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    Clinical Trial Results:
    A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of Atezolizumab Plus Carboplatin and Etoposide With or Without Tiragolumab (Anti-Tigit Antibody) in Patients With Untreated Extensive-Stage Small Cell Lung Cancer

    Summary
    EudraCT number
    		 2019-003301-97
    Trial protocol
    		 DE   GB   PL   AT   HU   BE   ES   GR   IT  
    Global end of trial date

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Sep 2025
    First version publication date
    11 Sep 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GO41767
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04256421
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4058
    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
    06 Sep 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Sep 2022
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    This study will evaluate the efficacy of tiragolumab plus atezolizumab and carboplatin and etoposide (CE) compared with placebo plus atezolizumab and CE in participants with chemotherapy-naive extensive-stage small cell lung cancer (ES-SCLC).
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Feb 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    Austria: 9
    Country: Number of subjects enrolled
    Belgium: 14
    Country: Number of subjects enrolled
    Brazil: 9
    Country: Number of subjects enrolled
    Switzerland: 4
    Country: Number of subjects enrolled
    Czechia: 14
    Country: Number of subjects enrolled
    Germany: 25
    Country: Number of subjects enrolled
    Spain: 29
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Greece: 17
    Country: Number of subjects enrolled
    Hungary: 18
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    Japan: 35
    Country: Number of subjects enrolled
    Korea, Republic of: 67
    Country: Number of subjects enrolled
    Netherlands: 16
    Country: Number of subjects enrolled
    New Zealand: 4
    Country: Number of subjects enrolled
    Poland: 52
    Country: Number of subjects enrolled
    Russian Federation: 18
    Country: Number of subjects enrolled
    Singapore: 4
    Country: Number of subjects enrolled
    Serbia: 15
    Country: Number of subjects enrolled
    Türkiye: 30
    Country: Number of subjects enrolled
    Taiwan: 23
    Country: Number of subjects enrolled
    United States: 53
    Worldwide total number of subjects
    490
    EEA total number of subjects
    215
    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)
    233
    From 65 to 84 years
    255
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 490 participants with extensive stage small cell lung cancer (SCLC) took part at 139 centers across 23 countries.

    Pre-assignment
    Screening details
    		 Participants were randomized to receive Placebo + Atezolizumab (P+A) or Tiragolumab + Atezolizumab (T+A) with carboplatin & etoposide as induction treatment followed by either P+A or T+A as maintenance treatment. 1 participant from P+A arm and 4 from T+A arm were randomized but not treated.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Carer, Data analyst, Subject, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo + Atezolizumab
    Arm description
    		 During induction treatment participants received atezolizumab, 1200 milligram (mg), followed by placebo and carboplatin, as intravenous (IV) infusion, to achieve an initial target area under the concentration-time curve (AUC) of 5 milligram/milliliter/minute (mg/mL/min) on Day 1 of each 21-day cycle for 4 cycles. Etoposide 100 milligram per square meter (mg/m^2) was also administered as IV infusion on Days 1, 2 and 3 of each 21-day cycle for 4 cycles. Participants then received maintenance treatment with atezolizumab+ placebo on Day 1 of each 21-day cycle at the same dose as during induction treatment until disease progression or loss of clinical benefit.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo administered by IV infusion on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin was administered by IV infusion on Day 1 of each 21-day cycle for 4 cycles.

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Etoposide 100 mg/m^2 administered by IV infusion on Days 1, 2 and 3 of each 21-day cycle for 4 cycles.

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Tecentriq
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab 1200 mg administered by IV infusion on Day 1 of each 21-day cycle.

    Arm title
    		 Tiragolumab + Atezolizumab
    Arm description
    		 During induction treatment participants received atezolizumab, 1200 mg, followed by tiragolumab, 600mg and carboplatin, as IV infusion, to achieve an initial target AUC of 5 mg/mL/min on Day 1 of each 21-day cycle for 4 cycles. Etoposide 100 mg/m^2 was also administered as IV infusion on Days 1, 2 and 3 of each 21-day cycle for 4 cycles. Participants then received maintenance treatment with atezolizumab+ tiragolumab on Day 1 of each 21-day cycle at the same dose as during induction treatment until disease progression or loss of clinical benefit.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiragolumab
    Investigational medicinal product code
    Other name
    MTIG7192A
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tiragolumab 600 milligrams (mg) administered by IV infusion on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Etoposide 100 mg/m^2 administered by IV infusion on Days 1, 2 and 3 of each 21-day cycle for 4 cycles.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin was administered by IV infusion on Day 1 of each 21-day cycle for 4 cycles.

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Tecentriq
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab 1200 mg administered by IV infusion on Day 1 of each 21-day cycle.

    Number of subjects in period 1
    		Placebo + Atezolizumab Tiragolumab + Atezolizumab
    Started
    247
    243
    Safety-evaluable Set
    246
    239
    Completed
    0
    0
    Not completed
    247
    243
         Adverse event, serious fatal
    171
    180
         Consent withdrawn by subject
    9
    10
         Ongoing in Study
    66
    52
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo + Atezolizumab
    Reporting group description
    		 During induction treatment participants received atezolizumab, 1200 milligram (mg), followed by placebo and carboplatin, as intravenous (IV) infusion, to achieve an initial target area under the concentration-time curve (AUC) of 5 milligram/milliliter/minute (mg/mL/min) on Day 1 of each 21-day cycle for 4 cycles. Etoposide 100 milligram per square meter (mg/m^2) was also administered as IV infusion on Days 1, 2 and 3 of each 21-day cycle for 4 cycles. Participants then received maintenance treatment with atezolizumab+ placebo on Day 1 of each 21-day cycle at the same dose as during induction treatment until disease progression or loss of clinical benefit.

