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    Clinical Trial Results:
    A Phase III, Open-Label, Randomized Study of Atezolizumab (Anti-PD-L1 Antibody) in Combination with Bevacizumab versus Sunitinib in Patients with Untreated Advanced Renal Cell Carcinoma

    Summary
    EudraCT number
    2014-004684-20
    Trial protocol
    ES   GB   DK   CZ   DE   FR   PL  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    07 Sep 2018
    First version publication date
    07 Sep 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    WO29637
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02420821
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, 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
    Interim
    Date of interim/final analysis
    29 Sep 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Sep 2017
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of “Atezolizumab + Bevacizumab” compared with “Sunitinib” as measured by the coprimary endpoints of investigator-assessed progression-free survival (PFS) in the immune cell (IC)1/2/3 population per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) and overall survival (OS) in the Intent-To-Treat (ITT) Population.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP). Approval from the Independent Ethics Committee/Institutional Review Board (IEC/IRB) was obtained before study start and was documented in a letter to the Investigator specifying the date on which the committee met and granted the approval. The Sponsor also obtained approval from the relevant Competent Authority prior to starting the study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 May 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Safety
    Long term follow-up duration
    4 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Japan: 61
    Country: Number of subjects enrolled
    Korea, Republic of: 59
    Country: Number of subjects enrolled
    Singapore: 8
    Country: Number of subjects enrolled
    Thailand: 16
    Country: Number of subjects enrolled
    Taiwan: 9
    Country: Number of subjects enrolled
    Brazil: 15
    Country: Number of subjects enrolled
    Mexico: 13
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 3
    Country: Number of subjects enrolled
    Czech Republic: 30
    Country: Number of subjects enrolled
    Poland: 26
    Country: Number of subjects enrolled
    Russian Federation: 57
    Country: Number of subjects enrolled
    Turkey: 23
    Country: Number of subjects enrolled
    Canada: 59
    Country: Number of subjects enrolled
    United States: 122
    Country: Number of subjects enrolled
    Australia: 51
    Country: Number of subjects enrolled
    Germany: 18
    Country: Number of subjects enrolled
    Denmark: 33
    Country: Number of subjects enrolled
    Spain: 83
    Country: Number of subjects enrolled
    France: 52
    Country: Number of subjects enrolled
    United Kingdom: 95
    Country: Number of subjects enrolled
    Italy: 82
    Worldwide total number of subjects
    915
    EEA total number of subjects
    419
    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)
    587
    From 65 to 84 years
    327
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 1228 participants were screened, out of which, 915 participants were enrolled into the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sunitinib
    Arm description
    Participants received sunitinib at a dose of 50 milligrams (mg) administered orally via capsules once daily on Days 1 to 28 of each 42-day cycle until loss of clinical benefit in the opinion of the investigator, unacceptable toxicity or symptomatic deterioration attributed to disease progression (PD) as determined by the investigator, withdrawal of consent, or death, whichever occurred first.
    Arm type
    Active comparator

    Investigational medicinal product name
    Sunitinib
    Investigational medicinal product code
    Other name
    Sutent
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Sunitinib was administered at a dose of 50 mg once daily, orally via capsule, on Day 1 through Day 28 of each 42-day cycle.

    Arm title
    Atezolizumab + Bevacizumab
    Arm description
    Participants received atezolizumab at a dose of 1200 mg and bevacizumab at a dose of 15 milligrams per kilogram (mg/kg) administered via intravenous (IV) infusions on Day 1 and Day 22 of each 42-day cycle until loss of clinical benefit in the opinion of the investigator, unacceptable toxicity or symptomatic deterioration attributed to PD as determined by the investigator, withdrawal of consent, or death, whichever occurred first.
    Arm type
    Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab was administered at a dose of 15 mg/kg via IV infusion on Days 1 and 22 of each 42-day cycle.

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Tecentriq, MPDL3280A
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab was administered at a fixed dose of 1200 mg via IV infusion on Days 1 and 22 of each 42-day cycle.

    Number of subjects in period 1
    Sunitinib Atezolizumab + Bevacizumab
    Started
    461
    454
    Completed
    293
    317
    Not completed
    168
    137
         Death
    129
    116
         Physician decision
    5
    2
         Non-compliance
    1
    2
         Consent withdrawn by subject
    31
    17
         Lost to follow-up
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sunitinib
    Reporting group description
    Participants received sunitinib at a dose of 50 milligrams (mg) administered orally via capsules once daily on Days 1 to 28 of each 42-day cycle until loss of clinical benefit in the opinion of the investigator, unacceptable toxicity or symptomatic deterioration attributed to disease progression (PD) as determined by the investigator, withdrawal of consent, or death, whichever occurred first.

    Reporting group title
    Atezolizumab + Bevacizumab
    Reporting group description
    Participants received atezolizumab at a dose of 1200 mg and bevacizumab at a dose of 15 milligrams per kilogram (mg/kg) administered via intravenous (IV) infusions on Day 1 and Day 22 of each 42-day cycle until loss of clinical benefit in the opinion of the investigator, unacceptable toxicity or symptomatic deterioration attributed to PD as determined by the investigator, withdrawal of consent, or death, whichever occurred first.

    Reporting group values
    Sunitinib Atezolizumab + Bevacizumab Total
    Number of subjects
    461 454 915
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    59.9 ± 9.9 61.6 ± 10.4 -
    Sex: Female, Male
    Units: Subjects
        Female
    109 137 246
        Male
    352 317 669
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    1 2 3
        Asian
    77 94 171
        Native Hawaiian or Other Pacific Islander
    0 1 1
        Black or African American
    4 1 5
        White
    334 326 660
        More than one race
    0 0 0
        Unknown or Not Reported
    45 30 75
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    32 25 57
        Not Hispanic or Latino
    386 391 777
        Unknown or Not Reported
    43 38 81

    End points

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    End points reporting groups
    Reporting group title
    Sunitinib
    Reporting group description
    Participants received sunitinib at a dose of 50 milligrams (mg) administered orally via capsules once daily on Days 1 to 28 of each 42-day cycle until loss of clinical benefit in the opinion of the investigator, unacceptable toxicity or symptomatic deterioration attributed to disease progression (PD) as determined by the investigator, withdrawal of consent, or death, whichever occurred first.

    Reporting group title
    Atezolizumab + Bevacizumab
    Reporting group description
    Participants received atezolizumab at a dose of 1200 mg and bevacizumab at a dose of 15 milligrams per kilogram (mg/kg) administered via intravenous (IV) infusions on Day 1 and Day 22 of each 42-day cycle until loss of clinical benefit in the opinion of the investigator, unacceptable toxicity or symptomatic deterioration attributed to PD as determined by the investigator, withdrawal of consent, or death, whichever occurred first.

    Primary: Percentage of Participants with PD as Determined by the Investigator According to RECIST v1.1 or Death from Any Cause in Programmed Death-Ligand 1 (PD-L1)-Selected Population

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    End point title
    Percentage of Participants with PD as Determined by the Investigator According to RECIST v1.1 or Death from Any Cause in Programmed Death-Ligand 1 (PD-L1)-Selected Population [1]
    End point description
    Tumor response was assessed by the investigator according to RECIST v1.1. The PD was defined as greater than or equal to (>/=) 20 percent (%) relative increase in the sum of diameters (SoD) of all target lesions (TLs), taking as reference the smallest SoD on study, including baseline, and an absolute increase of >/=5 millimeters (mm); >/=1 new lesion(s); and/or unequivocal progression of existing non-TLs. Analysis was performed on the PD-L1-Selected Population, which included all randomized participants whose PD-L1 status was IC1/2/3 at the time of randomization.
    End point type
    Primary
    End point timeframe
    Baseline until documented PD or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Results for this outcome measure were reported descriptively and were not planned to be analyzed for statistically significant differences between the arms.
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    184
    178
    Units: percentage of participants
        number (not applicable)
    69.6
    58.4
    No statistical analyses for this end point

    Primary: Progression-Free Survival (PFS) as Determined by the Investigator According to RECIST v1.1 in PD-L1-Selected Population

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    End point title
    Progression-Free Survival (PFS) as Determined by the Investigator According to RECIST v1.1 in PD-L1-Selected Population
    End point description
    PFS was defined as the time from randomization to PD, as determined by the investigator per RECIST v1.1, or death from any cause, whichever occurred first. PD: >/=20% relative increase in the SoD of all TLs, taking as reference the smallest SoD on study, including baseline, and an absolute increase of >/=5 mm; >/=1 new lesion(s); and/or unequivocal progression of non-TLs. Participants without PFS event were censored at the last tumor assessment date. Participants with no post-baseline tumor assessments were censored at the randomization date + 1 day. Participants with a PFS event who missed >/=2 scheduled assessments immediately prior to the PFS event were censored at the last tumor assessment prior to the missed visits. Median PFS was estimated by Kaplan-Meier method and 95% confidence interval (CI) was assessed using the method of Brookmeyer and Crowley. Analysis was performed on the PD-L1-Selected Population.
    End point type
    Primary
    End point timeframe
    Baseline until documented PD or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    184
    178
    Units: months
        median (confidence interval 95%)
    7.5 (6.8 to 9.7)
    11.2 (8.6 to 14.3)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Strata were presence of liver metastases, Motzer score, PD-L1 level per interactive voice/web response system (IxRS).
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    362
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    = 0.0205
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.57
         upper limit
    0.95
    Notes
    [2] - Hazard ratio was estimated by Cox regression.

    Primary: Percentage of Participants Who Died of Any Cause in ITT Population

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    End point title
    Percentage of Participants Who Died of Any Cause in ITT Population [3]
    End point description
    Percentage of participants who died of any cause was reported. Analysis was performed on the ITT Population, which included all randomized participants whether or not the assigned study treatment was received.
    End point type
    Primary
    End point timeframe
    Baseline until death from any cause (until data cut-off date 29 September 2017, up to approximately 27 months)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Results for this outcome measure were reported descriptively and were not planned to be analyzed for statistically significant differences between the arms.
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    461
    454
    Units: percentage of participants
        number (not applicable)
    30.6
    27.1
    No statistical analyses for this end point

    Primary: Overall Survival (OS) in ITT Population

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    End point title
    Overall Survival (OS) in ITT Population
    End point description
    OS was defined as the time from randomization to death due to any cause. Participants who were not reported as having died at the date of analysis were censored at the date when they were last known to be alive. Participants who did not have post-baseline information were censored at the date of randomization + 1 day. Median OS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley. Analysis was performed on the ITT Population. The data ‘99999’ in the results signifies that median and corresponding 95% CI could not be estimated due to high number of censored participants.
    End point type
    Primary
    End point timeframe
    Baseline until death from any cause (until data cut-off date 29 September 2017, up to approximately 27 months)
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    461
    454
    Units: months
        median (confidence interval 95%)
    99999 (23.3 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Strata were presence of liver metastases, Motzer score, PD-L1 level per interactive voice/web response system (IxRS).
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    915
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    P-value
    = 0.0895
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.63
         upper limit
    1.03
    Notes
    [4] - Hazard ratio was estimated by Cox regression.

