjects analysed
    245
    240
    Units: Percentage of Subjects
        number (confidence interval 90%)
    80.2 (75.57 to 84.36)
    77 (72.06 to 81.41)
    Statistical analysis title
    		 Disease Control Rate
    Statistical analysis description
    The stratification factors for Cochran-Mantel-Haenszel test are the type of planned 2nd-line SoC treatment, the number of cycles of Bevacizumab maintenance treatment prior to PD1 and the smoking status.
    Comparison groups
    Bevacizumab + Standard of Care v Standard of Care
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0218
    Method
    		 Stratified Cochran-Mantel-Haenszel test
    Parameter type
    		 Estimated difference in Disease Control
    Point estimate
    0.0326
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.0288
         upper limit
    		 0.094

    Secondary: Duration of Response (DoR) According to RECIST v1.1

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    End point title
    		 Duration of Response (DoR) According to RECIST v1.1
    End point description
    DOR is defined as the time that measurement criteria are met for objective response (CR/PR) (whichever status is recorded first) until the first date of progression or death is documented. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumour marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than < 10 mm. PR was defined as greater than or equal to ≥30 % decrease in sum of longest diameter of target lesions in reference to baseline sum longest diameter. Intent to treat population included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Up to data cut-off date 24 June 2016 (approximately 5 years)
    End point values
    		 Bevacizumab + Standard of Care Standard of Care
    Number of subjects analysed
    245
    240
    Units: Months
        median (confidence interval 90%)
    7.46 (5.39 to 8.54)
    6.24 (3.52 to 6.83)
    Statistical analysis title
    		 DOR
    Statistical analysis description
    The stratification factors for Log-Rank test are the type of planned 2nd-line SoC treatment, the number of cycles of Bevacizumab maintenance treatment prior to PD1 and the smoking status.
    Comparison groups
    Bevacizumab + Standard of Care v Standard of Care
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.06
    Method
    		 Stratified Log-Rank test
    Parameter type
    		 Stratified Hazard Ratio
    Point estimate
    0.29
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.09
         upper limit
    		 0.9

    Secondary: Percentage of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Percentage of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study and laboratory or clinical tests that resulted in a change in treatment or discontinuation from study drug were reported as adverse events. A SAE was any experience that: resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or was medically significant. The safety population included all subjects who had received at least one dose of any study drug.
    End point type
    Secondary
    End point timeframe
    Up to data cut-off date 24 June 2016 (approximately 5 years)
    End point values
    		 Bevacizumab + Standard of Care Standard of Care
    Number of subjects analysed
    243
    232
    Units: Percentage of Subjects
    number (not applicable)
        AEs
    97.5
    96.1
        SAEs
    51.9
    37.1
    No statistical analyses for this end point

    Secondary: Time to Progression (TTP) According to RECIST v1.1

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    End point title
    		 Time to Progression (TTP) According to RECIST v1.1
    End point description
    The time to progression was defined as the time from baseline until disease progression as determined by the RECIST v1.1. TTP2 is defined as the interval between the day of randomization at PD1 and PD2. TTP3 is defined as the interval between the day of PD2 and PD3. PD was defined as ≥20% increase in sum LD in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Intent to treat population included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Up to data cut-off date 24 June 2016 (approximately 5 years)
    End point values
    		 Bevacizumab + Standard of Care Standard of Care
    Number of subjects analysed
    245
    240
    Units: Months
    median (confidence interval 90%)
        TTP2
    5.55 (4.86 to 6.18)
    4.21 (3.75 to 5.06)
        TTP3
    4.07 (3.25 to 4.63)
    2.73 (2.37 to 3.06)
    Statistical analysis title
    		 TTP2
    Statistical analysis description
    TTP2: The stratification factors for Log-Rank test are the type of planned 2nd-line SoC treatment, the number of cycles of Bevacizumab maintenance treatment prior to PD1 and the smoking status.
    Comparison groups
    Bevacizumab + Standard of Care v Standard of Care
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0311
    Method
    		 Stratified Log-Rank test
    Parameter type
    		 Stratified Hazard Ratio
    Point estimate
    0.79
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 0.95
    Statistical analysis title
    		 TTP3
    Statistical analysis description
    TTP3: The stratification factors for Log-Rank test are the type of planned 2nd-line SoC treatment, the number of cycles of Bevacizumab maintenance treatment prior to PD1 and the smoking status.
    Comparison groups
    Bevacizumab + Standard of Care v Standard of Care
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0326
    Method
    		 Stratified Log-Rank test
    Parameter type
    		 Stratified Hazard Ratio
    Point estimate
    0.69
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 0.92