    Reporting group title
    Tiragolumab + Atezolizumab
    Reporting group description
    		 During induction treatment participants received atezolizumab, 1200 mg, followed by tiragolumab, 600mg and carboplatin, as IV infusion, to achieve an initial target AUC of 5 mg/mL/min on Day 1 of each 21-day cycle for 4 cycles. Etoposide 100 mg/m^2 was also administered as IV infusion on Days 1, 2 and 3 of each 21-day cycle for 4 cycles. Participants then received maintenance treatment with atezolizumab+ tiragolumab on Day 1 of each 21-day cycle at the same dose as during induction treatment until disease progression or loss of clinical benefit.

    Reporting group values
    		 Placebo + Atezolizumab Tiragolumab + Atezolizumab Total
    Number of subjects
    		 247 243 490
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.1 ( 7.9 ) 64.5 ( 8.2 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 83 81 164
        Male
    		 164 162 326

    End points

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    End points reporting groups
    Reporting group title
    Placebo + Atezolizumab
    Reporting group description
    		 During induction treatment participants received atezolizumab, 1200 milligram (mg), followed by placebo and carboplatin, as intravenous (IV) infusion, to achieve an initial target area under the concentration-time curve (AUC) of 5 milligram/milliliter/minute (mg/mL/min) on Day 1 of each 21-day cycle for 4 cycles. Etoposide 100 milligram per square meter (mg/m^2) was also administered as IV infusion on Days 1, 2 and 3 of each 21-day cycle for 4 cycles. Participants then received maintenance treatment with atezolizumab+ placebo on Day 1 of each 21-day cycle at the same dose as during induction treatment until disease progression or loss of clinical benefit.

    Reporting group title
    Tiragolumab + Atezolizumab
    Reporting group description
    		 During induction treatment participants received atezolizumab, 1200 mg, followed by tiragolumab, 600mg and carboplatin, as IV infusion, to achieve an initial target AUC of 5 mg/mL/min on Day 1 of each 21-day cycle for 4 cycles. Etoposide 100 mg/m^2 was also administered as IV infusion on Days 1, 2 and 3 of each 21-day cycle for 4 cycles. Participants then received maintenance treatment with atezolizumab+ tiragolumab on Day 1 of each 21-day cycle at the same dose as during induction treatment until disease progression or loss of clinical benefit.

    Primary: Investigator-Assessed Progression Free Survival (PFS) in the Primary Analysis Set (PAS)

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    End point title
    		 Investigator-Assessed Progression Free Survival (PFS) in the Primary Analysis Set (PAS)
    End point description
    PFS was defined as the time from randomization to the first documented disease progression (PD) as determined by the investigator with the use of Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or death from any cause, whichever occurred first. PD: at least a 20% increase in the sum of diameters (SOD) of target lesions, taking as reference the smallest SOD on study (including baseline). In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of >/= 5 millimeters (mm). PAS: All randomized participants without presence or history of brain metastases at baseline.
    End point type
    Primary
    End point timeframe
    From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first (up to approximately 24 months)
    End point values
    		 Placebo + Atezolizumab Tiragolumab + Atezolizumab
    Number of subjects analysed
    201
    196
    Units: months
        median (confidence interval 95%)
    5.55 (5.36 to 5.85)
    5.36 (4.67 to 5.52)
    Statistical analysis title
    		 Stratified Analysis for PFS (PAS)
    Statistical analysis description
    Stratification factors were LDH (> upper limit of normal [ULN] vs. </= ULN) and Eastern Cooperative Oncology Group (ECOG; 0 vs. 1).
    Comparison groups
    Placebo + Atezolizumab v Tiragolumab + Atezolizumab
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3504
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 1.38

    Primary: Overall Survival (OS) in the PAS

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    End point title
    		 Overall Survival (OS) in the PAS
    End point description
    OS was defined as the time from randomization to death from any cause. PAS: All randomized participants without presence or history of brain metastases at baseline.
    End point type
    Primary
    End point timeframe
    From randomization to death from any cause (up to approximately 24 months)
    End point values
    		 Placebo + Atezolizumab Tiragolumab + Atezolizumab
    Number of subjects analysed
    201
    196
    Units: months
        median (confidence interval 95%)
    13.14 (12.16 to 15.11)
    13.11 (10.84 to 14.39)
    Statistical analysis title
    		 Stratified Analysis for OS (PAS)
    Statistical analysis description
    Stratification factors were LDH (> ULN vs. </= ULN) and ECOG (0 vs. 1).
    Comparison groups
    Placebo + Atezolizumab v Tiragolumab + Atezolizumab
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2859
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 1.44

    Secondary: PFS in the FAS

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    End point title
    		 PFS in the FAS
    End point description
    PFS was defined as the time from randomization to the first documented PD as determined by the investigator with the use of RECIST v1.1 or death from any cause, whichever occurred first. PD: at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD on study (including baseline). In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of >/= 5 mm. FAS: All randomized participants, whether or not the participant received the assigned treatment.
    End point type
    Secondary
    End point timeframe
    From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first (up to approximately 24 months)
    End point values
    		 Placebo + Atezolizumab Tiragolumab + Atezolizumab
    Number of subjects analysed
    247
    243
    Units: months
        median (confidence interval 95%)
    5.42 (4.47 to 5.65)
    5.06 (4.40 to 5.42)
    Statistical analysis title
    		 Stratified Analysis for PFS (FAS)
    Statistical analysis description
    Stratification factors were LDH (> ULN vs. </= ULN) and ECOG (0 vs. 1).
    Comparison groups
    Placebo + Atezolizumab v Tiragolumab + Atezolizumab
    Number of subjects included in analysis
    490
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.444
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 1.31