    Secondary: Percentage of Participants Who Died of Any Cause in PD-L1-Selected Population

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    End point title
    Percentage of Participants Who Died of Any Cause in PD-L1-Selected Population
    End point description
    Percentage of participants who died of any cause was reported. Analysis was performed on the PD-L1-Selected Population.
    End point type
    Secondary
    End point timeframe
    Baseline until death from any cause (until data cut-off date 29 September 2017, up to approximately 27 months)
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    184
    178
    Units: percentage of participants
        number (not applicable)
    34.8
    25.3
    No statistical analyses for this end point

    Secondary: OS in PD-L1-Selected Population

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    End point title
    OS in PD-L1-Selected Population
    End point description
    OS was defined as the time from randomization to death due to any cause. Participants who were not reported as having died at the date of analysis were censored at the date when they were last known to be alive. Participants who did not have post-baseline information were censored at the date of randomization + 1 day. Median OS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley. Analysis was performed on the PD-L1-Selected Population. The data ‘99999’ in the results signifies that median and/or corresponding 95% CI could not be estimated due to high number of censored participants.
    End point type
    Secondary
    End point timeframe
    Baseline until death from any cause (until data cut-off date 29 September 2017, up to approximately 27 months)
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    184
    178
    Units: months
        median (confidence interval 95%)
    23.3 (21.3 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Strata were presence of liver metastases, Motzer score, PD-L1 level per interactive voice/web response system (IxRS).
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    362
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    = 0.047
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.46
         upper limit
    1
    Notes
    [5] - Hazard ratio was estimated by Cox regression.

    Secondary: Percentage of Participants with PD as Determined by an Independent Review Committee (IRC) According to RECIST v1.1 or Death from Any Cause in ITT Population

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    End point title
    Percentage of Participants with PD as Determined by an Independent Review Committee (IRC) According to RECIST v1.1 or Death from Any Cause in ITT Population
    End point description
    Tumor response was assessed by an IRC according to RECIST v1.1. PD was defined as >/=20% relative increase in the SoD of all TLs, taking as reference the smallest SoD on study, including baseline, and an absolute increase of >/=5 mm; >/=1 new lesion(s); and/or unequivocal progression of non-TLs. Analysis was performed on the ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline until documented PD or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    461
    454
    Units: percentage of participants
        number (not applicable)
    63.6
    60.4
    No statistical analyses for this end point

    Secondary: PFS as Determined by an IRC According to RECIST v1.1 in ITT Population

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    End point title
    PFS as Determined by an IRC According to RECIST v1.1 in ITT Population
    End point description
    PFS was defined as the time from randomization to PD, as determined by an IRC per RECIST v1.1, or death from any cause, whichever occurred first. PD: >/=20% relative increase and >/=5 mm of absolute increase in the SoD of all TLs, taking as reference the smallest SoD recorded since treatment started; >/=1 new lesion(s); and/or unequivocal progression of non-TLs. Participants without PFS event were censored at the last tumor assessment date. Participants with no post-baseline tumor assessments were censored at the randomization date + 1 day. Median PFS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley. Analysis was performed on the ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline until documented PD or death, whichever occurred first (up to approximately 24 months)
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    461
    454
    Units: months
        median (confidence interval 95%)
    8.3 (7.0 to 9.7)
    9.6 (8.3 to 11.5)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Strata were presence of liver metastases, Motzer score, PD-L1 level per interactive voice/web response system (IxRS).
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    915
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    P-value
    = 0.1218
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.74
         upper limit
    1.04
    Notes
    [6] - Hazard ratio was estimated by Cox regression.

    Secondary: Percentage of Participants with PD as Determined by an IRC According to RECIST v1.1 or Death from Any Cause in PD-L1-Selected Population

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    End point title
    Percentage of Participants with PD as Determined by an IRC According to RECIST v1.1 or Death from Any Cause in PD-L1-Selected Population
    End point description
    Tumor response was assessed by an IRC according to RECIST v1.1. PD was defined as >/=20% relative increase in the SoD of all TLs, taking as reference the smallest SoD on study, including baseline, and an absolute increase of >/=5 mm; >/=1 new lesion(s); and/or unequivocal progression of non-TLs. Analysis was performed on the PD-L1-Selected Population.
    End point type
    Secondary
    End point timeframe
    Baseline until documented PD or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    184
    178
    Units: percentage of participants
        number (not applicable)
    64.7
    62.9
    No statistical analyses for this end point

    Secondary: PFS as Determined by an IRC According to RECIST v1.1 in PD-L1-Selected Population

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    End point title
    PFS as Determined by an IRC According to RECIST v1.1 in PD-L1-Selected Population
    End point description
    PFS was defined as the time from randomization to PD, as determined by an IRC per RECIST v1.1, or death from any cause, whichever occurred first. PD: >/=20% relative increase in the SoD of all TLs, taking as reference the smallest SoD on study, including baseline, and an absolute increase of >/=5 mm; >/=1 new lesion(s); and/or unequivocal progression of non-TLs. Participants without PFS event were censored at the last tumor assessment date. Participants with no post-baseline tumor assessments were censored at the randomization date + 1 day. Median PFS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley. Analysis was performed on the PD-L1-Selected Population.
    End point type
    Secondary
    End point timeframe
    Baseline until documented PD or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    184
    178
    Units: months
        median (confidence interval 95%)
    7.2 (6.1 to 11.1)
    8.9 (6.9 to 12.5)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Strata were presence of liver metastases, Motzer score, PD-L1 level per interactive voice/web response system (IxRS).
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    362
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.6138
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.72
         upper limit
    1.21
    Notes
    [7] - Hazard ratio was estimated by Cox regression.

    Secondary: Percentage of Participants with an Objective Response of Complete Response (CR) or Partial Response (PR) as Determined by the Investigator According to RECIST v1.1 in Objective Response Rate (ORR)-Evaluable Population

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    End point title
    Percentage of Participants with an Objective Response of Complete Response (CR) or Partial Response (PR) as Determined by the Investigator According to RECIST v1.1 in Objective Response Rate (ORR)-Evaluable Population
    End point description
    Tumor response was assessed by the investigator according to RECIST v1.1. Objective response was defined as percentage of participants with a documented CR or PR. CR was defined as disappearance of all TLs/non-TLs and (if applicable) normalization of tumor marker level or reduction in short axis of any pathological lymph nodes to less than (<) 10 mm. PR was defined as >/=30% decrease in the SoD of TLs (taking as reference the baseline SoD) or persistence of >/=1 non-TL(s) and/or (if applicable) maintenance of tumor marker level above the normal limits. The 95% CI was computed using Clopper-Pearson approach. Participants without any post-baseline tumor assessments were considered non-responders. Analysis was performed on the ORR-Evaluable Population, which included all participants in the ITT population with measurable disease at baseline, as determined by the investigator.
    End point type
    Secondary
    End point timeframe
    Baseline until documented CR/PR, PD, or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    460
    454
    Units: percentage of participants
        number (confidence interval 95%)
    33.3 (28.97 to 37.77)
    36.6 (32.12 to 41.18)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Strata were presence of liver metastases, Motzer score, PD-L1 level per interactive voice/web response system (IxRS).
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    914
    Analysis specification
    Pre-specified
    Analysis type
    superiority [8]
    P-value
    = 0.2733
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Response Rates
    Point estimate
    3.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.09
         upper limit
    9.7
    Notes
    [8] - 95% CI for difference in response rates was constructed using Wald method.

    Secondary: Duration of Response (DOR) as Determined by the Investigator According to RECIST v1.1 in DOR-Evaluable Population

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    End point title
    Duration of Response (DOR) as Determined by the Investigator According to RECIST v1.1 in DOR-Evaluable Population
    End point description
    DOR: the time from the first CR/PR to PD as determined by the investigator per RECIST v1.1 or death from any cause. CR: disappearance of TLs/non-TLs and normalization of tumor marker level or reduction in short axis of any pathological lymph nodes to <10 mm. PR: >/=30% decrease in the SoD of TLs or persistence of >/=1 non-TL(s) and/or maintenance of tumor marker level above the normal limits. PD: >/=20% relative increase in the SoD of all TLs, taking as reference the smallest SoD on study, including baseline, and an absolute increase of >/=5 mm; >/=1 new lesion(s); and/or unequivocal progression of non-TLs. Participants without PD or death after a CR/PR were censored at last tumor assessment. Participants without tumor assessments after a CR/PR were censored at first CR/PR + 1 day. Median DOR was estimated by Kaplan-Meier method and 95% CI by the method of Brookmeyer and Crowley. DOR-Evaluable Population: all participants with a CR/PR in the ORR-Evaluable Population.
    End point type
    Secondary
    End point timeframe
    Baseline until documented CR/PR, PD, or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    153 [9]
    166 [10]
    Units: months
        median (confidence interval 95%)
    14.2 (11.3 to 99999)
    16.6 (15.4 to 99999)
    Notes
    [9] - 99999 = Upper limit of 95% CI could not be estimated due to high number of censored participants.
    [10] - 99999 = Upper limit of 95% CI could not be estimated due to high number of censored participants.
    No statistical analyses for this end point

    Secondary: Percentage of Participants with an Objective Response of CR or PR as Determined by an IRC According to RECIST v1.1 in ORR-Evaluable Population

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    End point title
    Percentage of Participants with an Objective Response of CR or PR as Determined by an IRC According to RECIST v1.1 in ORR-Evaluable Population
    End point description
    Tumor response was assessed by an IRC according to RECIST v1.1. Objective response was defined as percentage of participants with a documented CR or PR. CR was defined as disappearance of all TLs/non-TLs and (if applicable) normalization of tumor marker level or reduction in short axis of any pathological lymph nodes to <10 mm. PR was defined as >/=30% decrease in the SoD of TLs (taking as reference the baseline SoD) or persistence of >/=1 non-TL(s) and/or (if applicable) maintenance of tumor marker level above the normal limits. The 95% CI was computed using Clopper-Pearson approach. Participants without any post-baseline tumor assessments were considered non-responders. Analysis was performed on the ORR-Evaluable Population.
    End point type
    Secondary
    End point timeframe
    Baseline until documented CR/PR, PD, or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    460
    454
    Units: percentage of participants
        number (confidence interval 95%)
    31.3 (27.09 to 35.76)
    33.3 (28.94 to 37.80)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Strata were presence of liver metastases, Motzer score, PD-L1 level per interactive voice/web response system (IxRS).
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    914
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    = 0.5121
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Response Rates
    Point estimate
    1.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.32
         upper limit
    8.24
    Notes
    [11] - 95% CI for difference in response rates was constructed using Wald method.

