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    Clinical Trial Results:
    A Phase III, Multicenter, Randomized, Open-Label, Controlled Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Atezolizumab Given in Combination With Cabozantinib Versus Docetaxel Monotherapy in Patients With Metastatic Non-Small Lung Cancer Previously Treated With an Anti-PD-L1/PD-1 Antibody and Platinum-Containing Chemotherapy

    Summary
    EudraCT number
    		 2020-000100-11
    Trial protocol
    		 DE   PT   BE   GB   GR   PL   FR   IT  
    Global end of trial date

    Results information
    Results version number
    		 v2(current)
    This version publication date
    13 Apr 2024
    First version publication date
    14 Oct 2023
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GO41892
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04471428
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland,
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, + 41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, + 41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    28 Sep 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Sep 2022
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study is to evaluate the efficacy, safety, and pharmacokinetics of atezolizumab when given in combination with cabozantinib (Atezo + Cabo) compared with docetaxel monotherapy in subjects with metastatic non-small cell lung cancer (NSCLC), with no sensitizing endothelial growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) translocation, who have progressed on prior treatment with both anti-PD-L1/PD-1 antibody and platinum-containing chemotherapy.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Oct 2020
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 8
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Germany: 23
    Country: Number of subjects enrolled
    Spain: 35
    Country: Number of subjects enrolled
    France: 27
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    Greece: 31
    Country: Number of subjects enrolled
    Italy: 45
    Country: Number of subjects enrolled
    Japan: 23
    Country: Number of subjects enrolled
    Korea, Republic of: 61
    Country: Number of subjects enrolled
    Poland: 18
    Country: Number of subjects enrolled
    Portugal: 16
    Country: Number of subjects enrolled
    Russian Federation: 24
    Country: Number of subjects enrolled
    United States: 29
    Worldwide total number of subjects
    366
    EEA total number of subjects
    210
    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)
    178
    From 65 to 84 years
    187
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants are enrolled in the study at study centers in 15 countries. The study is ongoing.

    Pre-assignment
    Screening details
    		 Of the 366 participants, 180 participants were randomized to receive Docetaxel monotherapy whereas 186 participants were randomized to receive Atezolizumab and Cabozantinib combination therapy.

    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
    		 Docetaxel
    Arm description
    		 Participants received docetaxel intravenously at a starting dose of 75mg/m^2 on Day 1 of each 21-day cycle.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    RO0647746
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel was administered on Day 1 of each 21-day cycle.

    Arm title
    		 Atezolizumab + Cabozantinib
    Arm description
    		 Participants received atezolizumab intravenously at a fixed dose of 1200 mg on Day 1 of each 21-day cycle. Cabozantinib was administered orally, once daily at a dose of 40 mg in each 21-day cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cabozantinib
    Investigational medicinal product code
    RO7047650
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cabozantinib was administered orally, once daily at a dose of 40 mg in each 21-day cycle.

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    RO5541267
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 1200 mg atezolizumab on Day 1 of each 21-day cycle

    Number of subjects in period 1
    		Docetaxel Atezolizumab + Cabozantinib
    Started
    180
    186
    Completed
    0
    0
    Not completed
    180
    186
         Physician decision
    -
    1
         Death
    106
    114
         Reason Not Specified
    -
    2
         Withdrawal by Subject
    29
    1
         Ongoing in the study
    45
    68

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Docetaxel
    Reporting group description
    		 Participants received docetaxel intravenously at a starting dose of 75mg/m^2 on Day 1 of each 21-day cycle.

    Reporting group title
    Atezolizumab + Cabozantinib
    Reporting group description
    		 Participants received atezolizumab intravenously at a fixed dose of 1200 mg on Day 1 of each 21-day cycle. Cabozantinib was administered orally, once daily at a dose of 40 mg in each 21-day cycle.

    Reporting group values
    		 Docetaxel Atezolizumab + Cabozantinib Total
    Number of subjects
    		 180 186 366
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 83 95 178
        From 65-84 years
    		 96 91 187
        85 years and over
    		 1 0 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.4 ( 9.4 ) 63.8 ( 9.5 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 53 52 105
        Male
    		 127 134 261
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 53 41 94
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 1 2 3
        White
    		 111 130 241
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 15 13 28
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 7 4 11
        Not Hispanic or Latino
    		 158 164 322
        Not Stated
    		 12 15 27
        Unknown
    		 3 3 6

    End points

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    End points reporting groups
    Reporting group title
    Docetaxel
    Reporting group description
    		 Participants received docetaxel intravenously at a starting dose of 75mg/m^2 on Day 1 of each 21-day cycle.