    Secondary: OS in the FAS

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    End point title
    		 OS in the FAS
    End point description
    OS was defined as the time from randomization to death from any cause. FAS: All randomized participants, whether or not the participant received the assigned treatment.
    End point type
    Secondary
    End point timeframe
    From randomization to death from any cause (up to approximately 24 months)
    End point values
    		 Placebo + Atezolizumab Tiragolumab + Atezolizumab
    Number of subjects analysed
    247
    243
    Units: months
        median (confidence interval 95%)
    12.91 (11.99 to 14.52)
    12.75 (10.84 to 14.29)
    Statistical analysis title
    		 Stratified Analysis for OS (FAS)
    Statistical analysis description
    Stratification factors were LDH (> ULN vs. </= ULN) and ECOG (0 vs. 1).
    Comparison groups
    Placebo + Atezolizumab v Tiragolumab + Atezolizumab
    Number of subjects included in analysis
    490
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4205
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.35

    Secondary: Investigator-Assessed Confirmed Objective Response Rate (ORR) in the PAS

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    End point title
    		 Investigator-Assessed Confirmed Objective Response Rate (ORR) in the PAS
    End point description
    ORR was defined as the percentage of participants with a complete response (CR) or a partial response (PR) as determined by the investigator with the use of RECIST v1.1. CR was defined as disappearance of all target lesions or any pathological lymph nodes must have reduction in short axis to < 10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PAS: All randomized participants without presence or history of brain metastases at baseline.
    End point type
    Secondary
    End point timeframe
    From randomization up to approximately 24 months
    End point values
    		 Placebo + Atezolizumab Tiragolumab + Atezolizumab
    Number of subjects analysed
    201
    196
    Units: percentage of participants
        number (confidence interval 95%)
    66.7 (59.64 to 73.05)
    73.5 (66.61 to 79.39)
    Statistical analysis title
    		 Stratified Analysis for ORR (PAS)
    Statistical analysis description
    Stratification factors were LDH (> ULN vs. </= ULN) and ECOG (0 vs. 1).
    Comparison groups
    Placebo + Atezolizumab v Tiragolumab + Atezolizumab
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1418
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Overall Response Rates
    Point estimate
    6.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.57
         upper limit
    		 15.99

    Secondary: Investigator-Assessed Confirmed ORR in the FAS

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    End point title
    		 Investigator-Assessed Confirmed ORR in the FAS
    End point description
    ORR was defined as the percentage of participants with CR or PR as determined by the investigator with the use of RECIST v1.1. CR was defined as disappearance of all target lesions or any pathological lymph nodes must have reduction in short axis to < 10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. FAS: All randomized participants, whether or not the participant received the assigned treatment.
    End point type
    Secondary
    End point timeframe
    From randomization up to approximately 24 months
    End point values
    		 Placebo + Atezolizumab Tiragolumab + Atezolizumab
    Number of subjects analysed
    247
    243
    Units: percentage of participants
        number (confidence interval 95%)
    65.6 (59.26 to 71.42)
    70.8 (64.56 to 76.33)
    Statistical analysis title
    		 Stratified Analysis for ORR (FAS)
    Statistical analysis description
    Stratification factors were LDH (> ULN vs. </= ULN) and ECOG (0 vs. 1).
    Comparison groups
    Placebo + Atezolizumab v Tiragolumab + Atezolizumab
    Number of subjects included in analysis
    490
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2191
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Overall Response Rates
    Point estimate
    5.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.33
         upper limit
    		 13.61

    Secondary: Investigator-Assessed Duration of Response (DOR) in the PAS

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    End point title
    		 Investigator-Assessed Duration of Response (DOR) in the PAS
    End point description
    DOR was defined as the time from the first occurrence of a documented objective response (OR) to PD or death from any cause, whichever occurred first, as determined by the investigator with the use of RECIST v1.1. CR: was defined as disappearance of all target lesions or any pathological lymph nodes must have reduction in short axis to < 10 mm PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD= at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD on study (including baseline). In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of >/= 5 mm. PAS: All randomized participants without presence or history of brain metastases at baseline.
    End point type
    Secondary
    End point timeframe
    From the first occurrence of a documented confirmed objective response to disease progression or death from any cause, whichever occurs first (up to approximately 24 months)
    End point values
    		 Placebo + Atezolizumab Tiragolumab + Atezolizumab
    Number of subjects analysed
    134 [1]
    144 [2]
    Units: months
        median (confidence interval 95%)
    5.59 (4.57 to 6.93)
    4.19 (4.14 to 4.60)
    Notes
    [1] - DOR was analyzed in confirmed responders by investigator.
    [2] - DOR was analyzed in confirmed responders by investigator.
    No statistical analyses for this end point

    Secondary: Investigator-Assessed DOR in the FAS

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    End point title
    		 Investigator-Assessed DOR in the FAS
    End point description
    DOR was defined as the time from the first occurrence of a documented OR to PD or death from any cause, whichever occurred first, as determined by the investigator with the use of RECIST v1.1. CR: was defined as disappearance of all target lesions or any pathological lymph nodes must have reduction in short axis to < 10 mm PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD= at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD on study (including baseline). In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of >/= 5 mm. FAS: All randomized participants, whether or not the participant received the assigned treatment.
    End point type
    Secondary
    End point timeframe
    From the first occurrence of a documented confirmed objective response to disease progression or death from any cause, whichever occurs first (up to approximately 24 months)
    End point values
    		 Placebo + Atezolizumab Tiragolumab + Atezolizumab
    Number of subjects analysed
    162 [3]
    172 [4]
    Units: months
        median (confidence interval 95%)
    5.11 (4.37 to 5.75)
    4.17 (4.07 to 4.37)
    Notes
    [3] - DOR was analyzed in confirmed responders by investigator.
    [4] - DOR was analyzed in confirmed responders by investigator.
    No statistical analyses for this end point