    Secondary: DOR as Determined by an IRC According to RECIST v1.1 in DOR-Evaluable Population

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    End point title
    DOR as Determined by an IRC According to RECIST v1.1 in DOR-Evaluable Population
    End point description
    DOR was defined as the time from the first occurrence of CR/PR to PD as determined by an IRC per RECIST v1.1, or death from any cause, whichever occurred first. CR: disappearance of TLs/non-TLs and normalization of tumor marker level or reduction in short axis of any pathological lymph nodes to <10 mm. PR: >/=30% decrease in the SoD of TLs or persistence of >/=1 non-TL(s) and/or maintenance of tumor marker level above the normal limits. PD: >/=20% relative increase in the SoD of all TLs, taking as reference the smallest SoD on study, including baseline, and an absolute increase of >/=5 mm; >/=1 new lesion(s); and/or unequivocal progression of non-TLs. Participants without PD or death after a CR/PR were censored at last tumor assessment. Participants without tumor assessments after a CR/PR were censored at first CR/PR + 1 day. Median DOR was estimated by Kaplan-Meier method and 95% CI by the method of Brookmeyer and Crowley. Analysis was performed on the DOR-Evaluable Population.
    End point type
    Secondary
    End point timeframe
    Baseline until documented CR/PR, PD, or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    144 [12]
    151 [13]
    Units: months
        median (confidence interval 95%)
    18.6 (13.8 to 99999)
    99999 (16.8 to 99999)
    Notes
    [12] - 99999 = Upper limit of 95% CI could not be estimated due to high number of censored participants.
    [13] - 99999=Median/Upper limit of CI could not be estimated due to high number of censored participants.
    No statistical analyses for this end point

    Secondary: Percentage of Participants with PD as Determined by the Investigator According to Immune-Modified RECIST or Death from Any Cause in ITT Population

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    End point title
    Percentage of Participants with PD as Determined by the Investigator According to Immune-Modified RECIST or Death from Any Cause in ITT Population
    End point description
    Tumor response was assessed by the investigator according to immune-modified RECIST. PD was defined as >/=20% relative increase in the SoD of all TLs and all new measurable lesions, taking as reference the smallest SoD on study, including baseline, and an absolute increase of >/=5 mm. Analysis was performed on the ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline until documented PD or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    461
    454
    Units: percentage of participants
        number (not applicable)
    58.1
    55.1
    No statistical analyses for this end point

    Secondary: PFS as Determined by the Investigator According to Immune-Modified RECIST in ITT Population

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    End point title
    PFS as Determined by the Investigator According to Immune-Modified RECIST in ITT Population
    End point description
    PFS was defined as the time from randomization to PD, as determined by the investigator per immune-modified RECIST or death from any cause, whichever occurred first. PD: >/=20% relative increase in the SoD of all TLs and all new measurable lesions, taking as reference the smallest SoD on study, including baseline, and an absolute increase of >/=5 mm. Participants without PFS event were censored at the last tumor assessment date. Participants with no post-baseline tumor assessments were censored at the randomization date + 1 day. Median PFS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley. Analysis was performed on the ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline until documented PD or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    461
    454
    Units: months
        median (confidence interval 95%)
    12.3 (9.8 to 13.7)
    13.9 (12.5 to 15.3)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Strata were presence of liver metastases, Motzer score, PD-L1 level per interactive voice/web response system (IxRS).
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    915
    Analysis specification
    Pre-specified
    Analysis type
    superiority [14]
    P-value
    = 0.0606
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.71
         upper limit
    1.01
    Notes
    [14] - Hazard ratio was estimated by Cox regression.

    Secondary: Percentage of Participants with an Objective Response of CR or PR as Determined by the Investigator According to Immune-Modified RECIST in ORR-Evaluable Population

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    End point title
    Percentage of Participants with an Objective Response of CR or PR as Determined by the Investigator According to Immune-Modified RECIST in ORR-Evaluable Population
    End point description
    Tumor response was assessed by the investigator according to immune-modified RECIST. Objective response was defined as percentage of participants with a documented CR or PR. CR was defined as disappearance of all TLs/non-TLs or reduction in short axis of any pathological lymph nodes to <10 mm. PR was defined as >/=30% decrease in the SoD of TLs and all new measurable lesions (taking as reference the baseline SoD), in the absence of CR. The 95% CI was computed using Clopper-Pearson approach. Participants without any post-baseline tumor assessments were considered non-responders. Analysis was performed on the ORR-Evaluable Population.
    End point type
    Secondary
    End point timeframe
    Baseline until documented CR/PR, PD, or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    460
    454
    Units: percentage of participants
        number (confidence interval 95%)
    35.0 (30.64 to 39.55)
    40.1 (35.55 to 44.76)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Strata were presence of liver metastases, Motzer score, PD-L1 level per interactive voice/web response system (IxRS).
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    914
    Analysis specification
    Pre-specified
    Analysis type
    superiority [15]
    P-value
    = 0.1011
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Response Rates
    Point estimate
    5.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.4
         upper limit
    11.58
    Notes
    [15] - 95% CI for difference in response rates was constructed using Wald method.

    Secondary: DOR as Determined by the Investigator According to Immune-Modified RECIST in DOR-Evaluable Population

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    End point title
    DOR as Determined by the Investigator According to Immune-Modified RECIST in DOR-Evaluable Population
    End point description
    DOR was defined as the time from the first occurrence of CR/PR to PD as determined by the investigator per immune-modified RECIST or death from any cause, whichever occurred first. CR: disappearance of TLs/non-TLs or reduction in short axis of any pathological lymph nodes to <10 mm. PR: >/=30% decrease in the SoD of TLs and all new measurable lesions (taking as reference the baseline SoD), in the absence of CR. PD: >/=20% relative increase in the SoD of all TLs and all new measurable lesions, taking as reference the smallest SoD on study, including baseline, and an absolute increase of >/=5 mm. Participants without PD or death after a CR/PR were censored at last tumor assessment. Participants without tumor assessments after a CR/PR were censored at first CR/PR + 1 day. Median DOR was estimated by Kaplan-Meier method and 95% CI by the method of Brookmeyer and Crowley. Analysis was performed on DOR-evaluable population.
    End point type
    Secondary
    End point timeframe
    Baseline until documented CR/PR, PD, or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    161
    182 [16]
    Units: months
        median (confidence interval 95%)
    19.4 (13.1 to 20.0)
    19.4 (16.5 to 99999)
    Notes
    [16] - 99999 = Upper limit of 95% CI could not be estimated due to high number of censored participants.
    No statistical analyses for this end point

    Secondary: Percentage of Participants with PD as Determined by the Investigator According to RECIST v1.1 or Death from Any Cause in ITT Population

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    End point title
    Percentage of Participants with PD as Determined by the Investigator According to RECIST v1.1 or Death from Any Cause in ITT Population
    End point description
    Tumor response was assessed by the investigator according to RECIST v1.1. PD was defined as >/=20% relative increase in the SoD of all TLs, taking as reference the smallest SoD on study, including baseline, and an absolute increase of >/=5 mm; >/=1 new lesion(s); and/or unequivocal progression of non-TLs. Analysis was performed on the ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline until documented PD or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    461
    454
    Units: percentage of participants
        number (not applicable)
    63.8
    60.1
    No statistical analyses for this end point

    Secondary: PFS as Determined by the Investigator According to RECIST v1.1 in ITT Population

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    End point title
    PFS as Determined by the Investigator According to RECIST v1.1 in ITT Population
    End point description
    PFS was defined as the time from randomization to PD, as determined by the investigator per RECIST v1.1 or death from any cause, whichever occurred first. PD: >/=20% relative increase in the SoD of all TLs, taking as reference the smallest SoD on study, including baseline, and an absolute increase of >/=5 mm; >/=1 new lesion(s); and/or unequivocal progression of non-TLs. Participants without PFS event were censored at the last tumor assessment date. Participants with no post-baseline tumor assessments were censored at the randomization date + 1 day. Participants with a PFS event who missed >/=2 scheduled assessments immediately prior to the PFS event were censored at the last tumor assessment prior to the missed visits. Median PFS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley. Analysis was performed on the ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline until documented PD or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    461
    454
    Units: months
        median (confidence interval 95%)
    8.4 (7.5 to 9.7)
    11.2 (9.6 to 13.6)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Strata were presence of liver metastases, Motzer score, PD-L1 level per interactive voice/web response system (IxRS).
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    915
    Analysis specification
    Pre-specified
    Analysis type
    superiority [17]
    P-value
    = 0.0254
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    0.98
    Notes
    [17] - Hazard ratio was estimated by Cox regression.

    Secondary: Percentage of Participants with PD as Determined by the Investigator According to RECIST v1.1 or Death from Any Cause in Participants with Sarcomatoid Histology

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    End point title
    Percentage of Participants with PD as Determined by the Investigator According to RECIST v1.1 or Death from Any Cause in Participants with Sarcomatoid Histology
    End point description
    Tumor response was assessed by the investigator according to RECIST v1.1. PD was defined as >/=20% relative increase in the SoD of all TLs, taking as reference the smallest SoD on study, including baseline, and an absolute increase of >/=5 mm; >/=1 new lesion(s); and/or unequivocal progression of non-TLs. Analysis was performed on the ITT Population participants with sarcomatoid histology (defined by investigator-assessed conventional histopathology).
    End point type
    Secondary
    End point timeframe
    Baseline until documented PD or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    74
    68
    Units: percentage of participants
        number (not applicable)
    85.1
    67.6
    No statistical analyses for this end point

    Secondary: PFS as Determined by the Investigator According to RECIST v1.1 in Participants with Sarcomatoid Histology

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    End point title
    PFS as Determined by the Investigator According to RECIST v1.1 in Participants with Sarcomatoid Histology
    End point description
    PFS was defined as the time from randomization to PD, as determined by the investigator per RECIST v1.1 or death from any cause, whichever occurred first. PD: >/=20% relative increase in the SoD of all TLs, taking as reference the smallest SoD on study, including baseline, and an absolute increase of >/=5 mm; >/=1 new lesion(s); and/or unequivocal progression of non-TLs. Participants without PFS event were censored at the last tumor assessment date. Participants with no post-baseline tumor assessments were censored at the randomization date + 1 day. Median PFS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley. Analysis was performed on the ITT Population participants with sarcomatoid histology.
    End point type
    Secondary
    End point timeframe
    Baseline until documented PD or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    74
    68
    Units: months
        median (confidence interval 95%)
    5.3 (3.3 to 6.7)
    8.3 (5.4 to 12.9)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Strata were presence of liver metastases, Motzer score, PD-L1 level per interactive voice/web response system (IxRS).
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    superiority [18]
    P-value
    = 0.002
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.52
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.34
         upper limit
    0.79
    Notes
    [18] - Hazard ratio was estimated by Cox regression.

    Secondary: Percentage of Participants Who Died of Any Cause in Participants with Sarcomatoid Histology

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    End point title
    Percentage of Participants Who Died of Any Cause in Participants with Sarcomatoid Histology
    End point description
    Percentage of participants who died of any cause was reported. Analysis was performed on the ITT Population participants with sarcomatoid histology.
    End point type
    Secondary
    End point timeframe
    Baseline until death from any cause (until data cut-off date 29 September 2017, up to approximately 27 months)
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    74
    68
    Units: percentage of participants
        number (not applicable)
    50.0
    38.2
    No statistical analyses for this end point

    Secondary: OS in Participants with Sarcomatoid Histology

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    End point title
    OS in Participants with Sarcomatoid Histology
    End point description
    OS was defined as the time from randomization to death due to any cause. Participants who were not reported as having died at the date of analysis were censored at the date when they were last known to be alive. Participants who did not have post-baseline information were censored at the date of randomization + 1 day. Median OS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley. Analysis was performed on the ITT Population participants with sarcomatoid histology. The data ‘99999’ in the results signifies that median and/or upper limit of 95% CI could not be estimated due to high number of censored participants.
    End point type
    Secondary
    End point timeframe
    Baseline until death from any cause (until data cut-off date 29 September 2017, up to approximately 27 months)
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    74
    68
    Units: months
        median (confidence interval 95%)
    15.0 (8.7 to 99999)
    99999 (18.3 to 99999)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Strata were presence of liver metastases, Motzer score, PD-L1 level per interactive voice/web response system (IxRS).
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    superiority [19]
    P-value
    = 0.0323
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.32
         upper limit
    0.96
    Notes
    [19] - Hazard ratio was estimated by Cox regression.