    Secondary: Percentage of Subjects Who Are Alive at Month 6, 12, and 18

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    End point title
    		 Percentage of Subjects Who Are Alive at Month 6, 12, and 18
    End point description
    Percentage of subjects who were alive at Month 6, 12 and 18 were reported. Intent to treat population included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Month 6, 12, 18
    End point values
    		 Bevacizumab + Standard of Care Standard of Care
    Number of subjects analysed
    245
    240
    Units: Percentage of Subjects
    number (confidence interval 90%)
        Month 6
    0.8 (0.73 to 0.82)
    0.7 (0.62 to 0.72)
        Month 12
    0.5 (0.44 to 0.54)
    0.4 (0.39 to 0.5)
        Month 18
    0.4 (0.31 to 0.41)
    0.3 (0.25 to 0.36)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to data cut-off date 24 June 2016 (approximately 5 years)
    Adverse event reporting additional description
    The safety population included all subjects who had received at least one dose of any study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Standard of Care
    Reporting group description
    		 Subjects received investigator's choice of standard of care (Erlotinib or Docetaxel or Pemetrexed) according to local practice until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).

    Reporting group title
    Bevacizumab + Standard of Care
    Reporting group description
    		 Subjects received bevacizumab on Day 1 of every 21-days cycle along with standard of care (Erlotinib or Docetaxel or Pemetrexed) as second line treatment, until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).