    Secondary: Investigator-Assessed PFS Rates at 6 Months and 12 Months in the PAS

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    End point title
    		 Investigator-Assessed PFS Rates at 6 Months and 12 Months in the PAS
    End point description
    PFS rate at 6 months and 12 months was defined as the percentage of participants who were event free at these specific time points. PAS: All randomized participants without presence or history of brain metastases at baseline. Number analyzed is the number of participants with data available for analyses. n= number of participants with data available for analyses at the specified timepoints.
    End point type
    Secondary
    End point timeframe
    Month 6, Month 12
    End point values
    		 Placebo + Atezolizumab Tiragolumab + Atezolizumab
    Number of subjects analysed
    84
    67
    Units: percentage of participants
    number (confidence interval 95%)
        Month 6 (n= 84, 67)
    42.42 (35.54 to 49.31)
    35.15 (28.41 to 41.90)
        Month 12 (n= 26, 17)
    17.29 (11.90 to 22.69)
    14.21 (9.06 to 19.35)
    No statistical analyses for this end point

    Secondary: Investigator-Assessed PFS Rates at 6 Months and 12 Months in the FAS

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    End point title
    		 Investigator-Assessed PFS Rates at 6 Months and 12 Months in the FAS
    End point description
    PFS rate at 6 months and 12 months was defined as the percentage of participants who were event free at these specific time points. FAS: All randomized participants, whether or not the participant received the assigned treatment. Number analyzed is the number of participants with data available for analyses. n= number of participants with data available for analyses at the specified timepoints.
    End point type
    Secondary
    End point timeframe
    Month 6, Month 12
    End point values
    		 Placebo + Atezolizumab Tiragolumab + Atezolizumab
    Number of subjects analysed
    92
    74
    Units: percentage of participants
    number (confidence interval 95%)
        Month 6 (n= 92, 74)
    37.95 (31.85 to 44.05)
    31.30 (25.41 to 37.19)
        Month 12 (n= 26, 18)
    14.07 (9.59 to 18.55)
    12.33 (7.90 to 16.75)
    No statistical analyses for this end point

    Secondary: Overall Survival Rates at 12 Months and 24 Months in the PAS

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    End point title
    		 Overall Survival Rates at 12 Months and 24 Months in the PAS
    End point description
    Overall survival rate at 12 months and 24 months was defined as the percentage of participants who were alive at these specific time points. PAS: All randomized participants without presence or history of brain metastases at baseline. Number analyzed is the number of participants with data available for analyses. n= number of participants with data available for analyses at the specified timepoints.
    End point type
    Secondary
    End point timeframe
    Month 12, Month 24
    End point values
    		 Placebo + Atezolizumab Tiragolumab + Atezolizumab
    Number of subjects analysed
    112
    103
    Units: percentage of participants
    number (confidence interval 95%)
        Month 12 (n= 112, 103)
    57.74 (50.82 to 64.66)
    54.00 (46.97 to 61.03)
        Month 24 (n= 12, 10)
    27.68 (20.43 to 34.94)
    19.56 (13.16 to 25.96)
    Statistical analysis title
    		 Month 12
    Comparison groups
    Placebo + Atezolizumab v Tiragolumab + Atezolizumab
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.458
    Method
    		 Z-test
    Parameter type
    		 Difference in Event Free Rate
    Point estimate
    -3.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.6
         upper limit
    		 6.13
    Statistical analysis title
    		 Month 24
    Comparison groups
    Placebo + Atezolizumab v Tiragolumab + Atezolizumab
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0999
    Method
    		 Z-test
    Parameter type
    		 Difference in Event Free Rate
    Point estimate
    -8.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.8
         upper limit
    		 1.55

    Secondary: Overall Survival Rates at 12 Months and 24 Months in the FAS

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    End point title
    		 Overall Survival Rates at 12 Months and 24 Months in the FAS
    End point description
    Overall survival rate at 12 months and 24 months was defined as the percentage of participants who were alive at these specific time points. FAS: All randomized participants, whether or not the participant received the assigned treatment. Number analyzed is the number of participants with data available for analyses. n= number of participants with data available for analyses at the specified timepoints.
    End point type
    Secondary
    End point timeframe
    Month 12, Month 24
    End point values
    		 Placebo + Atezolizumab Tiragolumab + Atezolizumab
    Number of subjects analysed
    247
    243
    Units: percentage of participants
    number (confidence interval 95%)
        Month 12 (n= 133, 125)
    55.84 (49.58 to 62.10)
    52.82 (46.49 to 59.15)
        Month 24 (n= 12, 10)
    25.82 (19.19 to 32.46)
    20.53 (14.54 to 26.52)
    Statistical analysis title
    		 Month 24
    Comparison groups
    Placebo + Atezolizumab v Tiragolumab + Atezolizumab
    Number of subjects included in analysis
    490
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2458
    Method
    		 Z-test
    Parameter type
    		 Difference in Event Free Rate
    Point estimate
    -5.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.23
         upper limit
    		 3.65
    Statistical analysis title
    		 Month 12
    Comparison groups
    Placebo + Atezolizumab v Tiragolumab + Atezolizumab
    Number of subjects included in analysis
    490
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5059
    Method
    		 Z-test
    Parameter type
    		 Difference in Event Free Rate
    Point estimate
    -3.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.92
         upper limit
    		 5.88

    Secondary: Time to Confirmed Deterioration (TTCD) of European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core (QLQ-C30) Physical Functioning in the PAS