    Secondary: Change from Baseline in Symptom Interference as Determined by M.D. Anderson Symptom Inventory (MDASI) Part II Score

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    End point title
    Change from Baseline in Symptom Interference as Determined by M.D. Anderson Symptom Inventory (MDASI) Part II Score
    End point description
    The MDASI is a self-report questionnaire that comprises of 23 items and two subscales: symptom severity (17 items) and symptom interference (6 items). In Part II, participants were asked to rate how much the symptoms have interfered with 6 areas of function (general activity, walking, work, mood, relations with other people, and enjoyment of life) in the last 24 hours. Each item was rated on a scale of 0 (does not interfere) to 10 (interfered completely) and total Part II score was calculated as an average of 6-item scores. Repeated measures model-estimated least-squares (LS) mean score for changes from baseline is reported at each timepoint, where a negative value indicates improvement. Analysis was performed on the patient-reported outcome (PRO)-Evaluable Population, which included all participants with a non-missing baseline PRO assessment and >/=1 post-baseline PRO assessment. Here, 'n’= number of participants evaluable at specified time point for different arms, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1 Cycle 1); Day 22 Cycle 1; Day 1 and 22 of every cycle from Cycle 2 up to Cycle 19; Cycle length = 42 days
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    359 [20]
    373
    Units: units on a scale
    least squares mean (standard error)
        Change at Cycle1 Day 22 (n=260,301)
    1.28 ± 0.13
    0.54 ± 0.13
        Change at Cycle 2 Day 1 (n=276,305)
    0.76 ± 0.13
    0.56 ± 0.13
        Change at Cycle 2 Day 22 (n=248,284)
    1.58 ± 0.13
    0.56 ± 0.13
        Change at Cycle 3 Day 1 (n=253,297)
    1.05 ± 0.13
    0.53 ± 0.13
        Change at Cycle 3 Day 22 (n=226,279)
    1.63 ± 0.14
    0.61 ± 0.13
        Change at Cycle 4 Day 1 (n=230,266)
    1.02 ± 0.14
    0.59 ± 0.13
        Change at Cycle 4 Day 22 (n=217,252)
    1.55 ± 0.14
    0.57 ± 0.14
        Change at Cycle 5 Day 1 (n=211,238)
    1.18 ± 0.15
    0.72 ± 0.14
        Change at Cycle 5 Day 22 (n=196,238)
    1.56 ± 0.15
    0.78 ± 0.14
        Change at Cycle 6 Day 1 (n=198,224)
    1.03 ± 0.15
    0.82 ± 0.14
        Change at Cycle 6 Day 22 (n=183,207)
    1.44 ± 0.15
    0.80 ± 0.15
        Change at Cycle 7 Day 1 (n=173,200)
    1.15 ± 0.16
    0.72 ± 0.15
        Change at Cycle 7 Day 22 (n=163,191)
    1.43 ± 0.16
    0.66 ± 0.15
        Change at Cycle 8 Day 1 (n=161,192)
    1.06 ± 0.16
    0.76 ± 0.15
        Change at Cycle 8 Day 22 (n=150,186)
    1.34 ± 0.17
    0.69 ± 0.15
        Change at Cycle 9 Day 1 (n=146,185)
    1.05 ± 0.17
    0.67 ± 0.16
        Change at Cycle 9 Day 22 (n=135,172)
    1.46 ± 0.18
    0.56 ± 0.16
        Change at Cycle 10 Day 1 (n=131,169)
    1.24 ± 0.18
    0.61 ± 0.16
        Change at Cycle 10 Day 22 (n=78,151)
    1.61 ± 0.20
    0.60 ± 0.17
        Change at Cycle 11 Day 1 (n=100,134)
    1.12 ± 0.19
    0.62 ± 0.17
        Change at Cycle 11 Day 22 (n=59,122)
    1.45 ± 0.21
    0.61 ± 0.18
        Change at Cycle 12 Day 1 (n=73,110)
    1.02 ± 0.21
    0.53 ± 0.18
        Change at Cycle 12 Day 22 (n=47,93)
    1.45 ± 0.24
    0.69 ± 0.20
        Change at Cycle 13 Day 1 (n=52,81)
    0.79 ± 0.24
    0.80 ± 0.21
        Change at Cycle 13 Day 22 (n=36,72)
    1.09 ± 0.27
    0.73 ± 0.22
        Change at Cycle 14 Day 1 (n=39,57)
    0.86 ± 0.27
    0.73 ± 0.24
        Change at Cycle 14 Day 22 (n=27,54)
    1.22 ± 0.31
    0.83 ± 0.25
        Change at Cycle 15 Day 1 (n=31,43)
    0.93 ± 0.31
    0.78 ± 0.27
        Change at Cycle 15 Day 22 (n=17,36)
    1.67 ± 0.37
    0.88 ± 0.29
        Change at Cycle 16 Day 1 (n=20,27)
    0.90 ± 0.38
    0.98 ± 0.32
        Change at Cycle 16 Day 22 (n=13,22)
    1.30 ± 0.43
    1.32 ± 0.36
        Change at Cycle 17 Day 1 (n=13,19)
    0.80 ± 0.46
    1.18 ± 0.40
        Change at Cycle 17 Day 22 (n=9,11)
    0.92 ± 0.53
    0.95 ± 0.47
        Change at Cycle 18 Day 1 (n=6,9)
    0.75 ± 0.64
    0.75 ± 0.53
        Change at Cycle 18 Day 22 (n=3,6)
    0.65 ± 0.86
    0.87 ± 0.63
        Change at Cycle 19 Day 1 (n=1,5)
    0.29 ± 1.58
    0.80 ± 0.73
        Change at Cycle 19 Day 22 (n=0,2)
    99999 ± 99999
    0.88 ± 1.03
    Notes
    [20] - ‘99999’ = data not available as no participant was evaluable at specified time point.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Cycle 1 Day 22 (Actual number of participants included in the analysis = 561): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [21]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.06
         upper limit
    -0.43
    Notes
    [21] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Cycle 2 Day 1 (Actual number of participants included in the analysis = 581): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [22]
    P-value
    = 0.2085
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.51
         upper limit
    0.11
    Notes
    [22] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Cycle 2 Day 22 (Actual number of participants included in the analysis = 532): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [23]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    -1.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.33
         upper limit
    -0.71
    Notes
    [23] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    Cycle 3 Day 1 (Actual number of participants included in the analysis = 550): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [24]
    P-value
    = 0.0013
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.51
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.82
         upper limit
    -0.2
    Notes
    [24] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 5
    Statistical analysis description
    Cycle 3 Day 22 (Actual number of participants included in the analysis = 505): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [25]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    -1.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.34
         upper limit
    -0.7
    Notes
    [25] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 6
    Statistical analysis description
    Cycle 4 Day 1 (Actual number of participants included in the analysis = 496): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [26]
    P-value
    = 0.0098
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.76
         upper limit
    -0.1
    Notes
    [26] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 7
    Statistical analysis description
    Cycle 4 Day 22 (Actual number of participants included in the analysis = 469): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [27]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.32
         upper limit
    -0.65
    Notes
    [27] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 8
    Statistical analysis description
    Cycle 5 Day 1 (Actual number of participants included in the analysis = 449): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [28]
    P-value
    = 0.008
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.8
         upper limit
    -0.12
    Notes
    [28] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 9
    Statistical analysis description
    Cycle 5 Day 22 (Actual number of participants included in the analysis = 434): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [29]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.13
         upper limit
    -0.44
    Notes
    [29] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 10
    Statistical analysis description
    Cycle 6 Day 1 (Actual number of participants included in the analysis = 422): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [30]
    P-value
    = 0.2512
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.56
         upper limit
    0.15
    Notes
    [30] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 11
    Statistical analysis description
    Cycle 6 Day 22 (Actual number of participants included in the analysis = 390): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [31]
    P-value
    = 0.0005
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.01
         upper limit
    -0.28
    Notes
    [31] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 12
    Statistical analysis description
    Cycle 7 Day 1 (Actual number of participants included in the analysis = 373): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [32]
    P-value
    = 0.0247
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.8
         upper limit
    -0.05
    Notes
    [32] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 13
    Statistical analysis description
    Cycle 7 Day 22 (Actual number of participants included in the analysis = 354): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [33]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.15
         upper limit
    -0.39
    Notes
    [33] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 14
    Statistical analysis description
    Cycle 8 Day 1 (Actual number of participants included in the analysis = 353): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [34]
    P-value
    = 0.1411
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.29
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.68
         upper limit
    0.1
    Notes
    [34] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 15
    Statistical analysis description
    Cycle 8 Day 22 (Actual number of participants included in the analysis = 336): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [35]
    P-value
    = 0.0014
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.05
         upper limit
    -0.25
    Notes
    [35] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 16
    Statistical analysis description
    Cycle 9 Day 1 (Actual number of participants included in the analysis = 331): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [36]
    P-value
    = 0.0728
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.37
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.78
         upper limit
    0.03
    Notes
    [36] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 17
    Statistical analysis description
    Cycle 9 Day 22 (Actual number of participants included in the analysis = 307): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [37]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.32
         upper limit
    -0.49
    Notes
    [37] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 18
    Statistical analysis description
    Cycle 10 Day 1 (Actual number of participants included in the analysis = 300): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [38]
    P-value
    = 0.0041
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.05
         upper limit
    -0.2
    Notes
    [38] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 19
    Statistical analysis description
    Cycle 10 Day 22 (Actual number of participants included in the analysis = 229): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [39]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    -1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.46
         upper limit
    -0.55
    Notes
    [39] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 20
    Statistical analysis description
    Cycle 11 Day 1 (Actual number of participants included in the analysis = 234): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [40]
    P-value
    = 0.0353
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.96
         upper limit
    -0.03
    Notes
    [40] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 21
    Statistical analysis description
    Cycle 11 Day 22 (Actual number of participants included in the analysis = 181): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [41]
    P-value
    = 0.0011
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.35
         upper limit
    -0.34
    Notes
    [41] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 22
    Statistical analysis description
    Cycle 12 Day 1 (Actual number of participants included in the analysis = 183): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [42]
    P-value
    = 0.0582
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.01
         upper limit
    0.02
    Notes
    [42] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 23
    Statistical analysis description
    Cycle 12 Day 22 (Actual number of participants included in the analysis = 140): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [43]
    P-value
    = 0.0089
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.32
         upper limit
    -0.19
    Notes
    [43] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 24
    Statistical analysis description
    Cycle 13 Day 1 (Actual number of participants included in the analysis = 133): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [44]
    P-value
    = 0.9575
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.57
         upper limit
    0.61
    Notes
    [44] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 25
    Statistical analysis description
    Cycle 13 Day 22 (Actual number of participants included in the analysis = 108): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [45]
    P-value
    = 0.2745
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.36
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.01
         upper limit
    0.29
    Notes
    [45] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 26
    Statistical analysis description
    Cycle 14 Day 1 (Actual number of participants included in the analysis = 96): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [46]
    P-value
    = 0.7088
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.81
         upper limit
    0.55
    Notes
    [46] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 27
    Statistical analysis description
    Cycle 14 Day 22 (Actual number of participants included in the analysis = 81): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [47]
    P-value
    = 0.3077
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.13
         upper limit
    0.36
    Notes
    [47] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 28
    Statistical analysis description
    Cycle 15 Day 1 (Actual number of participants included in the analysis = 74): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [48]
    P-value
    = 0.7112
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.93
         upper limit
    0.63
    Notes
    [48] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 29
    Statistical analysis description
    Cycle 15 Day 22 (Actual number of participants included in the analysis = 53): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [49]
    P-value
    = 0.0837
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.69
         upper limit
    0.11
    Notes
    [49] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 30
    Statistical analysis description
    Cycle 16 Day 1 (Actual number of participants included in the analysis = 47): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [50]
    P-value
    = 0.8655
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.88
         upper limit
    1.04
    Notes
    [50] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 31
    Statistical analysis description
    Cycle 16 Day 22 (Actual number of participants included in the analysis = 35): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [51]
    P-value
    = 0.9725
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.07
         upper limit
    1.11
    Notes
    [51] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 32
    Statistical analysis description
    Cycle 17 Day 1 (Actual number of participants included in the analysis = 32): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [52]
    P-value
    = 0.5285
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.8
         upper limit
    1.55
    Notes
    [52] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 33
    Statistical analysis description
    Cycle 17 Day 22 (Actual number of participants included in the analysis = 20): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [53]
    P-value
    = 0.9663
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.34
         upper limit
    1.4
    Notes
    [53] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 34
    Statistical analysis description
    Cycle 18 Day 1 (Actual number of participants included in the analysis = 15): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [54]
    P-value
    = 0.9914
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.61
         upper limit
    1.63
    Notes
    [54] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 35
    Statistical analysis description
    Cycle 18 Day 22 (Actual number of participants included in the analysis = 9): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [55]
    P-value
    = 0.8345
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.85
         upper limit
    2.3
    Notes
    [55] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 36
    Statistical analysis description
    Cycle 19 Day 1 (Actual number of participants included in the analysis = 6): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [56]
    P-value
    = 0.7725
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.9
         upper limit
    3.91
    Notes
    [56] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.