    Reporting group title
    Atezolizumab + Cabozantinib
    Reporting group description
    		 Participants received atezolizumab intravenously at a fixed dose of 1200 mg on Day 1 of each 21-day cycle. Cabozantinib was administered orally, once daily at a dose of 40 mg in each 21-day cycle.

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as time from randomization to death from any cause. Participants alive at time of analysis were censored at date when they were last known to be alive as documented by investigator. Kaplan-Meier method was used to estimate median. 95% CI for median was computed using method of Brookmeyer and Crowley. Intent-to-treat (ITT) population included all randomised participants, whether or not the participant received the assigned treatment.
    End point type
    Primary
    End point timeframe
    Up to approximately 24 months
    End point values
    		 Docetaxel Atezolizumab + Cabozantinib
    Number of subjects analysed
    180
    186
    Units: months
        median (confidence interval 95%)
    10.5 (8.6 to 13.0)
    10.7 (8.8 to 12.3)
    Statistical analysis title
    		 Docetaxel, Atezolizumab + Cabozantinib
    Statistical analysis description
    Unstratified Analysis
    Comparison groups
    Docetaxel v Atezolizumab + Cabozantinib
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4709
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.907
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.696
         upper limit
    		 1.182
    Statistical analysis title
    		 Docetaxel, Atezolizumab + Cabozantinib
    Statistical analysis description
    Stratified Analysis
    Comparison groups
    Docetaxel v Atezolizumab + Cabozantinib
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.3668
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.884
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.676
         upper limit
    		 1.156
    Notes
    [1] - Stratification factors include histology, and prior NSCLC treatment regimens

    Secondary: Progression-Free Survival (PFS) as Determined by Investigator

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    End point title
    		 Progression-Free Survival (PFS) as Determined by Investigator
    End point description
    PFS was defined as time from randomisation to first occurrence of disease progression, as determined by investigator according to RECIST v1.1, or death from any cause (whichever occurred first). Progressive disease(PD) was defined as at least 20% increase in sum of longest diameters(D) of target lesions, taking as reference smallest sum of longest D of target lesions recorded since treatment started, including screening, or appearance of 1 or more new lesions. Participants who were alive & did not experience disease progression at time of analysis, were censored on date of last tumor assessment. Participants with no post-baseline tumor assessment were censored at date of randomisation.ITT population included all randomised participants, whether or not participant received the assigned treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 24 months
    End point values
    		 Docetaxel Atezolizumab + Cabozantinib
    Number of subjects analysed
    180
    186
    Units: months
        median (confidence interval 95%)
    4.0 (3.1 to 4.4)
    4.6 (4.1 to 5.6)
    Statistical analysis title
    		 Docetaxel, Atezolizumab + Cabozantinib
    Statistical analysis description
    Stratified Analysis
    Comparison groups
    Docetaxel v Atezolizumab + Cabozantinib
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.0079
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.735
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.585
         upper limit
    		 0.923
    Notes
    [2] - Stratification factors include histology, and prior NSCLC treatment regimens
    Statistical analysis title
    		 Docetaxel, Atezolizumab + Cabozantinib
    Statistical analysis description
    Unstratified Analysis
    Comparison groups
    Docetaxel v Atezolizumab + Cabozantinib
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0061
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.731
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.583
         upper limit
    		 0.915