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    End point title
    		 Time to Confirmed Deterioration (TTCD) of European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core (QLQ-C30) Physical Functioning in the PAS
    End point description
    TTCD= time from randomization until the first confirmed clinically meaningful deterioration in physical functioning.TTCD was determined based on patient-reported physical functioning (items 1-5) as collected & measured by the EORTC QLQ-C30.PF is measured on 4-point scale (1='Not at all' to 4='Very much').A high score for the physical function subscale= a high/healthy level of functioning. The scale was linearly transformed so that each score ranged from 0-100. A score change of at least 10-point in physical functioning subscale score was perceived by participants as clinically meaningful. Confirmed clinically meaningful deterioration= clinically meaningful decrease from baseline that was held for at least two consecutive assessments/ an initial clinically meaningful decrease from baseline followed by death from any cause within 3 weeks. PAS: All randomized participants without presence or history of brain metastases at baseline.9999=not estimable due to insufficient number of events.
    End point type
    Secondary
    End point timeframe
    From randomization until the first confirmed clinically meaningful deterioration up to approximately 24 months
    End point values
    		 Placebo + Atezolizumab Tiragolumab + Atezolizumab
    Number of subjects analysed
    201
    196
    Units: months
        median (confidence interval 95%)
    19.35 (19.35 to 9999)
    15.67 (12.81 to 9999)
    Statistical analysis title
    		 Stratified Analysis for TTCD Physical (PAS)
    Statistical analysis description
    Stratification factors were LDH (> ULN vs. </= ULN) and ECOG (0 vs. 1).
    Comparison groups
    Placebo + Atezolizumab v Tiragolumab + Atezolizumab
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9819
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.48

    Secondary: TTCD of EORTC QLQ-C30 Physical Functioning in the FAS

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    End point title
    		 TTCD of EORTC QLQ-C30 Physical Functioning in the FAS
    End point description
    TTCD= time from randomization until the first confirmed clinically meaningful deterioration in physical functioning.TTCD was determined based on patient-reported physical functioning (items 1-5) as collected & measured by the EORTC QLQ-C30.PF is measured on 4-point scale (1='Not at all' to 4='Very much').A high score for the physical function subscale= a high/healthy level of functioning.The scale was linearly transformed so that each score ranged from 0-100.A score change of at least 10-point in physical functioning subscale score was perceived by participants as clinically meaningful.Confirmed clinically meaningful deterioration= clinically meaningful decrease from baseline that was held for at least two consecutive assessments/ an initial clinically meaningful decrease from baseline followed by death from any cause within 3 weeks.FAS: All randomized participants, whether or not the participant received the assigned treatment.9999=not estimable due to insufficient number of events.
    End point type
    Secondary
    End point timeframe
    From randomization until the first confirmed clinically meaningful deterioration up to approximately 24 months
    End point values
    		 Placebo + Atezolizumab Tiragolumab + Atezolizumab
    Number of subjects analysed
    247
    243
    Units: months
        median (confidence interval 95%)
    19.35 (12.42 to 9999)
    15.67 (11.83 to 9999)
    Statistical analysis title
    		 Stratified Analysis for TTCD Physical (FAS)
    Statistical analysis description
    Stratification factors were LDH (> ULN vs. </= ULN) and ECOG (0 vs. 1).
    Comparison groups
    Placebo + Atezolizumab v Tiragolumab + Atezolizumab
    Number of subjects included in analysis
    490
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5122
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.55

    Secondary: TTCD of EORTC QLQ-C30 Global Health Status (GHS)/Quality of Life (QoL) in the PAS

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    End point title
    		 TTCD of EORTC QLQ-C30 Global Health Status (GHS)/Quality of Life (QoL) in the PAS
    End point description
    TTCD=time from randomization until the first confirmed clinically meaningful deterioration in patient-reported GHS/ QoL.TTCD was determined based on patient-reported GHS/QoL (items 29-30) as collected & measured by the EORTC QLQ-C30.HS/QoL items are scored on a 7-point scale that ranges from "very poor" to "excellent".A high score for the GHS/QoL subscale represented a high health related quality of life. The scale was linearly transformed so that each score ranged from 0-100. A score change of at least 10-point in GHS/QoL subscale score was perceived by participants as clinically meaningful. Confirmed clinically meaningful deterioration= clinically meaningful decrease from baseline that was held for at least 2 consecutive assessments/ an initial clinically meaningful decrease from baseline followed by death from any cause within 3 weeks. PAS: All randomized participants without presence/history of brain metastases at baseline. 9999=not estimable due to insufficient number of events.
    End point type
    Secondary
    End point timeframe
    From randomization until the first confirmed clinically meaningful deterioration up to approximately 24 months
    End point values
    		 Placebo + Atezolizumab Tiragolumab + Atezolizumab
    Number of subjects analysed
    201
    196
    Units: months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (14.55 to 9999)
    Statistical analysis title
    		 Stratified Analysis for TTCD GHS/QoL (PAS)
    Statistical analysis description
    Stratification factors were LDH (> ULN vs. </= ULN) and ECOG (0 vs. 1).
    Comparison groups
    Placebo + Atezolizumab v Tiragolumab + Atezolizumab
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3614
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.79

    Secondary: TTCD of EORTC QLQ-C30 GHS/QoL in the FAS

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    End point title
    		 TTCD of EORTC QLQ-C30 GHS/QoL in the FAS
    End point description
    TTCD=time from randomization until the first confirmed clinically meaningful deterioration in patient-reported GHS/ QoL.TTCD was determined based on patient-reported GHS/QoL (items 29-30) as collected & measured by the EORTC QLQ-C30.HS/QoL items are scored on a 7-point scale that ranges from "very poor" to "excellent".A high score for the GHS/QoL subscale represented a high health related quality of life. The scale was linearly transformed so that each score ranged from 0-100. A score change of at least 10-point in GHS/QoL subscale score was perceived by participants as clinically meaningful. Confirmed clinically meaningful deterioration= clinically meaningful decrease from baseline that was held for at least 2 consecutive assessments/ an initial clinically meaningful decrease from baseline followed by death from any cause within 3 weeks. FAS: All randomized participants, whether the participant received the assigned treatment. 9999=not estimable due to insufficient number of events.
    End point type
    Secondary
    End point timeframe
    From randomization until the first confirmed clinically meaningful deterioration up to approximately 24 months
    End point values
    		 Placebo + Atezolizumab Tiragolumab + Atezolizumab
    Number of subjects analysed
    247
    243
    Units: months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (14.55 to 9999)
    Statistical analysis title
    		 Stratified Analysis for TTCD GHS/QoL (FAS)
    Statistical analysis description
    Stratification factors were LDH (> ULN vs. </= ULN) and ECOG (0 vs. 1).
    Comparison groups
    Placebo + Atezolizumab v Tiragolumab + Atezolizumab
    Number of subjects included in analysis
    490
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1681
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 1.84