    Secondary: Change from Baseline in Symptom Severity as Determined by MDASI Part I Score

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    End point title
    Change from Baseline in Symptom Severity as Determined by MDASI Part I Score
    End point description
    The MDASI is a cancer-related, multi-symptom, valid, and reliable self-report questionnaire that comprises of 23 items and two subscales: symptom severity (17 items) and symptom interference (6 items). In Part I, participants were asked to rate how severe the symptoms (pain, fatigue, nausea, disturbed sleep, feeling of being distressed, shortness of breath, remembering things, lack of appetite, drowsy, dry mouth, feeling sad, vomiting, numbness or tingling, rash/skin changes, headache, mouth/throat sores, and diarrhea) were when “at their worst” in the last 24 hours. Each item was rated on a scale of 0 (not present) to 10 (as bad as you can imagine). Mixed-effects model-estimated LS mean score for change from baseline at the end-of-treatment is reported for each item, where a negative value indicates improvement. Analysis was performed on the PRO-Evaluable Population. Here, ‘Number of Subject Analysed’ = number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline; End of Treatment (EoT) visit (up to approximately 27 months)
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    337
    358
    Units: units on a scale
    least squares mean (standard error)
        Pain: Change at EoT
    1.41 ± 0.15
    0.92 ± 0.15
        Fatigue: Change at EoT
    1.83 ± 0.15
    1.20 ± 0.15
        Nausea: Change at EoT
    1.20 ± 0.11
    0.29 ± 0.11
        Disturbed sleep: Change at EoT
    0.71 ± 0.14
    0.19 ± 0.14
        Feeling of Being distressed: Change at EoT
    0.82 ± 0.14
    0.25 ± 0.14
        Shortness of breath: Change at EoT
    1.15 ± 0.13
    0.58 ± 0.13
        Remembering things: Change at EoT
    0.93 ± 0.12
    0.60 ± 0.11
        Lack of appetite: Change at EoT
    1.59 ± 0.14
    0.40 ± 0.14
        Drowsy: Change at EoT
    1.32 ± 0.14
    0.79 ± 0.14
        Dry mouth: Change at EoT
    1.67 ± 0.15
    0.67 ± 0.15
        Feeling sad: Change at EoT
    0.88 ± 0.14
    0.28 ± 0.14
        Vomiting: Change at EoT
    0.66 ± 0.09
    0.08 ± 0.09
        Numbness or tingling: Change at EoT
    1.01 ± 0.12
    0.67 ± 0.12
        Rash/skin changes: Change at EoT
    2.08 ± 0.13
    1.00 ± 0.13
        Headache: Change at EoT
    0.70 ± 0.11
    0.66 ± 0.11
        Mouth/throat sores: Change at EoT
    1.76 ± 0.13
    0.74 ± 0.13
        Diarrhea: Change at EoT
    1.37 ± 0.10
    0.29 ± 0.10
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Pain: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    superiority [57]
    P-value
    = 0.001
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -0.49
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.77
         upper limit
    -0.2
    Notes
    [57] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Fatigue: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    superiority [58]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -0.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.91
         upper limit
    -0.34
    Notes
    [58] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Nausea: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    superiority [59]
    P-value
    < 0.0001
    Method
    Mixed Models Analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -0.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.13
         upper limit
    -0.69
    Notes
    [59] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    Disturbed sleep: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    superiority [60]
    P-value
    = 0.0002
    Method
    Mixed Models Analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -0.52
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.79
         upper limit
    -0.25
    Notes
    [60] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 5
    Statistical analysis description
    Being distressed: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    superiority [61]
    P-value
    < 0.0001
    Method
    Mixed Models Analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -0.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.84
         upper limit
    -0.29
    Notes
    [61] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 6
    Statistical analysis description
    Shortness of breath: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    superiority [62]
    P-value
    < 0.0001
    Method
    Mixed Models Analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -0.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.81
         upper limit
    -0.32
    Notes
    [62] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 7
    Statistical analysis description
    Remembering things: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    superiority [63]
    P-value
    = 0.0036
    Method
    Mixed Models Analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -0.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.56
         upper limit
    -0.11
    Notes
    [63] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 8
    Statistical analysis description
    Lack of appetite: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    superiority [64]
    P-value
    < 0.0001
    Method
    Mixed Models Analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -1.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.46
         upper limit
    -0.91
    Notes
    [64] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 9
    Statistical analysis description
    Drowsy: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    superiority [65]
    P-value
    = 0.0001
    Method
    Mixed Models Analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -0.54
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.81
         upper limit
    -0.27
    Notes
    [65] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 10
    Statistical analysis description
    Dry mouth: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    superiority [66]
    P-value
    < 0.0001
    Method
    Mixed Models Analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.28
         upper limit
    -0.71
    Notes
    [66] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 11
    Statistical analysis description
    Feeling sad: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    superiority [67]
    P-value
    < 0.0001
    Method
    Mixed Models Analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.87
         upper limit
    -0.33
    Notes
    [67] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 12
    Statistical analysis description
    Vomiting: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    superiority [68]
    P-value
    < 0.0001
    Method
    Mixed Models Analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -0.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.75
         upper limit
    -0.41
    Notes
    [68] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 13
    Statistical analysis description
    Numbness or tingling: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    superiority [69]
    P-value
    = 0.0051
    Method
    Mixed Models Analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -0.34
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.58
         upper limit
    -0.1
    Notes
    [69] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 14
    Statistical analysis description
    Rash/Skin Changes: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    superiority [70]
    P-value
    < 0.0001
    Method
    Mixed Models Analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -1.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.33
         upper limit
    -0.83
    Notes
    [70] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 15
    Statistical analysis description
    Headache: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    superiority [71]
    P-value
    = 0.6541
    Method
    Mixed Models Analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -0.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.26
         upper limit
    0.16
    Notes
    [71] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 16
    Statistical analysis description
    Mouth/Throat Sores: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    superiority [72]
    P-value
    < 0.0001
    Method
    Mixed Models Analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -1.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.28
         upper limit
    -0.76
    Notes
    [72] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 17
    Statistical analysis description
    Diarrhea: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    superiority [73]
    P-value
    < 0.0001
    Method
    Mixed Models Analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -1.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.27
         upper limit
    -0.88
    Notes
    [73] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.

    Secondary: Change from Baseline in Symptom Severity as Determined by Brief Fatigue Inventory (BFI) Interference Scale Score

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    End point title
    Change from Baseline in Symptom Severity as Determined by Brief Fatigue Inventory (BFI) Interference Scale Score
    End point description
    The BFI is a valid and reliable self-report questionnaire used to assess the severity and impact of cancer-related fatigue. BFI interference subscale (6 items) assessed the impact of fatigue on global domains (general activity, mood, walking ability, normal work, relations with other people, and enjoyment of life) in the last 24 hours. Each item was rated on a scale of 0 (does not interfere) to 10 (interfered completely). Change from baseline in the mean score of all 6 items at each timepoint is reported, where a negative value indicates improvement. Analysis was performed on the PRO-Evaluable Population. Here, ‘Number of Subject Analysed’ = number of participants evaluable for this outcome measure; 'n’= number of participants evaluable at specified time point for different arms, respectively; ‘9999’ = data not available as no participant was evaluable at specified time point; and ‘99999’ = Standard Deviation (SD) could not be estimated as only 1 participant was evaluable.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1 Cycle 1); every week for first 12 weeks, Days 1 and 22 of each cycle (Cycle 3 up to 19), within 30 days of PD (up to 27 months), at EoT (up to 27 months) and at 6, 12, 24, and 36 weeks after EoT (overall up to 27 months); 1 cycle=42 days
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    368
    381
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=368,381)
    2.11 ± 2.23
    2.08 ± 2.38
        Change at Cycle 1 Day 8 (n=352,356)
    0.30 ± 1.88
    0.37 ± 1.76
        Change at Cycle 1 Day 15 (n=339,352)
    1.26 ± 2.49
    1.06 ± 2.42
        Change at Cycle 1 Day 22 (n=258,298)
    1.34 ± 2.44
    0.57 ± 2.04
        Change at Cycle 1 Day 29 (n=329,348)
    1.48 ± 2.63
    0.66 ± 2.28
        Change at Cycle 1 Day 36 (n=311,344)
    0.95 ± 2.29
    0.74 ± 2.20
        Change at Cycle 2 Day 1 (n=271,293)
    0.38 ± 2.03
    0.43 ± 2.09
        Change at Cycle 2 Day 8 (n=307,336)
    0.63 ± 2.17
    0.68 ± 2.33
        Change at Cycle 2 Day 15 (n=310,319)
    1.10 ± 2.35
    0.55 ± 2.29
        Change at Cycle 2 Day 22 (n=245,277)
    1.24 ± 2.65
    0.26 ± 2.14
        Change at Cycle 2 Day 29 (n=302,303)
    1.45 ± 2.61
    0.51 ± 2.14
        Change at Cycle 2 Day 36 (n=291,311)
    1.11 ± 2.46
    0.43 ± 2.17
        Change at Cycle 3 Day 1 (n=238,278)
    0.76 ± 2.27
    0.21 ± 2.12
        Change at Cycle 3 Day 22 (n=229,279)
    1.43 ± 2.41
    0.36 ± 2.20
        Change at Cycle 4 Day 1 (n=231,266)
    0.76 ± 2.27
    0.38 ± 2.16
        Change at Cycle 4 Day 22 (n=219,252)
    1.47 ± 2.60
    0.44 ± 2.33
        Change at Cycle 5 Day 1 (n=212,239)
    1.01 ± 2.46
    0.52 ± 2.31
        Change at Cycle 5 Day 22 (n=197,238)
    1.38 ± 2.22
    0.61 ± 2.27
        Change at Cycle 6 Day 1 (n=199,224)
    0.88 ± 2.24
    0.59 ± 2.15
        Change at Cycle 6 Day 22 (n=184,207)
    1.25 ± 2.42
    0.52 ± 2.22
        Change at Cycle 7 Day 1 (n=174,200)
    0.82 ± 2.35
    0.61 ± 2.17
        Change at Cycle 7 Day 22 (n=164,191)
    1.05 ± 2.31
    0.47 ± 2.16
        Change at Cycle 8 Day 1 (n=162,192)
    0.87 ± 2.21
    0.63 ± 2.36
        Change at Cycle 8 Day 22 (n=151,186)
    1.22 ± 2.21
    0.52 ± 2.05
        Change at Cycle 9 Day 1 (n=147,185)
    0.93 ± 2.25
    0.57 ± 2.27
        Change at Cycle 9 Day 22 (n=136,172)
    1.35 ± 2.37
    0.37 ± 2.15
        Change at Cycle 10 Day 1 (n=132,169)
    1.09 ± 2.53
    0.56 ± 1.96
        Change at Cycle 10 Day 22 (n=78,151)
    1.62 ± 2.75
    0.52 ± 1.95
        Change at Cycle 11 Day 1 (n=101,134)
    0.95 ± 2.29
    0.60 ± 1.92
        Change at Cycle 11 Day 22 (n=59,122)
    0.88 ± 2.57
    0.57 ± 1.78
        Change at Cycle 12 Day 1 (n=73,111)
    0.89 ± 2.45
    0.35 ± 1.75
        Change at Cycle 12 Day 22 (n=47,93)
    0.97 ± 2.46
    0.58 ± 1.96
        Change at Cycle 13 Day 1 (n=52,81)
    0.84 ± 2.29
    0.36 ± 1.88
        Change at Cycle 13 Day 22 (n=36,72)
    0.76 ± 2.70
    0.56 ± 2.06
        Change at Cycle 14 Day 1 (n=39,57)
    0.80 ± 2.33
    0.73 ± 1.80
        Change at Cycle 14 Day 22 (n=27,54)
    0.69 ± 2.73
    0.94 ± 1.96
        Change at Cycle 15 Day 1 (n=31,43)
    0.95 ± 2.42
    0.61 ± 1.41
        Change at Cycle 15 Day 22 (n=17,36)
    1.05 ± 3.22
    0.91 ± 1.28
        Change at Cycle 16 Day 1 (n=20,27)
    0.13 ± 1.49
    1.02 ± 1.69
        Change at Cycle 16 Day 22 (n=13,22)
    1.05 ± 1.83
    1.55 ± 1.96
        Change at Cycle 17 Day 1 (n=13,19)
    0.53 ± 1.41
    1.25 ± 1.97
        Change at Cycle 17 Day 22 (n=9,11)
    1.43 ± 2.16
    0.41 ± 1.48
        Change at Cycle 18 Day 1 (n=7,9)
    0.79 ± 1.34
    0.35 ± 1.46
        Change at Cycle 18 Day 22 (n=3,6)
    1.28 ± 2.21
    0.17 ± 1.15
        Change at Cycle 19 Day 1 (n=1,5)
    0.00 ± 99999
    -0.80 ± 0.84
        Change at Cycle 19 Day 22 (n=0,2)
    9999 ± 9999
    -0.25 ± 0.82
        Change at 6 weeks after EoT (n=70,42)
    2.31 ± 2.52
    1.83 ± 2.52
        Change at 12 weeks after EoT (n=59,36)
    1.71 ± 2.66
    1.97 ± 2.63
        Change at 24 weeks after EoT (n=31,25)
    2.38 ± 3.11
    2.15 ± 3.30
        Change at 36 weeks after EoT (n=14,18)
    2.40 ± 3.32
    1.15 ± 2.72
        Change at EoT (n=168,127)
    1.57 ± 2.80
    1.62 ± 2.98
        Change Within 30 Days of PD (n=194,184)
    1.74 ± 2.64
    0.74 ± 2.35
    No statistical analyses for this end point