    Secondary: Confirmed Objective Response Rate (ORR) as Determined by Investigator

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    End point title
    		 Confirmed Objective Response Rate (ORR) as Determined by Investigator
    End point description
    Confirmed ORR was defined as the percentage of participants with a complete response (CR) or partial response (PR) on two consecutive occasions >=4 weeks apart, as determined by the investigator according to RECIST v1.1. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters. The ITT population included all randomised participants, whether or not the participant received the assigned treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 24 months
    End point values
    		 Docetaxel Atezolizumab + Cabozantinib
    Number of subjects analysed
    180
    186
    Units: percentage of participants
        number (confidence interval 95%)
    13.3 (8.73 to 19.19)
    11.8 (7.56 to 17.36)
    Statistical analysis title
    		 Docetaxel, Atezolizumab + Cabozantinib
    Statistical analysis description
    Stratified analysis
    Comparison groups
    Docetaxel v Atezolizumab + Cabozantinib
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.6846
    Method
    		 Chi-square with Schouten Correction
    Parameter type
    		 Difference in Response Rates
    Point estimate
    -1.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.85
         upper limit
    		 5.84
    Notes
    [3] - Stratification factors: histology, prior NSCLC treatment regimens
    Statistical analysis title
    		 Docetaxel, Atezolizumab + Cabozantinib
    Statistical analysis description
    Unstratified Analysis
    Comparison groups
    Docetaxel v Atezolizumab + Cabozantinib
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 1.62
    Statistical analysis title
    		 Docetaxel, Atezolizumab + Cabozantinib
    Statistical analysis description
    Unstratified Analysis
    Comparison groups
    Docetaxel v Atezolizumab + Cabozantinib
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7216
    Method
    		 Chi-squared corrected
    Parameter type
    		 Difference in Response Rates
    Point estimate
    -1.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.85
         upper limit
    		 5.84
    Statistical analysis title
    		 Docetaxel, Atezolizumab + Cabozantinib
    Statistical analysis description
    Stratified analysis
    Comparison groups
    Docetaxel v Atezolizumab + Cabozantinib
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 1.63
    Notes
    [4] - Stratification factors: histology, prior NSCLC treatment regimens

    Secondary: Duration of response (DOR) as Determined by Investigator

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    End point title
    		 Duration of response (DOR) as Determined by Investigator
    End point description
    DOR for participants with confirmed ORR was defined as time from first occurrence of a documented objective response to disease progression (PD), as determined by investigator according to RECIST v1.1, or death from any cause (whichever occurred first). PD was defined as at least 20% increase in sum of longest diameters of target lesions, taking as reference smallest sum of longest diameters of target lesions recorded since treatment started, including screening, or appearance of one or more new lesions. Participants who had not progressed and who did not die at time of analysis were censored at the time of last tumor assessment date. Kaplan-Meier method was used to estimate median. 95% CI for median was computed using the method of Brookmeyer and Crowley (B&C). Participants in the ITT population who had a confirmed objective response (CR or PR) as determined by the investigator per RECIST v1.1 were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Up to approximately 24 months
    End point values
    		 Docetaxel Atezolizumab + Cabozantinib
    Number of subjects analysed
    24
    22
    Units: months
        median (confidence interval 95%)
    4.30 (3.29 to 5.62)
    5.55 (3.12 to 10.25)
    No statistical analyses for this end point

    Secondary: Time to Confirmed Deterioration (TTCD) in Patient-Reported Physical Functioning (PF)

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    End point title
    		 Time to Confirmed Deterioration (TTCD) in Patient-Reported Physical Functioning (PF)
    End point description
    TTCD for PF is time from date of randomization to 1st confirmed clinically meaningful decrease from baseline in PF score held for at least 2 assessments/initial clinically meaningful decrease from baseline followed by death from any cause within 21 days/until next tumor assessment, whichever occurs 1st. Score change >=of 10-point on European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 Questionnaire (EORTC QLQ-C30) PF scale=clinically meaningful. Scores were averaged, transformed to 0-100 scale; where higher score=high/healthy level of functioning. Kaplan-Meier method was used to estimate median. 95% CI for median was computed using B&C method. ITT population was used. Participants without confirmed deterioration at time of analysis were censored at last time they were known to have not deteriorated. 9999=Upper limit (UL) of 95% CI was not estimable as there were not enough events after median estimate to satisfy constraints required to calculate the UL.
    End point type
    Secondary
    End point timeframe
    Up to approximately 24 months
    End point values
    		 Docetaxel Atezolizumab + Cabozantinib
    Number of subjects analysed
    180
    186
    Units: months
        median (confidence interval 95%)
    5.6 (4.0 to 9999)
    7.7 (4.8 to 14.7)
    Statistical analysis title
    		 Docetaxel, Atezolizumab + Cabozantinib
    Statistical analysis description
    Unstratified Analysis
    Comparison groups
    Docetaxel v Atezolizumab + Cabozantinib
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3031
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.17
    Statistical analysis title
    		 Docetaxel, Atezolizumab + Cabozantinib
    Statistical analysis description
    Stratified Analysis
    Comparison groups
    Docetaxel v Atezolizumab + Cabozantinib
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.27
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 1.16
    Notes
    [5] - Stratification factors include histology, and prior NSCLC treatment regimens