    Secondary: Minimum Serum Concentration (Cmin) of Tiragolumab

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    End point title
    		 Minimum Serum Concentration (Cmin) of Tiragolumab [5]
    End point description
    PK-evaluable set: All participants who received at least one dose of study treatment and who had at least one post-baseline PK sample available. n= number of participants with data available for analyses at the specified timepoints.
    End point type
    Secondary
    End point timeframe
    At the end of each cycle (each cycle is 21 days) of Cycles 1, 2, 3, 7, 11 and 15
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint is reporting data only for the Tiragolumab arm.
    End point values
    		 Tiragolumab + Atezolizumab
    Number of subjects analysed
    218
    Units: microgram/milliliter (mcg/mL)
    geometric mean (geometric coefficient of variation)
        Cycle 1, n=218
    29.5 ( 49.2 )
        Cycle 2, n=213
    46.5 ( 47.5 )
        Cycle 3, n=201
    56.3 ( 83.5 )
        Cycle 7, n=111
    76.3 ( 48.2 )
        Cycle 11, n=45
    78.8 ( 246 )
        Cycle 15, n=17
    96.4 ( 43.8 )
    No statistical analyses for this end point

    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 subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
    End point type
    Secondary
    End point timeframe
    Up to 65 months
    End point values
    		 Placebo + Atezolizumab Tiragolumab + Atezolizumab
    Number of subjects analysed
    0 [6]
    0 [7]
    Units: percentage of participants
        number (not applicable)
    Notes
    [6] - Final analysis to be reported after study completion.
    [7] - Final analysis to be reported after study completion.
    No statistical analyses for this end point

    Secondary: Cmin of Atezolizumab

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    End point title
    		 Cmin of Atezolizumab
    End point description
    PK-evaluable set: All participants who received at least one dose of study treatment and who had at least one post-baseline PK sample available. Number analyzed is the number of participants with data available for analyses. n= number of participants with data available for analyses at the specified timepoints.
    End point type
    Secondary
    End point timeframe
    At the end of each cycle (each cycle is 21 days) of Cycles 1, 2, 3, 7, 11 and 15
    End point values
    		 Placebo + Atezolizumab Tiragolumab + Atezolizumab
    Number of subjects analysed
    226
    217
    Units: mcg/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1, n=226, 217
    75.0 ( 63.2 )
    75.4 ( 70.8 )
        Cycle 2, n=221, 213
    121 ( 55.8 )
    125 ( 38.4 )
        Cycle 3, n=200, 198
    144 ( 49.8 )
    155 ( 81.5 )
        Cycle 7, n=115, 110
    205 ( 45.3 )
    198 ( 46.4 )
        Cycle 11, n=52, 45
    226 ( 37.3 )
    244 ( 37 )
        Cycle 15, n=26, 17
    198 ( 75.5 )
    253 ( 36.6 )
    No statistical analyses for this end point

    Secondary: Maximum Serum Concentration (Cmax) of Tiragolumab

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    End point title
    		 Maximum Serum Concentration (Cmax) of Tiragolumab [8]
    End point description
    PK-evaluable set: All participants who received at least one dose of study treatment and who had at least one post-baseline PK sample available. Number analyzed is the number of participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Predose and 30 minutes post end of infusion (EOI) on Day 1 of Cycle 1 (each cycle is 21 days)
    Notes
    [8] - 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: Endpoint is reporting data only for the Tiragolumab arm.
    End point values
    		 Tiragolumab + Atezolizumab
    Number of subjects analysed
    213
    Units: mcg/mL
        geometric mean (geometric coefficient of variation)
    188 ( 24.2 )
    No statistical analyses for this end point

    Secondary: Cmax of Atezolizumab

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    End point title
    		 Cmax of Atezolizumab
    End point description
    End point type
    Secondary
    End point timeframe
    Predose and 30 minutes post EOI on Day 1 of Cycle 1 (each cycle is 21 days)
    End point values
    		 Placebo + Atezolizumab Tiragolumab + Atezolizumab
    Number of subjects analysed
    233
    224
    Units: mcg/mL
        geometric mean (geometric coefficient of variation)
    398 ( 28.2 )
    405 ( 23.0 )
    No statistical analyses for this end point

    Secondary: Number of Participants With Anti-Drug Antibodies (ADAs) to Tiragolumab

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    End point title
    		 Number of Participants With Anti-Drug Antibodies (ADAs) to Tiragolumab [9]
    End point description
    Reported here=number of participants who had a positive ADA assay result at baseline & number of participants positive for treatment emergent ADAs. Participants positive for treatment emergent ADAs include treatment-induced & treatment-enhanced ADA positive participants. Treatment-induced ADAs are participants with negative/missing baseline ADA result(s) & at least one positive post-baseline ADA result. Treatment-enhanced ADAs are participants with a positive ADA result at baseline who had one or more post-baseline titer results that were at least 0.60 t.u. greater than the baseline titer result.Total number of participants who developed ADAs to tiragolumab was determined by summing the ADA-positive participants across all timepoints. Tiragolumab ADA-evaluable set: All participants who received at least one dose of tiragolumab treatment & with an ADA assay result from at least one sample result.n=number of participants with data available for analyses at the specified timepoints.
    End point type
    Secondary
    End point timeframe
    Predose on Day 1 of Cycles 1 (each cycle is 21 days), 2, 3, 4, 8,12 and 16 and at treatment discontinuation (TD) visit (up to 24 months)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint is reporting data only for the Tiragolumab arm.
    End point values
    		 Tiragolumab + Atezolizumab
    Number of subjects analysed
    235
    Units: participants
        Positive Sample at Baseline (n=235)
    2
        Positive for Treatment Emergent ADAs (n=229)
    3
        Treatment-induced ADAs (n=229)
    3
        Treatment-enhanced ADAs (n=229)
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With ADAs to Atezolizumab