    Secondary: Change from Baseline in Symptom Severity as Determined by BFI Worst Fatigue Item

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    End point title
    Change from Baseline in Symptom Severity as Determined by BFI Worst Fatigue Item
    End point description
    The BFI is a valid and reliable self-report questionnaire used to assess the severity and impact of cancer-related fatigue. BFI worst fatigue item assessed the severity of fatigue at its worst in the last 24 hours. The item was rated on a scale of 0 (not present) to 10 (as bad as you can imagine). Change from baseline in the score at each time point is reported, where a negative value indicates improvement. Analysis was performed on the PRO-Evaluable Population. Here, ‘Number of Subject Analysed’ = number of participants evaluable for this outcome measure; 'n’= number of participants evaluable at specified time point for different arms, respectively; ‘9999’ = data not available as no participant was evaluable at specified time point; and ‘99999’ = SD could not be estimated as only 1 participant was evaluable.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1 Cycle 1); every week for first 12 weeks, Days 1 and 22 of each cycle (Cycle 3 up to 19), within 30 days of PD (up to 27 months), at EoT (up to 27 months) and at 6, 12, 24, and 36 weeks after EoT (overall up to 27 months); 1 cycle=42 days
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    368
    381
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=368,381)
    3.08 ± 2.66
    2.98 ± 2.69
        Change at Cycle 1 Day 8 (n=352,356)
    0.34 ± 2.35
    0.50 ± 2.29
        Change at Cycle 1 Day 15 (n=339,352)
    1.32 ± 2.82
    1.26 ± 2.92
        Change at Cycle 1 Day 22 (n=258,298)
    1.52 ± 2.86
    0.49 ± 2.30
        Change at Cycle 1 Day 29 (n=329,348)
    1.55 ± 2.99
    0.88 ± 2.62
        Change at Cycle 1 Day 36 (n=311,344)
    0.77 ± 2.82
    0.86 ± 2.50
        Change at Cycle 2 Day 1 (n=271,293)
    0.40 ± 2.50
    0.45 ± 2.52
        Change at Cycle 2 Day 8 (n=307,336)
    0.56 ± 2.68
    0.87 ± 2.82
        Change at Cycle 2 Day 15 (n=310,319)
    1.09 ± 2.82
    0.71 ± 2.78
        Change at Cycle 2 Day 22 (n=245,277)
    1.42 ± 3.01
    0.31 ± 2.53
        Change at Cycle 2 Day 29 (n=302,303)
    1.43 ± 3.08
    0.62 ± 2.66
        Change at Cycle 2 Day 36 (n=291,311)
    1.09 ± 3.01
    0.48 ± 2.76
        Change at Cycle 3 Day 1 (n=238,278)
    0.42 ± 2.68
    0.40 ± 2.57
        Change at Cycle 3 Day 22 (n=229,279)
    1.57 ± 2.98
    0.57 ± 2.64
        Change at Cycle 4 Day 1 (n=231,266)
    0.64 ± 2.76
    0.54 ± 2.49
        Change at Cycle 4 Day 22 (n=219,252)
    1.46 ± 3.14
    0.58 ± 2.74
        Change at Cycle 5 Day 1 (n=212,239)
    0.81 ± 2.75
    0.62 ± 2.79
        Change at Cycle 5 Day 22 (n=197,238)
    1.60 ± 2.87
    0.69 ± 2.83
        Change at Cycle 6 Day 1 (n=199,224)
    0.90 ± 2.78
    0.86 ± 2.73
        Change at Cycle 6 Day 22 (n=184,207)
    1.35 ± 2.79
    0.53 ± 2.66
        Change at Cycle 7 Day 1 (n=174,200)
    0.79 ± 2.78
    0.79 ± 2.70
        Change at Cycle 7 Day 22 (n=164,191)
    1.22 ± 2.85
    0.65 ± 2.56
        Change at Cycle 8 Day 1 (n=162,192)
    0.79 ± 2.69
    0.75 ± 2.84
        Change at Cycle 8 Day 22 (n=151,186)
    1.40 ± 2.64
    0.78 ± 2.67
        Change at Cycle 9 Day 1 (n=147,185)
    0.97 ± 2.54
    0.61 ± 2.62
        Change at Cycle 9 Day 22 (n=136,172)
    1.54 ± 2.92
    0.57 ± 2.55
        Change at Cycle 10 Day 1 (n=132,169)
    0.95 ± 2.73
    0.69 ± 2.46
        Change at Cycle 10 Day 22 (n=78,151)
    1.74 ± 3.09
    0.63 ± 2.48
        Change at Cycle 11 Day 1 (n=101,134)
    0.73 ± 2.80
    0.74 ± 2.69
        Change at Cycle 11 Day 22 (n=59,122)
    1.15 ± 3.18
    0.74 ± 2.52
        Change at Cycle 12 Day 1 (n=73,111)
    0.78 ± 2.79
    0.61 ± 2.29
        Change at Cycle 12 Day 22 (n=47,93)
    1.32 ± 2.89
    0.74 ± 2.69
        Change at Cycle 13 Day 1 (n=52,81)
    0.35 ± 2.54
    0.49 ± 2.46
        Change at Cycle 13 Day 22 (n=36,72)
    0.72 ± 3.48
    0.65 ± 2.70
        Change at Cycle 14 Day 1 (n=39,57)
    0.56 ± 2.84
    0.81 ± 2.60
        Change at Cycle 14 Day 22 (n=27,54)
    0.37 ± 3.01
    1.04 ± 2.40
        Change at Cycle 15 Day 1 (n=31,43)
    0.52 ± 3.15
    0.93 ± 2.25
        Change at Cycle 15 Day 22 (n=17,36)
    0.59 ± 4.08
    0.97 ± 1.84
        Change at Cycle 16 Day 1 (n=20,27)
    -0.05 ± 2.61
    1.33 ± 1.92
        Change at Cycle 16 Day 22 (n=13,22)
    0.77 ± 3.70
    1.68 ± 2.10
        Change at Cycle 17 Day 1 (n=13,19)
    -0.62 ± 3.75
    1.68 ± 1.97
        Change at Cycle 17 Day 22 (n=9,11)
    1.44 ± 3.91
    1.18 ± 1.99
        Change at Cycle 18 Day 1 (n=7,9)
    0.00 ± 2.00
    1.33 ± 1.58
        Change at Cycle 18 Day 22 (n=3,6)
    1.00 ± 1.73
    1.00 ± 2.10
        Change at Cycle 19 Day 1 (n=1,5)
    -4.00 ± 99999
    0.60 ± 1.34
        Change at Cycle 19 Day 22 (n=0,2)
    9999 ± 9999
    0.00 ± 0.00
        Change at 6 weeks after EoT (n=70,42)
    2.43 ± 3.25
    2.40 ± 2.89
        Change at 12 weeks after EoT (n=59,36)
    1.56 ± 3.41
    2.06 ± 3.14
        Change at 24 weeks after EoT (n=31,25)
    1.58 ± 3.82
    1.92 ± 3.46
        Change at 36 weeks after EoT (n=14,18)
    1.86 ± 4.37
    0.78 ± 2.86
        Change at EoT (n=168,127)
    1.40 ± 3.13
    1.72 ± 2.84
        Change Within 30 Days of PD (n=194,184)
    1.81 ± 3.16
    0.89 ± 2.58
    No statistical analyses for this end point

    Secondary: Change from Baseline in Treatment Side Effects Burden as Determined by Functional Assessment of Cancer Therapy Kidney Symptom Index (FKSI-19) General Population 5 (GP5) Item Score