    Secondary: TTCD in Patient-Reported Global Health Status (GHS)

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    End point title
    		 TTCD in Patient-Reported Global Health Status (GHS)
    End point description
    TTCD analyses was performed for GHS/quality of life (QoL) items of EORTC QLQ-C30 on a 7-point scale with range = very poor to excellent. TTCD is time from date of randomization to 1st confirmed clinically meaningful decrease from baseline in GHS/QoL score held for at least 2 consecutive assessments/initial clinically meaningful decrease from baseline followed by death from any cause within 21 days/ until next tumor assessment, whichever occurs 1st. Change of >=10-point on GHS/QoL subs scale=clinically meaningful. Scores were transformed to 0-100 scale; high score =better health-related QoL. Kaplan-Meier method was used to estimate median. Participants without confirmed deterioration at time of analysis were censored at last time they were known to have not deteriorated. ITT population was used. Only responders were analysed in this endpoint. 9999=UL of 95% CI was not estimable as there were not enough events after median estimate to satisfy constraints required to calculate the UL.
    End point type
    Secondary
    End point timeframe
    Up to approximately 24 months
    End point values
    		 Docetaxel Atezolizumab + Cabozantinib
    Number of subjects analysed
    180
    186
    Units: months
        median (confidence interval 95%)
    14.1 (6.3 to 9999)
    8.1 (5.6 to 14.5)
    Statistical analysis title
    		 Docetaxel, Atezolizumab + Cabozantinib
    Statistical analysis description
    Unstratified Analysis
    Comparison groups
    Docetaxel v Atezolizumab + Cabozantinib
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1992
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.81
    Statistical analysis title
    		 Docetaxel, Atezolizumab + Cabozantinib
    Statistical analysis description
    Stratified Analysis
    Comparison groups
    Docetaxel v Atezolizumab + Cabozantinib
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.2408
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.79
    Notes
    [6] - Stratification factors include histology, and prior NSCLC treatment regimens

    Secondary: PFS Rates Assessed by Investigator

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    End point title
    		 PFS Rates Assessed by Investigator
    End point description
    PFS rates were defined as the percentage of participants alive and without progression as assessed by the investigator according to RECIST v1.1. PD was defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum of the longest diameters of the target lesions recorded since the treatment started, including screening, or the appearance of one or more new lesions. Participants with no post-baseline tumor assessment were censored at the date of randomization. ITT population is defined as all randomised participants, whether or not the participant received the assigned treatment. The overall number analyzed are the participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    6 months and 1 year
    End point values
    		 Docetaxel Atezolizumab + Cabozantinib
    Number of subjects analysed
    180
    186
    Units: percentage of participants
    number (confidence interval 95%)
        At 6 months
    23.66 (16.98 to 30.33)
    39.51 (32.42 to 46.59)
        At 1 year
    8.38 (3.95 to 12.80)
    14.70 (9.43 to 19.97)
    Statistical analysis title
    		 Docetaxel, Atezolizumab + Cabozantinib
    Statistical analysis description
    At 6 months
    Comparison groups
    Docetaxel v Atezolizumab + Cabozantinib
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0014
    Method
    		 z-test
    Parameter type
    		 Difference in Event Free Rate
    Point estimate
    15.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.12
         upper limit
    		 25.59
    Statistical analysis title
    		 Docetaxel, Atezolizumab + Cabozantinib
    Statistical analysis description
    At 1 year
    Comparison groups
    Docetaxel v Atezolizumab + Cabozantinib
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0719
    Method
    		 z-test
    Parameter type
    		 Difference in Event Free Rate
    Point estimate
    6.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.56
         upper limit
    		 13.21