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    End point title
    		 Number of Participants With ADAs to Atezolizumab
    End point description
    Reported here=number of participants who had a positive ADA assay result at baseline & number of participants positive for treatment emergent ADAs. Participants positive for treatment emergent ADAs include treatment-induced & treatment-enhanced ADA positive participants. Treatment-induced ADAs are participants with negative/missing baseline ADA result(s) & at least one positive post-baseline ADA result. Treatment-enhanced ADAs are participants with a positive ADA result at baseline who had one or more post-baseline titer results that were at least 0.60 t.u. greater than the baseline titer result.Total number of participants who developed ADAs to tiragolumab was determined by summing the ADA-positive participants across all timepoints. Atezolizumab ADA-evaluable set: All participants who received at least one dose of atezolizumab treatment & with an ADA assay result from at least one sample result.n=number of participants with data available for analyses at the specified timepoints.
    End point type
    Secondary
    End point timeframe
    Predose on Day 1 of Cycles 1 (each cycle is 21 days), 2, 3, 4, 8,12 and 16 and at TD visit (up to 24 months)
    End point values
    		 Placebo + Atezolizumab Tiragolumab + Atezolizumab
    Number of subjects analysed
    244
    236
    Units: participants
        Positive Sample at Baseline (n=244,236)
    2
    1
        Positive for Treatment Emergent ADAs (n=238,228)
    48
    22
        Treatment-induced ADAs(n=238,228)
    48
    22
        Treatment-enhanced ADAs (n=238,228)
    0
    0
    No statistical analyses for this end point

    Secondary: Change from Baseline in EuroQol 5-Dimension, 5-Level (EQ-5D-5L) Index-based and Visual Analog Scale Scores

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    End point title
    		 Change from Baseline in EuroQol 5-Dimension, 5-Level (EQ-5D-5L) Index-based and Visual Analog Scale Scores
    End point description
    The EQ-5D-5L is a validated self-report health status questionnaire that was used to calculate a health status utility score for use in health economic analyses. There were two components to the EQ-5D-5L: a five-item health state profile that assessed mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, as well as a visual analog scale (VAS) that measured health state. The EQ VAS records the participant's self-rated health on a vertical visual analogue scale ranging from 0 to 100 A single composite score was calculated based on the responses as an indicator of the participant's health status. The scale ranges 0-100, 0=worst health and 100=best health.
    End point type
    Secondary
    End point timeframe
    From baseline up to 65 months
    End point values
    		 Placebo + Atezolizumab Tiragolumab + Atezolizumab
    Number of subjects analysed
    0 [10]
    0 [11]
    Units: score on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [10] - Final analysis to be reported after study completion.
    [11] - Final analysis to be reported after study completion.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 24 months
    Adverse event reporting additional description
    All-cause mortality: FAS: All randomized participants, whether or not the participant received the assigned treatment. SAE and nSAE: Safety-evaluable set included all randomized participants who received at least one dose of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Tiragolumab + Atezolizumab
    Reporting group description
    		 During induction treatment participants received atezolizumab, 1200 mg, followed by tiragolumab, 600mg and carboplatin, as IV infusion, to achieve an initial target AUC of 5 mg/mL/min on Day 1 of each 21-day cycle for 4 cycles. Etoposide 100 mg/m^2 was also administered as IV infusion on Days 1, 2 and 3 of each 21-day cycle for 4 cycles. Participants will then receive maintenance treatment with atezolizumab+ tiragolumab on Day 1 of each 21-day cycle at the same dose as during induction treatment until disease progression or loss of clinical benefit.

    Reporting group title
    Placebo + Atezolizumab
    Reporting group description
    		 During induction treatment participants received atezolizumab, 1200 mg, followed by placebo and carboplatin, as IV infusion, to achieve an initial target AUC of 5 mg/mL/min on Day 1 of each 21-day cycle for 4 cycles. Etoposide 100 mg/m^2 was also administered as IV infusion on Days 1, 2 and 3 of each 21-day cycle for 4 cycles. Participants will then receive maintenance treatment with atezolizumab+ placebo on Day 1 of each 21-day cycle at the same dose as during induction treatment until disease progression or loss of clinical benefit.