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    End point title
    Change from Baseline in Treatment Side Effects Burden as Determined by Functional Assessment of Cancer Therapy Kidney Symptom Index (FKSI-19) General Population 5 (GP5) Item Score
    End point description
    The FKSI-19 is a 19-item tool designed to assess the most important symptoms and concerns related to treatment effectiveness in advanced kidney cancer. The FKSI-19 GP5 item (bothered by the side effect of treatment) assessed side effects burden in the past 7 days on a 5-point scale (0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much). Repeated measures model-estimated LS mean score for changes from baseline is reported at each timepoint, where a negative value indicates improvement. Analysis was performed on the PRO-Evaluable Population. Here, 'n’= number of participants evaluable at specified time point for different arms, respectively. ‘99999’ = data not available as no participant was evaluable at specified time point.
    End point type
    Secondary
    End point timeframe
    Day 1 and 22 of every cycle (Baseline = Day 1 Cycle 1) up to Cycle 19; Cycle length = 42 days
    End point values
    Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    359
    373
    Units: units on a scale
    least squares mean (standard error)
        Change at Cycle1 Day 22 (n=260,301)
    -1.08 ± 0.06
    -0.36 ± 0.06
        Change at Cycle 2 Day 1 (n=276,305)
    -0.87 ± 0.06
    -0.45 ± 0.06
        Change at Cycle 2 Day 22 (n=248,283)
    -1.13 ± 0.06
    -0.43 ± 0.06
        Change at Cycle 3 Day 1 (n=253,297)
    -1.07 ± 0.06
    -0.49 ± 0.06
        Change at Cycle 3 Day 22 (n=226,279)
    -1.22 ± 0.06
    -0.45 ± 0.06
        Change at Cycle 4 Day 1 (n=230,266)
    -1.07 ± 0.06
    -0.45 ± 0.06
        Change at Cycle 4 Day 22 (n=215,252)
    -1.31 ± 0.07
    -0.49 ± 0.06
        Change at Cycle 5 Day 1 (n=210,238)
    -1.17 ± 0.07
    -0.52 ± 0.06
        Change at Cycle 5 Day 22 (n=196,238)
    -1.38 ± 0.07
    -0.55 ± 0.06
        Change at Cycle 6 Day 1 (n=198,223)
    -1.14 ± 0.07
    -0.51 ± 0.06
        Change at Cycle 6 Day 22 (n=183,207)
    -1.27 ± 0.07
    -0.56 ± 0.07
        Change at Cycle 7 Day 1 (n=173,200)
    -1.09 ± 0.07
    -0.61 ± 0.07
        Change at Cycle 7 Day 22 (n=163,191)
    -1.25 ± 0.07
    -0.58 ± 0.07
        Change at Cycle 8 Day 1 (n=161,191)
    -1.08 ± 0.08
    -0.61 ± 0.07
        Change at Cycle 8 Day 22 (n=150,186)
    -1.22 ± 0.08
    -0.62 ± 0.07
        Change at Cycle 9 Day 1 (n=146,185)
    -1.08 ± 0.08
    -0.60 ± 0.07
        Change at Cycle 9 Day 22 (n=135,172)
    -1.23 ± 0.08
    -0.52 ± 0.07
        Change at Cycle 10 Day 1 (n=131,169)
    -1.06 ± 0.08
    -0.53 ± 0.07
        Change at Cycle 10 Day 22 (n=77,150)
    -1.30 ± 0.09
    -0.57 ± 0.08
        Change at Cycle 11 Day 1 (n=100,134)
    -1.16 ± 0.09
    -0.52 ± 0.08
        Change at Cycle 11 Day 22 (n=59,122)
    -1.28 ± 0.11
    -0.54 ± 0.08
        Change at Cycle 12 Day 1 (n=73,110)
    -1.05 ± 0.10
    -0.62 ± 0.09
        Change at Cycle 12 Day 22 (n=47,93)
    -1.17 ± 0.12
    -0.56 ± 0.09
        Change at Cycle 13 Day 1 (n=52,81)
    -1.15 ± 0.12
    -0.62 ± 0.10
        Change at Cycle 13 Day 22 (n=36,72)
    -1.20 ± 0.14
    -0.64 ± 0.11
        Change at Cycle 14 Day 1 (n=39,57)
    -0.94 ± 0.14
    -0.61 ± 0.12
        Change at Cycle 14 Day 22 (n=27,54)
    -1.32 ± 0.16
    -0.65 ± 0.12
        Change at Cycle 15 Day 1 (n=31,43)
    -0.91 ± 0.15
    -0.62 ± 0.13
        Change at Cycle 15 Day 22 (n=17,36)
    -1.16 ± 0.19
    -0.72 ± 0.14
        Change at Cycle 16 Day 1 (n=20,27)
    -1.06 ± 0.19
    -0.58 ± 0.16
        Change at Cycle 16 Day 22 (n=13,22)
    -1.34 ± 0.22
    -0.41 ± 0.18
        Change at Cycle 17 Day 1 (n=13,19)
    -1.10 ± 0.23
    -0.56 ± 0.20
        Change at Cycle 17 Day 22 (n=9,11)
    -1.02 ± 0.27
    -0.44 ± 0.24
        Change at Cycle 18 Day 1 (n=6,9)
    -1.01 ± 0.33
    -0.38 ± 0.27
        Change at Cycle 18 Day 22 (n=3,6)
    -0.81 ± 0.46
    -0.48 ± 0.33
        Change at Cycle 19 Day 1 (n=1,5)
    -1.27 ± 0.84
    -0.75 ± 0.38
        Change at Cycle 19 Day 22 (n=0,2)
    99999 ± 99999
    -0.93 ± 0.55
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Cycle 1 Day 22 (Actual number of participants included in the analysis = 561): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [74]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.73
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.58
         upper limit
    0.87
    Notes
    [74] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Cycle 2 Day 1 (Actual number of participants included in the analysis = 581): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [75]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.28
         upper limit
    0.57
    Notes
    [75] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Cycle 2 Day 22 (Actual number of participants included in the analysis = 531): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [76]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.55
         upper limit
    0.84
    Notes
    [76] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    Cycle 3 Day 1 (Actual number of participants included in the analysis = 550): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [77]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.44
         upper limit
    0.73
    Notes
    [77] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 5
    Statistical analysis description
    Cycle 3 Day 22 (Actual number of participants included in the analysis = 505): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [78]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.62
         upper limit
    0.92
    Notes
    [78] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 6
    Statistical analysis description
    Cycle 4 Day 1 (Actual number of participants included in the analysis = 496): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [79]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.46
         upper limit
    0.78
    Notes
    [79] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 7
    Statistical analysis description
    Cycle 4 Day 22 (Actual number of participants included in the analysis = 467): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [80]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.82
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.66
         upper limit
    0.97
    Notes
    [80] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 8
    Statistical analysis description
    Cycle 5 Day 1 (Actual number of participants included in the analysis = 448): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [81]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.49
         upper limit
    0.81
    Notes
    [81] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 9
    Statistical analysis description
    Cycle 5 Day 22 (Actual number of participants included in the analysis = 434): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [82]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.66
         upper limit
    0.99
    Notes
    [82] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 10
    Statistical analysis description
    Cycle 6 Day 1 (Actual number of participants included in the analysis = 421): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [83]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.46
         upper limit
    0.8
    Notes
    [83] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 11
    Statistical analysis description
    Cycle 6 Day 22 (Actual number of participants included in the analysis = 390): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [84]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.54
         upper limit
    0.89
    Notes
    [84] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 12
    Statistical analysis description
    Cycle 7 Day 1 (Actual number of participants included in the analysis = 373): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [85]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.47
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.3
         upper limit
    0.65
    Notes
    [85] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 13
    Statistical analysis description
    Cycle 7 Day 22 (Actual number of participants included in the analysis = 354): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [86]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.49
         upper limit
    0.86
    Notes
    [86] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 14
    Statistical analysis description
    Cycle 8 Day 1 (Actual number of participants included in the analysis = 352): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [87]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.47
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.29
         upper limit
    0.66
    Notes
    [87] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 16
    Statistical analysis description
    Cycle 9 Day 1 (Actual number of participants included in the analysis = 331): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [88]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.49
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.29
         upper limit
    0.68
    Notes
    [88] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 15
    Statistical analysis description
    Cycle 8 Day 22 (Actual number of participants included in the analysis = 336): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [89]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.41
         upper limit
    0.79
    Notes
    [89] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 17
    Statistical analysis description
    Cycle 9 Day 22 (Actual number of participants included in the analysis = 307): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [90]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.71
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.52
         upper limit
    0.91
    Notes
    [90] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 19
    Statistical analysis description
    Cycle 10 Day 22 (Actual number of participants included in the analysis = 227): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [91]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.51
         upper limit
    0.96
    Notes
    [91] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 18
    Statistical analysis description
    Cycle 10 Day 1 (Actual number of participants included in the analysis = 300): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [92]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.53
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.33
         upper limit
    0.73
    Notes
    [92] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 20
    Statistical analysis description
    Cycle 11 Day 1 (Actual number of participants included in the analysis = 234): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [93]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.41
         upper limit
    0.86
    Notes
    [93] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 21
    Statistical analysis description
    Cycle 11 Day 22 (Actual number of participants included in the analysis = 181): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [94]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.49
         upper limit
    0.99
    Notes
    [94] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 22
    Statistical analysis description
    Cycle 12 Day 1 (Actual number of participants included in the analysis = 183): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [95]
    P-value
    = 0.001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.17
         upper limit
    0.68
    Notes
    [95] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 23
    Statistical analysis description
    Cycle 12 Day 22 (Actual number of participants included in the analysis = 140): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [96]
    P-value
    < 0.0001
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.32
         upper limit
    0.89
    Notes
    [96] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 24
    Statistical analysis description
    Cycle 13 Day 1 (Actual number of participants included in the analysis = 133): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [97]
    P-value
    = 0.0005
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.52
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.23
         upper limit
    0.82
    Notes
    [97] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 25
    Statistical analysis description
    Cycle 13 Day 22 (Actual number of participants included in the analysis = 108): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [98]
    P-value
    = 0.0008
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.23
         upper limit
    0.88
    Notes
    [98] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 27
    Statistical analysis description
    Cycle 14 Day 22 (Actual number of participants included in the analysis = 81): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [99]
    P-value
    = 0.0005
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.29
         upper limit
    1.05
    Notes
    [99] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 26
    Statistical analysis description
    Cycle 14 Day 1 (Actual number of participants included in the analysis = 96): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [100]
    P-value
    = 0.0591
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.01
         upper limit
    0.67
    Notes
    [100] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 28
    Statistical analysis description
    Cycle 15 Day 1 (Actual number of participants included in the analysis = 74): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [101]
    P-value
    = 0.1378
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.09
         upper limit
    0.68
    Notes
    [101] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 29
    Statistical analysis description
    Cycle 15 Day 22 (Actual number of participants included in the analysis = 53): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [102]
    P-value
    = 0.065
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.03
         upper limit
    0.89
    Notes
    [102] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 30
    Statistical analysis description
    Cycle 16 Day 1 (Actual number of participants included in the analysis = 47): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [103]
    P-value
    = 0.0531
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.48
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.01
         upper limit
    0.96
    Notes
    [103] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 31
    Statistical analysis description
    Cycle 16 Day 22 (Actual number of participants included in the analysis = 35): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [104]
    P-value
    = 0.0011
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.37
         upper limit
    1.49
    Notes
    [104] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 33
    Statistical analysis description
    Cycle 17 Day 22 (Actual number of participants included in the analysis = 20): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [105]
    P-value
    = 0.1078
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.13
         upper limit
    1.29
    Notes
    [105] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 32
    Statistical analysis description
    Cycle 17 Day 1 (Actual number of participants included in the analysis = 32): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [106]
    P-value
    = 0.0708
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.05
         upper limit
    1.14
    Notes
    [106] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 34
    Statistical analysis description
    Cycle 18 Day 1 (Actual number of participants included in the analysis = 15): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [107]
    P-value
    = 0.1487
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.22
         upper limit
    1.47
    Notes
    [107] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 35
    Statistical analysis description
    Cycle 18 Day 22 (Actual number of participants included in the analysis = 9): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [108]
    P-value
    = 0.5537
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.77
         upper limit
    1.43
    Notes
    [108] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    Statistical Analysis 36
    Statistical analysis description
    Cycle 19 Day 1 (Actual number of participants included in the analysis = 6): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    superiority [109]
    P-value
    = 0.5743
    Method
    Repeated measures model
    Parameter type
    LS Mean Difference
    Point estimate
    0.52
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.29
         upper limit
    2.33
    Notes
    [109] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.