    Secondary: OS Rates

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    End point title
    		 OS Rates
    End point description
    Overall Survival (OS) rate is defined as the percentage of participants who were alive at 1 year and 2 years. Participants alive at the time of the analysis were censored at the date when they were last known to be alive as documented by the investigator. The ITT population is defined as all randomized participants, whether or not the participant received the assigned treatment. Here 99999 indicates that at the time of the analysis, there were no participants with 24 months or more of survival follow-up, therefore, survival rate at the 2-year timepoint was not estimable.
    End point type
    Secondary
    End point timeframe
    At 1 and 2 years
    End point values
    		 Docetaxel Atezolizumab + Cabozantinib
    Number of subjects analysed
    180
    186
    Units: percentage of participants
    number (confidence interval 95%)
        At 1 year
    44.12 (36.20 to 52.05)
    43.27 (35.97 to 50.57)
        At 2 years
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 Docetaxel, Atezolizumab + Cabozantinib
    Statistical analysis description
    At 1 year
    Comparison groups
    Docetaxel v Atezolizumab + Cabozantinib
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8767
    Method
    		 z-test
    Parameter type
    		 Difference in Event Free Rate
    Point estimate
    -0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.63
         upper limit
    		 9.92

    Secondary: Percentage of Participants With Adverse Events

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    End point title
    		 Percentage of Participants With Adverse Events
    End point description
    An adverse event is any untoward medical occurrence in a clinical investigation patient administered a pharmaceutical product, regardless of causal attribution. AEs were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE, v5.0). Safety population included treated participants, defined as all randomised participants who received any amount of study drug.
    End point type
    Secondary
    End point timeframe
    From signing the informed consent form up to the study completion date: 28 February 2024 (i.e., approximately 41 months)
    End point values
    		 Docetaxel Atezolizumab + Cabozantinib
    Number of subjects analysed
    0 [7]
    0 [8]
    Units: percentage of participants
        number (not applicable)
    Notes
    [7] - Data collection for this endpoint is ongoing and will be reported within 1 year of study completion.
    [8] - Data collection for this endpoint is ongoing and will be reported within 1 year of study completion.
    No statistical analyses for this end point

    Secondary: Minimum Serum Concentration (Cmin) of Atezolizumab

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    End point title
    		 Minimum Serum Concentration (Cmin) of Atezolizumab [9]
    End point description
    The pharmacokinetic (PK)-evaluable population included all participants who received any dose of atezolizumab or cabozantinib and who had evaluable PK samples. Overall number analyzed is the number of participants with data available for analysis. Number analysed is the number of participants with data available for analysis at the specified timepoints. 9999= the data was not evaluable as all samples were Below Limit of Quantitation (BLQ)
    End point type
    Secondary
    End point timeframe
    Predose on Day 1 of Cycles 1, 2, 3, 4, 8, 12 and 16 (each cycle is 21 days)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics was analyzed for Atezolizumab for this endpoint.
    End point values
    		 Atezolizumab + Cabozantinib
    Number of subjects analysed
    185
    Units: microgram/milliliter (μg/ml)
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1 (n=146)
    9999 ( 9999 )
        Cycle 2 Day 1 (n=162)
    96.8 ( 48.1 )
        Cycle 3 Day 1 (n=140)
    124 ( 104.4 )
        Cycle 4 Day 1 (n=130)
    167 ( 47.7 )
        Cycle 8 Day 1 (n=70)
    194 ( 62.4 )
        Cycle 12 Day 1 (n=52)
    233 ( 44.7 )
        Cycle 16 Day 1 (n=40)
    209 ( 56.1 )
    No statistical analyses for this end point

    Secondary: Maximum Serum Concentration (Cmax) of Atezolizumab

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    End point title
    		 Maximum Serum Concentration (Cmax) of Atezolizumab [10]
    End point description
    The PK-evaluable population included all participants who received any dose of atezolizumab or cabozantinib and who had evaluable PK samples. Overall number analyzed is the number of participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    30 min Post-dose on Day 1 of Cycle 1 (each cycle is 21 days)
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics was analyzed for Atezolizumab for this endpoint.
    End point values
    		 Atezolizumab + Cabozantinib
    Number of subjects analysed
    185
    Units: μg/ml
        geometric mean (geometric coefficient of variation)
    450 ( 34.0 )
    No statistical analyses for this end point