    Serious adverse events
    		 Standard of Care Bevacizumab + Standard of Care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    86 / 232 (37.07%)
    126 / 243 (51.85%)
         number of deaths (all causes)
    193
    194
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lymphoma
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to Adrenals
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 232 (0.43%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Embolism
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Osteosynthesis
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 232 (0.00%)
    4 / 243 (1.65%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 232 (0.86%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Fatigue
         subjects affected / exposed
    2 / 232 (0.86%)
    2 / 243 (0.82%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General Physical Health Deterioration
         subjects affected / exposed
    2 / 232 (0.86%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal Inflammation
         subjects affected / exposed
    1 / 232 (0.43%)
    3 / 243 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Performance Status Decreased
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    1 / 232 (0.43%)
    4 / 243 (1.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden Death
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Reproductive system and breast disorders
    Uterine Haemorrhage
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute Respiratory Failure
         subjects affected / exposed
    1 / 232 (0.43%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial Disorder
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    0 / 232 (0.00%)
    3 / 243 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 232 (1.29%)
    4 / 243 (1.65%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    2 / 232 (0.86%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    2 / 232 (0.86%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial Lung Disease
         subjects affected / exposed
    3 / 232 (1.29%)
    2 / 243 (0.82%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Disorder
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organizing Pneumonia
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Aspiration
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    4 / 232 (1.72%)
    3 / 243 (1.23%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 243 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    6 / 232 (2.59%)
    5 / 243 (2.06%)
         occurrences causally related to treatment / all
    0 / 6
    5 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary Haemorrhage
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Thrombosis
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Distress
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 243 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 243 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Apathy
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional State
         subjects affected / exposed
    2 / 232 (0.86%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide Attempt
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 243 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood Bilirubin Increased
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood Creatinine Increased
         subjects affected / exposed
    0 / 232 (0.00%)
    3 / 243 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver Function Test Increased
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocyte Count Decreased
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White Blood Cell Count Decreased
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol Poisoning
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar Vertebral Fracture
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial Injury
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Limb Fracture
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Compression Fracture
         subjects affected / exposed
    1 / 232 (0.43%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Aplasia
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheo-oesophageal Fistula
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    1 / 232 (0.43%)
    4 / 243 (1.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    1 / 232 (0.43%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cyanosis
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    1 / 232 (0.43%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Ischaemia
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Nervous system disorders
    Cerebral Infarction
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cerebral Ischaemia
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular Accident
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 232 (0.43%)
    2 / 243 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy Peripheral
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Motor Neuropathy
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parapalegia
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Posterior Reversible Encephalopathy Syndrome
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid Haemorrhage
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 232 (2.59%)
    2 / 243 (0.82%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone Marrow Failure
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile Bone Marrow Aplasia
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    9 / 232 (3.88%)
    12 / 243 (4.94%)
         occurrences causally related to treatment / all
    0 / 9
    2 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 243 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    6 / 232 (2.59%)
    9 / 243 (3.70%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    2 / 232 (0.86%)
    2 / 243 (0.82%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pure White Cell Aplasia
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 243 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    2 / 232 (0.86%)
    2 / 243 (0.82%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 232 (0.86%)
    7 / 243 (2.88%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal Ulcer
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Obstruction
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal Hernia Strangulated
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal Obstruction
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal Perforation
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Large Intestine Perforation
         subjects affected / exposed
    1 / 232 (0.43%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Mechanical Ileus
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 232 (0.43%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal Stenosis
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis Acute
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 243 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumatosis Intestinalis
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small Intestinal Perforation
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical Hernia
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 243 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile Duct Obstruction
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile Duct Stone
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver Disorder
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema Multiforme
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin Toxicity
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic Syndrome
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Prerenal Failure
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Tubular Disorder
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal Insufficiency
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone Pain
         subjects affected / exposed
    2 / 232 (0.86%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank Pain
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervetebral Disc Protrusion
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    2 / 232 (0.86%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal Pain
         subjects affected / exposed
    2 / 232 (0.86%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological Fracture
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anal Abcess
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis Perforated
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 232 (0.43%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary Aspergillosis
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Device related Infection
         subjects affected / exposed
    1 / 232 (0.43%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea Infectious
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile Infection
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Infection
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital Herpes Simplex
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Abcess
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Infection
         subjects affected / exposed
    1 / 232 (0.43%)
    3 / 243 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Periorbital Abcess