    Secondary: Number of Participants with Anti-Therapeutic Antibodies (ATAs) Against Atezolizumab

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    End point title
    Number of Participants with Anti-Therapeutic Antibodies (ATAs) Against Atezolizumab [110]
    End point description
    The number of participants with "Treatment-induced ATAs" and "Treatment-enhanced ATA" against atezolizumab at any time during or after treatment was reported. Treatment-induced ATA = a participant with negative or missing Baseline ATA result(s) and at least one positive post-Baseline ATA result. Treatment-enhanced ATA = a participant with positive ATA result at Baseline who has one or more post Baseline titer results that are at least 0.60 titer unit greater than the Baseline titer result. Analysis was performed on the ATA-Evaluable Population, which included all participants in the Atezolizumab + Bevacizumab arm with a non-missing baseline ATA sample and >/=1 post-baseline ATA sample. Here, ‘Number of Subject Analysed’ = number of participants with a non-missing baseline ATA sample; 'n’= number of participants with a non-missing ATA sample at indicated timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Predose [Hour 0] at Day 1 Cycle 1); Post-Baseline (Predose at Cycles 2, 4, and 8, and every eight cycles thereafter up to EoT [up to approximately 27 months] and 120 days after EoT [up to approximately 27 months]) (Cycle length=42 days)
    Notes
    [110] - 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: Reported analysis was planned to be carried out in the indicated arm only.
    End point values
    Atezolizumab + Bevacizumab
    Number of subjects analysed
    446
    Units: participants
    number (not applicable)
        Baseline: ATA Positive Participants (n=446)
    16
        Post-Baseline: Treatment-Induced ATA (n=433)
    95
        Post-Baseline: Treatment-Enhanced ATA (n=433)
    1
    No statistical analyses for this end point

    Secondary: Number of Participants with ATAs Against Bevacizumab

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    End point title
    Number of Participants with ATAs Against Bevacizumab [111]
    End point description
    The number of participants with "Treatment-induced ATAs" and "Treatment-enhanced ATA" against bevacizumab at any time during or after treatment was reported. Treatment-induced ATA = a participant with negative or missing Baseline ATA result(s) and at least one positive post-Baseline ATA result. Treatment-enhanced ATA = a participant with positive ATA result at Baseline who has one or more post Baseline titer results that are at least 0.60 titer unit greater than the Baseline titer result. Analysis was performed on the ATA-Evaluable Population. Here, ‘Number of Subject Analysed’ = number of participants with a non-missing baseline ATA sample; 'n’= number of participants with a non-missing ATA sample at indicated timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Predose [Hour 0] at Day 1 Cycle 1); Post-Baseline (Predose at Cycle 3, at EoT [up to approximately 27 months] and at 120 days after EoT [up to approximately 27 months]) (Cycle length=42 days)
    Notes
    [111] - 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: Reported analysis was planned to be carried out in the indicated arm only.
    End point values
    Atezolizumab + Bevacizumab
    Number of subjects analysed
    444
    Units: participants
    number (not applicable)
        Baseline: ATA Positive Participants (n=444)
    24
        Post-Baseline: Treatment-Induced ATA (n=433)
    4
        Post-Baseline: Treatment-Enhanced ATA (n=433)
    0
    No statistical analyses for this end point

    Secondary: Maximum Observed Serum Concentration (Cmax) for Atezolizumab

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    End point title
    Maximum Observed Serum Concentration (Cmax) for Atezolizumab [112]
    End point description
    Cmax for atezolizumab was estimated from plasma concentration versus time data. Analysis was performed on the Atezolizumab Pharmacokinetic (PK) Population, which included all participants who received atezolizumab treatment and had evaluable PK samples. Here, 'Number of Subject Analysed’ = number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    30 minutes after the end of bevacizumab infusion (atezolizumab infusion duration: 30-60 min; bevacizumab infusion duration: 30-90 minutes) on Day 1 of Cycle 1 (Cycle length = 42 days)
    Notes
    [112] - 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: Reported analysis was planned to be carried out in the indicated arm only.
    End point values
    Atezolizumab + Bevacizumab
    Number of subjects analysed
    435
    Units: micrograms per milliliter (mcg/mL)
        arithmetic mean (standard deviation)
    376 ± 90.2
    No statistical analyses for this end point

    Secondary: Minimum Observed Serum Concentration (Cmin) for Atezolizumab

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    End point title
    Minimum Observed Serum Concentration (Cmin) for Atezolizumab [113]
    End point description
    Cmin for atezolizumab was estimated from plasma concentration versus time data. Analysis was performed on the Atezolizumab PK Population. Here, 'Number of Subject Analysed’ = number of participants evaluable for this outcome measure; ‘n’ = number of participants evaluable at specified time point.
    End point type
    Secondary
    End point timeframe
    Predose (Hour 0) on Day 22 of Cycle 1; predose (Hour 0) on Day 1 of Cycles 2; Cycle length = 42 days
    Notes
    [113] - 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: Reported analysis was planned to be carried out in the indicated arm only.
    End point values
    Atezolizumab + Bevacizumab
    Number of subjects analysed
    426
    Units: mcg/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 22 (n=426)
    85.6 ± 35.3
        Cycle 2 Day 1 (n=407)
    127 ± 49.6
    No statistical analyses for this end point

    Secondary: Cmax for Bevacizumab

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    End point title
    Cmax for Bevacizumab [114]
    End point description
    Cmax for bevacizumab was estimated from plasma concentration versus time data. Analysis was performed on the Bevacizumab PK Population, which included all participants who received bevacizumab treatment and had evaluable PK samples. Here, 'Number of Subject Analysed’ = number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    30 minutes after the end of bevacizumab infusion (atezolizumab infusion duration: 30-60 min; bevacizumab infusion duration: 30-90 minutes) on Day 1 of Cycle 1 (Cycle length = 42 days)
    Notes
    [114] - 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: Reported analysis was planned to be carried out in the indicated arm only.
    End point values
    Atezolizumab + Bevacizumab
    Number of subjects analysed
    427
    Units: mcg/mL
        arithmetic mean (standard deviation)
    339 ± 104
    No statistical analyses for this end point

    Secondary: Cmin for Bevacizumab

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    End point title
    Cmin for Bevacizumab [115]
    End point description
    Cmin for bevacizumab was estimated from plasma concentration versus time data. Analysis was performed on the Bevacizumab PK Population. Here, 'Number of Subject Analysed’ = number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Pre-dose (Hour 0) on Day 1 of Cycle 3 (Cycle length = 42 days)
    Notes
    [115] - 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: Reported analysis was planned to be carried out in the indicated arm only.
    End point values
    Atezolizumab + Bevacizumab
    Number of subjects analysed
    363
    Units: mcg/mL
        arithmetic mean (standard deviation)
    135 ± 56.1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to data cut-off date 29 September 2017 (overall approximately 27 months)
    Adverse event reporting additional description
    Analysis was performed on the safety-evaluable (SE) population, which included all randomized participants who received any amount of any component of the study treatments.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Sunitinib
    Reporting group description
    Participants received sunitinib at a dose of 50 mg administered orally via capsules once daily on Days 1 to 28 of each 42-day cycle until loss of clinical benefit in the opinion of the investigator, unacceptable toxicity or symptomatic deterioration attributed to PD as determined by the investigator, withdrawal of consent, or death, whichever occurred first.

    Reporting group title
    Atezolizumab + Bevacizumab
    Reporting group description
    Participants received atezolizumab at a dose of 1200 mg and bevacizumab at a dose of 15 mg/kg administered via IV infusions on Day 1 and Day 22 of each 42-day cycle until loss of clinical benefit in the opinion of the investigator, unacceptable toxicity or symptomatic deterioration attributed to PD as determined by the investigator, withdrawal of consent, or death, whichever occurred first.

    Serious adverse events
    Sunitinib Atezolizumab + Bevacizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    149 / 446 (33.41%)
    174 / 451 (38.58%)
         number of deaths (all causes)
    135
    122
         number of deaths resulting from adverse events
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 446 (0.00%)
    2 / 451 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 446 (0.22%)
    2 / 451 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 446 (0.22%)
    2 / 451 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic disorder
         subjects affected / exposed
    1 / 446 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic dissection
         subjects affected / exposed
    1 / 446 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 446 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery aneurysm
         subjects affected / exposed
    1 / 446 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    1 / 446 (0.22%)
    0 / 451 (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
    Fracture treatment
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernia repair
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth extraction
         subjects affected / exposed
    1 / 446 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour haemorrhage
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon neoplasm
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangiocarcinoma
         subjects affected / exposed
    1 / 446 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer stage III
         subjects affected / exposed
    1 / 446 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial tumour haemorrhage
         subjects affected / exposed
    1 / 446 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Immune system disorders
    Systemic immune activation
         subjects affected / exposed
    0 / 446 (0.00%)
    3 / 451 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytokine release syndrome
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    1 / 446 (0.22%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    7 / 446 (1.57%)
    12 / 451 (2.66%)
         occurrences causally related to treatment / all
    1 / 8
    10 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    3 / 446 (0.67%)
    3 / 451 (0.67%)
         occurrences causally related to treatment / all
    3 / 4
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 446 (0.22%)
    3 / 451 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 446 (0.00%)
    3 / 451 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 446 (0.00%)
    2 / 451 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 446 (0.45%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    4 / 446 (0.90%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ill-defined disorder
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Malaise
         subjects affected / exposed
    1 / 446 (0.22%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion site extravasation
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 446 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 446 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 446 (0.00%)
    2 / 451 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    1 / 446 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 446 (0.22%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Conjunctival laceration
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    2 / 446 (0.45%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal anastomotic leak
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound complication
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 446 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 446 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seroma
         subjects affected / exposed
    1 / 446 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth injury
         subjects affected / exposed
    1 / 446 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 446 (0.22%)
    2 / 451 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    1 / 446 (0.22%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood sodium decreased
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 446 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 446 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    1 / 446 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 446 (0.00%)
    3 / 451 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    0 / 446 (0.00%)
    3 / 451 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute coronary syndrome
         subjects affected / exposed
    1 / 446 (0.22%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 446 (0.22%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 446 (0.22%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Myocarditis
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 446 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 446 (0.67%)
    3 / 451 (0.67%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    4 / 446 (0.90%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 446 (0.45%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Factor VIII inhibition
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    0 / 446 (0.00%)
    7 / 451 (1.55%)
         occurrences causally related to treatment / all
    0 / 0
    7 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    5 / 446 (1.12%)
    4 / 451 (0.89%)
         occurrences causally related to treatment / all
    0 / 6
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    5 / 446 (1.12%)
    4 / 451 (0.89%)
         occurrences causally related to treatment / all
    1 / 5
    3 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 446 (0.22%)
    3 / 451 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 446 (0.00%)
    2 / 451 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Interstitial lung disease
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 446 (0.22%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleurisy
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary infarction
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary pain
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 446 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 446 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal oedema
         subjects affected / exposed
    1 / 446 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 446 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 446 (0.00%)
    2 / 451 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Ischaemic stroke
         subjects affected / exposed
    0 / 446 (0.00%)
    2 / 451 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 446 (0.45%)
    2 / 451 (0.44%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Altered state of consciousness
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 446 (0.22%)
    2 / 451 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Depressed level of consciousness
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gliosis
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 446 (0.22%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbosacral plexopathy
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 446 (0.22%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    2 / 446 (0.45%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 446 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 446 (0.45%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    1 / 446 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    1 / 446 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thalamus haemorrhage
         subjects affected / exposed
    1 / 446 (0.22%)
    0 / 451 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 446 (0.00%)
    1 / 451 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 446 (0.45%)
    7 / 451 (1.55%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 446 (0.45%)
    4 / 451 (0.89%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 446 (0.22%)
    4 / 451 (0.89%)
         occurrences causally related to treatment / all
    1 / 1
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 446 (0.22%)
    2 / 451 (0.44%)
         occurrences causally related to treatment / all