    Secondary: Minimum Plasma Concentration (Cmin) of Cabozantinib

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    End point title
    		 Minimum Plasma Concentration (Cmin) of Cabozantinib [11]
    End point description
    The PK-evaluable population included all participants who received any dose of atezolizumab or cabozantinib and who had evaluable PK samples. Overall number analyzed is the number of participants with data available for analysis. Number analysed is the number of participants with data available for analysis at the specified timepoints. 9999= the data was not evaluable as all samples were BLQ.
    End point type
    Secondary
    End point timeframe
    Predose on Day 1 of Cycles 1, 2, 3, 4, and 5 (each cycle is 21 days)
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics was analyzed for Cabozantinib only for this endpoint.
    End point values
    		 Atezolizumab + Cabozantinib
    Number of subjects analysed
    185
    Units: μg/ml
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1 (n=173)
    9999 ( 9999 )
        Cycle 2 Day 1 (n=163)
    0.746 ( 111.7 )
        Cycle 3 Day 1 (n=138)
    0.418 ( 640.7 )
        Cycle 4 Day 1 (n=131)
    0.469 ( 234.4 )
        Cycle 5 Day 1 (n=110)
    0.303 ( 402.3 )
    No statistical analyses for this end point

    Secondary: Maximum Plasma Concentration (Cmax) of Cabozantinib

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    End point title
    		 Maximum Plasma Concentration (Cmax) of Cabozantinib [12]
    End point description
    Cmax was not collected for this outcome measure because PK of cabozantinib was well characterized through the cabozantinib development for mono- therapy. An established population PK model for cabozantinib is available for the PK data from NCT04471428 (study GO41892). The PK data collected in the current study is sufficient for the population PK model to characterize the exposure of cabozantinib in this study.
    End point type
    Secondary
    End point timeframe
    Predose on Day 1 of Cycles 1, 2, 3, 4, and 5 (each cycle is 21 days)
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Cabozantinib's PK was well studied through development of it's monotherapy, no need to measure Cmax.
    End point values
    		 Atezolizumab + Cabozantinib
    Number of subjects analysed
    0 [13]
    Units: μg/ml
        geometric mean (geometric coefficient of variation)
    ( )
    Notes
    [13] - Cabozantinib's PK was well studied through development of it's monotherapy, no need to measure Cmax.
    No statistical analyses for this end point

    Secondary: Number of Participants with Anti-Drug Antibodies (ADAs) to Atezolizumab

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    End point title
    		 Number of Participants with Anti-Drug Antibodies (ADAs) to Atezolizumab [14]
    End point description
    Safety population included treated participants, defined as all randomised participants who received any amount of study drug. Overall number analysed is the number of participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Predose on Day 1 of Cycles 1,2,3,4,8,12 and 16 (each cycle is 21 days) and at post-treatment follow-up visit (≤ 30 days after final dose)
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Anti-Drug Antibodies (ADAs) were analyzed for Atezolizumab only for this endpoint.
    End point values
    		 Atezolizumab + Cabozantinib
    Number of subjects analysed
    177
    Units: participants
        ADA Prevalence at Baseline (n=177)
    2
        ADA Incidence after treatment (n=173)
    37
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing the informed consent form up to approximately 24 months. This study is still ongoing, and the AEs section will be updated 1 year after study completion.
    Adverse event reporting additional description
    All-cause mortality was assessed in the ITT population, which included all randomized participants whether or not they received treatment. Serious adverse events and non-serious adverse events were assessed in the safety population, which included treated participants, defined as all randomized participants who received any amount of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Atezolizumab + Cabozantinib
    Reporting group description
    		 Participants received atezolizumab intravenously at a fixed dose of 1200 mg on Day 1 of each 21-day cycle. Cabozantinib was administered orally, once daily at a dose of 40 mg in each 21-day cycle.

    Reporting group title
    Docetaxel
    Reporting group description
    		 Participants received docetaxel intravenously at a starting dose of 75mg/m^2 on Day 1 of each 21-day cycle.