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    19 / 232 (8.19%)
    13 / 243 (5.35%)
         occurrences causally related to treatment / all
    0 / 22
    2 / 13
         deaths causally related to treatment / all
    0 / 8
    0 / 2
    Post Procedural Infection
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psoas Abcess
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    1 / 232 (0.43%)
    6 / 243 (2.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory tract Infection Bacterial
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 232 (0.00%)
    3 / 243 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic Shock
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous Abcess
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheitis
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 232 (0.43%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    2 / 232 (0.86%)
    2 / 243 (0.82%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 232 (0.43%)
    3 / 243 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 232 (0.86%)
    2 / 243 (0.82%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tetany
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Standard of Care Bevacizumab + Standard of Care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    215 / 232 (92.67%)
    226 / 243 (93.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    25 / 232 (10.78%)
    52 / 243 (21.40%)
         occurrences all number
    36
    97
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    61 / 232 (26.29%)
    68 / 243 (27.98%)
         occurrences all number
    123
    169
    Fatigue
         subjects affected / exposed
    73 / 232 (31.47%)
    71 / 243 (29.22%)
         occurrences all number
    113
    144
    Malaise
         subjects affected / exposed
    14 / 232 (6.03%)
    24 / 243 (9.88%)
         occurrences all number
    26
    32
    Chest Pain
         subjects affected / exposed
    16 / 232 (6.90%)
    26 / 243 (10.70%)
         occurrences all number
    22
    37
    Mucosal Inflammation
         subjects affected / exposed
    22 / 232 (9.48%)
    49 / 243 (20.16%)
         occurrences all number
    28
    79
    Oedema Peripheral
         subjects affected / exposed
    32 / 232 (13.79%)
    34 / 243 (13.99%)
         occurrences all number
    41
    42
    Pain
         subjects affected / exposed
    13 / 232 (5.60%)
    10 / 243 (4.12%)
         occurrences all number
    18
    11
    Pyrexia
         subjects affected / exposed
    35 / 232 (15.09%)
    46 / 243 (18.93%)
         occurrences all number
    54
    76
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    56 / 232 (24.14%)
    56 / 243 (23.05%)
         occurrences all number
    74
    95
    Dysphonia
         subjects affected / exposed
    13 / 232 (5.60%)
    13 / 243 (5.35%)
         occurrences all number
    14
    14
    Cough
         subjects affected / exposed
    40 / 232 (17.24%)
    39 / 243 (16.05%)
         occurrences all number
    51
    53
    Epistaxis
         subjects affected / exposed
    20 / 232 (8.62%)
    53 / 243 (21.81%)
         occurrences all number
    22
    70
    Haemoptysis
         subjects affected / exposed
    11 / 232 (4.74%)
    17 / 243 (7.00%)
         occurrences all number
    13
    18
    Pleural Effusion
         subjects affected / exposed
    15 / 232 (6.47%)
    13 / 243 (5.35%)
         occurrences all number
    15
    25
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    15 / 232 (6.47%)
    14 / 243 (5.76%)
         occurrences all number
    15
    14
    Anxiety
         subjects affected / exposed
    12 / 232 (5.17%)
    11 / 243 (4.53%)
         occurrences all number
    13
    11
    Investigations
    Blood Creatinine Increased
         subjects affected / exposed
    4 / 232 (1.72%)
    13 / 243 (5.35%)
         occurrences all number
    6
    21
    Weight Decreased
         subjects affected / exposed
    24 / 232 (10.34%)
    42 / 243 (17.28%)
         occurrences all number
    35
    46
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    13 / 232 (5.60%)
    20 / 243 (8.23%)
         occurrences all number
    14
    28
    Paraesthesia
         subjects affected / exposed
    8 / 232 (3.45%)
    15 / 243 (6.17%)
         occurrences all number
    11
    32
    Neuropathy Peripheral
         subjects affected / exposed
    16 / 232 (6.90%)
    20 / 243 (8.23%)
         occurrences all number
    21
    28
    Dysgeusia
         subjects affected / exposed
    16 / 232 (6.90%)
    29 / 243 (11.93%)
         occurrences all number
    19
    32
    Headache
         subjects affected / exposed
    23 / 232 (9.91%)
    39 / 243 (16.05%)
         occurrences all number
    27
    56
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    69 / 232 (29.74%)
    54 / 243 (22.22%)
         occurrences all number
    129
    120
    Neutropenia
         subjects affected / exposed
    20 / 232 (8.62%)
    39 / 243 (16.05%)
         occurrences all number
    47
    78
    Leukopenia
         subjects affected / exposed
    10 / 232 (4.31%)
    16 / 243 (6.58%)
         occurrences all number
    22
    31
    Thrombocytopenia
         subjects affected / exposed
    9 / 232 (3.88%)
    15 / 243 (6.17%)
         occurrences all number
    18
    27
    Eye disorders
    Lacrimation Increased
         subjects affected / exposed
    12 / 232 (5.17%)
    18 / 243 (7.41%)
         occurrences all number
    13
    20
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    13 / 232 (5.60%)
    16 / 243 (6.58%)
         occurrences all number
    15
    22
    Constipation
         subjects affected / exposed
    49 / 232 (21.12%)
    64 / 243 (26.34%)
         occurrences all number
    71
    94
    Abdominal Pain Upper
         subjects affected / exposed
    14 / 232 (6.03%)
    25 / 243 (10.29%)
         occurrences all number
    14
    33
    Diarrhoea
         subjects affected / exposed
    72 / 232 (31.03%)
    90 / 243 (37.04%)
         occurrences all number
    112
    156
    Nausea
         subjects affected / exposed
    61 / 232 (26.29%)
    84 / 243 (34.57%)
         occurrences all number
    98
    184
    Vomiting
         subjects affected / exposed
    40 / 232 (17.24%)
    51 / 243 (20.99%)
         occurrences all number
    50
    70
    Stomatitis
         subjects affected / exposed
    26 / 232 (11.21%)
    39 / 243 (16.05%)
         occurrences all number
    47
    72
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    41 / 232 (17.67%)
    55 / 243 (22.63%)
         occurrences all number
    45
    66
    Dermatitis Acneiform
         subjects affected / exposed
    8 / 232 (3.45%)
    15 / 243 (6.17%)
         occurrences all number
    13
    43
    Dry Skin
         subjects affected / exposed
    22 / 232 (9.48%)
    29 / 243 (11.93%)
         occurrences all number
    26
    35
    Erythema
         subjects affected / exposed
    17 / 232 (7.33%)
    11 / 243 (4.53%)
         occurrences all number
    21
    14
    Rash
         subjects affected / exposed
    46 / 232 (19.83%)
    49 / 243 (20.16%)
         occurrences all number
    58
    76
    Pruritus
         subjects affected / exposed
    14 / 232 (6.03%)
    17 / 243 (7.00%)
         occurrences all number
    16
    20
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    23 / 232 (9.91%)
    51 / 243 (20.99%)
         occurrences all number
    40
    125
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    21 / 232 (9.05%)
    21 / 243 (8.64%)
         occurrences all number
    31
    24
    Back Pain
         subjects affected / exposed
    31 / 232 (13.36%)
    28 / 243 (11.52%)
         occurrences all number
    37
    34
    Musculoskeletal Chest Pain
         subjects affected / exposed
    8 / 232 (3.45%)
    13 / 243 (5.35%)
         occurrences all number
    10
    13
    Musculoskeletal Pain
         subjects affected / exposed
    18 / 232 (7.76%)
    22 / 243 (9.05%)
         occurrences all number
    20
    30
    Pain in Extremity
         subjects affected / exposed
    16 / 232 (6.90%)
    17 / 243 (7.00%)
         occurrences all number
    17
    22
    Myalgia
         subjects affected / exposed
    18 / 232 (7.76%)
    18 / 243 (7.41%)
         occurrences all number
    21
    50
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    12 / 232 (5.17%)
    9 / 243 (3.70%)
         occurrences all number
    15
    12
    Conjunctivitis
         subjects affected / exposed
    13 / 232 (5.60%)
    16 / 243 (6.58%)
         occurrences all number
    19
    47
    Bronchitis
         subjects affected / exposed
    12 / 232 (5.17%)
    23 / 243 (9.47%)
         occurrences all number
    14
    23
    Urinary Tract Infection
         subjects affected / exposed
    10 / 232 (4.31%)
    16 / 243 (6.58%)
         occurrences all number
    11
    27
    Respiratory Tract Infection
         subjects affected / exposed
    9 / 232 (3.88%)
    13 / 243 (5.35%)
         occurrences all number
    9
    16
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    59 / 232 (25.43%)
    83 / 243 (34.16%)
         occurrences all number
    81
    160
    Dehydration
         subjects affected / exposed
    2 / 232 (0.86%)
    13 / 243 (5.35%)
         occurrences all number
    2
    14