    Serious adverse events
    		 Atezolizumab + Cabozantinib Docetaxel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    71 / 185 (38.38%)
    58 / 167 (34.73%)
         number of deaths (all causes)
    114
    106
         number of deaths resulting from adverse events
    4
    1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intermittent claudication
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Mucosal inflammation
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    3 / 185 (1.62%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    5 / 185 (2.70%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    3 / 185 (1.62%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Condition aggravated
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Infusion related hypersensitivity reaction
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemophagocytic lymphohistiocytosis
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    3 / 185 (1.62%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 185 (1.08%)
    3 / 167 (1.80%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    3 / 185 (1.62%)
    5 / 167 (2.99%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 5
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 185 (0.00%)
    4 / 167 (2.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pulmonary infarction
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 185 (0.00%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary haemorrhage
         subjects affected / exposed
    2 / 185 (1.08%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Bronchial fistula
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal inflammation
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 185 (0.00%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    1 / 185 (0.54%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Spinal fracture
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    2 / 185 (1.08%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumopericardium
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 185 (0.00%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 185 (0.00%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Status epilepticus
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 185 (0.54%)
    3 / 167 (1.80%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 185 (0.00%)
    8 / 167 (4.79%)
         occurrences causally related to treatment / all
    0 / 0
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 167 (0.60%)
         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
    3 / 185 (1.62%)
    3 / 167 (1.80%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 185 (1.62%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastritis
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorectal disorder
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal fistula
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Hidradenitis
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    3 / 185 (1.62%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Bladder disorder
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    2 / 185 (1.08%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fistula
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Viral infection
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    10 / 185 (5.41%)
    10 / 167 (5.99%)
         occurrences causally related to treatment / all
    0 / 10
    4 / 10
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Herpes zoster
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine infection
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 185 (0.54%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Mycobacterium avium complex infection
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial colitis
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory tract infection
         subjects affected / exposed
    1 / 185 (0.54%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 185 (1.08%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    4 / 185 (2.16%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Atezolizumab + Cabozantinib Docetaxel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    172 / 185 (92.97%)
    147 / 167 (88.02%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    16 / 185 (8.65%)
    2 / 167 (1.20%)
         occurrences all number
    22
    3
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    17 / 185 (9.19%)
    12 / 167 (7.19%)
         occurrences all number
    18
    12
    Malaise
         subjects affected / exposed
    5 / 185 (2.70%)
    9 / 167 (5.39%)
         occurrences all number
    5
    9
    Mucosal inflammation
         subjects affected / exposed
    11 / 185 (5.95%)
    9 / 167 (5.39%)
         occurrences all number
    17
    10
    Asthenia
         subjects affected / exposed
    42 / 185 (22.70%)
    40 / 167 (23.95%)
         occurrences all number
    51
    45
    Fatigue
         subjects affected / exposed
    41 / 185 (22.16%)
    44 / 167 (26.35%)
         occurrences all number
    47
    48
    Oedema peripheral
         subjects affected / exposed
    6 / 185 (3.24%)
    12 / 167 (7.19%)
         occurrences all number
    6
    15
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    23 / 185 (12.43%)
    25 / 167 (14.97%)
         occurrences all number
    25
    25
    Dysphonia
         subjects affected / exposed
    15 / 185 (8.11%)
    1 / 167 (0.60%)
         occurrences all number
    18
    1
    Cough
         subjects affected / exposed
    18 / 185 (9.73%)
    12 / 167 (7.19%)
         occurrences all number
    20
    14
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    16 / 185 (8.65%)
    7 / 167 (4.19%)
         occurrences all number
    16
    7
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    8 / 185 (4.32%)
    12 / 167 (7.19%)
         occurrences all number
    16
    19
    Alanine aminotransferase increased
         subjects affected / exposed
    36 / 185 (19.46%)
    7 / 167 (4.19%)
         occurrences all number
    50
    7
    Aspartate aminotransferase increased
         subjects affected / exposed
    30 / 185 (16.22%)
    4 / 167 (2.40%)
         occurrences all number
    39
    4
    Platelet count decreased
         subjects affected / exposed
    15 / 185 (8.11%)
    0 / 167 (0.00%)
         occurrences all number
    27
    0
    Weight decreased
         subjects affected / exposed
    27 / 185 (14.59%)
    5 / 167 (2.99%)
         occurrences all number
    27
    6
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    20 / 185 (10.81%)
    10 / 167 (5.99%)
         occurrences all number
    24
    14
    Headache
         subjects affected / exposed
    13 / 185 (7.03%)
    14 / 167 (8.38%)
         occurrences all number
    14
    18
    Dizziness
         subjects affected / exposed
    14 / 185 (7.57%)
    5 / 167 (2.99%)
         occurrences all number
    15
    5
    Neuropathy peripheral
         subjects affected / exposed
    4 / 185 (2.16%)
    9 / 167 (5.39%)
         occurrences all number
    4
    9
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    16 / 185 (8.65%)
    1 / 167 (0.60%)
         occurrences all number
    19
    1
    Anaemia
         subjects affected / exposed
    22 / 185 (11.89%)
    37 / 167 (22.16%)
         occurrences all number
    23
    46
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    30 / 185 (16.22%)
    17 / 167 (10.18%)
         occurrences all number
    33
    17
    Nausea
         subjects affected / exposed
    44 / 185 (23.78%)
    29 / 167 (17.37%)
         occurrences all number
    53
    42
    Diarrhoea
         subjects affected / exposed
    80 / 185 (43.24%)
    38 / 167 (22.75%)
         occurrences all number
    118
    62
    Stomatitis
         subjects affected / exposed
    28 / 185 (15.14%)
    13 / 167 (7.78%)
         occurrences all number
    30
    14
    Vomiting
         subjects affected / exposed
    27 / 185 (14.59%)
    11 / 167 (6.59%)
         occurrences all number
    34
    14
    Abdominal pain upper
         subjects affected / exposed
    10 / 185 (5.41%)
    2 / 167 (1.20%)
         occurrences all number
    11
    2
    Abdominal pain
         subjects affected / exposed
    21 / 185 (11.35%)
    5 / 167 (2.99%)
         occurrences all number
    27
    5
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    14 / 185 (7.57%)
    6 / 167 (3.59%)
         occurrences all number
    17
    7
    Dry skin
         subjects affected / exposed
    10 / 185 (5.41%)
    7 / 167 (4.19%)
         occurrences all number
    10
    7
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    40 / 185 (21.62%)
    2 / 167 (1.20%)
         occurrences all number
    53
    2
    Alopecia
         subjects affected / exposed
    4 / 185 (2.16%)
    40 / 167 (23.95%)
         occurrences all number
    4
    40
    Rash
         subjects affected / exposed
    17 / 185 (9.19%)
    13 / 167 (7.78%)
         occurrences all number
    20
    14
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    19 / 185 (10.27%)
    3 / 167 (1.80%)
         occurrences all number
    24
    3
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    26 / 185 (14.05%)
    0 / 167 (0.00%)
         occurrences all number
    28
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    10 / 185 (5.41%)
    19 / 167 (11.38%)
         occurrences all number
    12
    23
    Muscle spasms
         subjects affected / exposed
    11 / 185 (5.95%)
    3 / 167 (1.80%)
         occurrences all number
    12
    3
    Arthralgia
         subjects affected / exposed
    25 / 185 (13.51%)
    19 / 167 (11.38%)
         occurrences all number
    29
    22
    Pain in extremity
         subjects affected / exposed
    12 / 185 (6.49%)
    4 / 167 (2.40%)
         occurrences all number
    14
    4
    Back pain
         subjects affected / exposed
    17 / 185 (9.19%)
    7 / 167 (4.19%)
         occurrences all number
    19
    9
    Infections and infestations
    COVID-19
         subjects affected / exposed
    12 / 185 (6.49%)
    4 / 167 (2.40%)
         occurrences all number
    12
    4
    Metabolism and nutrition disorders
    Hypoalbuminaemia
         subjects affected / exposed
    18 / 185 (9.73%)
    12 / 167 (7.19%)
         occurrences all number
    20
    16
    Hypomagnesaemia
         subjects affected / exposed
    20 / 185 (10.81%)
    4 / 167 (2.40%)
         occurrences all number
    26
    5
    Hyponatraemia
         subjects affected / exposed
    12 / 185 (6.49%)
    10 / 167 (5.99%)
         occurrences all number
    15
    10
    Hypokalaemia
         subjects affected / exposed
    15 / 185 (8.11%)
    8 / 167 (4.79%)
         occurrences all number
    15
    9
    Decreased appetite
         subjects affected / exposed
    56 / 185 (30.27%)
    28 / 167 (16.77%)
         occurrences all number
    62
    31
    Hypocalcaemia
         subjects affected / exposed
    18 / 185 (9.73%)
    7 / 167 (4.19%)
         occurrences all number
    32
    7

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Mar 2023
    Protocol GO41892, Version 5: has been amended primarily to update the adverse event management guidelines to align with the recent Atezolizumab Investigator's Brochure, Version 19, and Cabozantinib Investigator’s Brochure, Version 18.

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

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

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