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Dec 2011
    Archival tissue sample collection was added as current data on bevacizumab biomarker are inconclusive and more data were needed to better target therapies for subjects. Guidance on further treatment for subject with a complete response (CR) was added. Guidance on dose modification of bevacizumab according to weight changes was added as SOC at many participating sites was to use the “current” weight to calculate doses. The guidance for management of Grade 3 or Grade 4 bevacizumab-related AEs and management of hypertension was updated, in line with the updated bevacizumab Roche protocol template.
    02 Jul 2013
    It was clarified the approved (per label) dose of bevacizumab (7.5 or 15 mg/kg i.v) used during the 1st-line treatment was to be the same dose administered to each patient during the study. It was also clarified the same Q3W schedule was also to be used; this also applied to the SoC agents used as part of 2nd-line treatment. The 21-day cycle requirement for SoC agents was removed as this was based on local practice. Bevacizumab was to continue to be administered on a 21-day cycle. The definition of treatment interruptions was updated. No safety concerns regarding the use of radiotherapy with bevacizumab were raised from previous studies or the current study. Therefore, amendments were made to exclusion criteria and to conditions if palliative radiotherapy to the brain was given during the study. To comply with new European Union Pharmacovigilance regulations, the reporting requirements for serious AEs (SAEs) and selected adverse events of special interest (AESIs) were revised from within “one working day” to within “24 hours after learning of the event”. The recruitment period was extended from approximately 24 months to approximately 45 months. The number of sites was increased from 140 sites to approximately 160 sites.
    18 Aug 2014
    The total number of subjects to be recruited was reduced from 600 to approximately 500 subjects. The end of study was redefined to occur once 416 deaths had been observed (originally 519 deaths) or at 60 months from study start, whichever occurred first. Study design assumptions and properties for the comparison of the primary outcome (median OS beyond progression) were revised due to decreased planned sample size. An interim efficacy analysis was planned to occur after 70% of the OS events had been observed. In order to optimize the primary analysis, this interim analysis was no longer planned.

    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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