    Serious adverse events
    		 Tiragolumab + Atezolizumab Placebo + Atezolizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    108 / 239 (45.19%)
    104 / 246 (42.28%)
         number of deaths (all causes)
    180
    171
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (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 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    1 / 239 (0.42%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Asthenia
         subjects affected / exposed
    2 / 239 (0.84%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    2 / 239 (0.84%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (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 / 239 (0.42%)
    0 / 246 (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
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    3 / 239 (1.26%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 239 (0.84%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated lung disease
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract haemorrhage
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 239 (0.84%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pneumothorax
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 239 (0.42%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Mental status changes
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental disorder
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    2 / 239 (0.84%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    2 / 239 (0.84%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 239 (0.84%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    4 / 239 (1.67%)
    4 / 246 (1.63%)
         occurrences causally related to treatment / all
    4 / 4
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    2 / 239 (0.84%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    3 / 239 (1.26%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 239 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 239 (0.42%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         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 / 239 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (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 arrest
         subjects affected / exposed
    0 / 239 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrioventricular block complete
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 239 (1.26%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Loss of consciousness
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Motor dysfunction
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Limbic encephalitis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypoaesthesia
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 239 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    3 / 239 (1.26%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral venous sinus thrombosis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Balance disorder
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuromyotonia
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 239 (0.84%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    2 / 239 (0.84%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    3 / 239 (1.26%)
    5 / 246 (2.03%)
         occurrences causally related to treatment / all
    2 / 3
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Febrile neutropenia
         subjects affected / exposed
    16 / 239 (6.69%)
    14 / 246 (5.69%)
         occurrences causally related to treatment / all
    15 / 17
    15 / 15
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Bicytopenia
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    9 / 239 (3.77%)
    8 / 246 (3.25%)
         occurrences causally related to treatment / all
    9 / 10
    9 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 239 (0.42%)
    4 / 246 (1.63%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune colitis
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 239 (0.84%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated enterocolitis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Liver disorder
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatorenal syndrome
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    2 / 239 (0.84%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    2 / 239 (0.84%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoporosis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 239 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 239 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Candida sepsis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    3 / 239 (1.26%)
    7 / 246 (2.85%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 3
    0 / 3
    COVID-19
         subjects affected / exposed
    6 / 239 (2.51%)
    9 / 246 (3.66%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 9
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Bronchitis
         subjects affected / exposed
    2 / 239 (0.84%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 239 (0.42%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (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 / 239 (0.42%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 239 (1.26%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    7 / 239 (2.93%)
    12 / 246 (4.88%)
         occurrences causally related to treatment / all
    1 / 8
    2 / 15
         deaths causally related to treatment / all
    0 / 1
    1 / 2
    Pneumonia aspiration
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    6 / 239 (2.51%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    3 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    9 / 239 (3.77%)
    4 / 246 (1.63%)
         occurrences causally related to treatment / all
    1 / 17
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Tiragolumab + Atezolizumab Placebo + Atezolizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    228 / 239 (95.40%)
    233 / 246 (94.72%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    23 / 239 (9.62%)
    34 / 246 (13.82%)
         occurrences all number
    29
    46
    Chest pain
         subjects affected / exposed
    9 / 239 (3.77%)
    13 / 246 (5.28%)
         occurrences all number
    9
    14
    Fatigue
         subjects affected / exposed
    59 / 239 (24.69%)
    48 / 246 (19.51%)
         occurrences all number
    70
    61
    Oedema peripheral
         subjects affected / exposed
    13 / 239 (5.44%)
    11 / 246 (4.47%)
         occurrences all number
    16
    14
    Pyrexia
         subjects affected / exposed
    17 / 239 (7.11%)
    25 / 246 (10.16%)
         occurrences all number
    17
    26
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    18 / 239 (7.53%)
    28 / 246 (11.38%)
         occurrences all number
    20
    31
    Dyspnoea
         subjects affected / exposed
    19 / 239 (7.95%)
    31 / 246 (12.60%)
         occurrences all number
    20
    35
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    29 / 239 (12.13%)
    18 / 246 (7.32%)
         occurrences all number
    29
    19
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    17 / 239 (7.11%)
    15 / 246 (6.10%)
         occurrences all number
    21
    20
    Aspartate aminotransferase increased
         subjects affected / exposed
    14 / 239 (5.86%)
    13 / 246 (5.28%)
         occurrences all number
    18
    16
    Neutrophil count decreased
         subjects affected / exposed
    50 / 239 (20.92%)
    55 / 246 (22.36%)
         occurrences all number
    89
    99
    Weight decreased
         subjects affected / exposed
    11 / 239 (4.60%)
    15 / 246 (6.10%)
         occurrences all number
    11
    17
    White blood cell count decreased
         subjects affected / exposed
    28 / 239 (11.72%)
    26 / 246 (10.57%)
         occurrences all number
    50
    47
    Platelet count decreased
         subjects affected / exposed
    27 / 239 (11.30%)
    24 / 246 (9.76%)
         occurrences all number
    41
    32
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    32 / 239 (13.39%)
    17 / 246 (6.91%)
         occurrences all number
    39
    23
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    13 / 239 (5.44%)
    22 / 246 (8.94%)
         occurrences all number
    15
    23
    Headache
         subjects affected / exposed
    18 / 239 (7.53%)
    17 / 246 (6.91%)
         occurrences all number
    20
    20
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    86 / 239 (35.98%)
    97 / 246 (39.43%)
         occurrences all number
    106
    127
    Leukopenia
         subjects affected / exposed
    13 / 239 (5.44%)
    13 / 246 (5.28%)
         occurrences all number
    17
    21
    Thrombocytopenia
         subjects affected / exposed
    29 / 239 (12.13%)
    31 / 246 (12.60%)
         occurrences all number
    46
    53
    Neutropenia
         subjects affected / exposed
    63 / 239 (26.36%)
    72 / 246 (29.27%)
         occurrences all number
    91
    136
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    12 / 239 (5.02%)
    8 / 246 (3.25%)
         occurrences all number
    19
    8
    Constipation
         subjects affected / exposed
    58 / 239 (24.27%)
    61 / 246 (24.80%)
         occurrences all number
    67
    67
    Diarrhoea
         subjects affected / exposed
    20 / 239 (8.37%)
    37 / 246 (15.04%)
         occurrences all number
    24
    46
    Nausea
         subjects affected / exposed
    59 / 239 (24.69%)
    61 / 246 (24.80%)
         occurrences all number
    66
    73
    Vomiting
         subjects affected / exposed
    21 / 239 (8.79%)
    26 / 246 (10.57%)
         occurrences all number
    27
    36
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    36 / 239 (15.06%)
    28 / 246 (11.38%)
         occurrences all number
    44
    33
    Alopecia
         subjects affected / exposed
    62 / 239 (25.94%)
    67 / 246 (27.24%)
         occurrences all number
    62
    68
    Dry skin
         subjects affected / exposed
    12 / 239 (5.02%)
    6 / 246 (2.44%)
         occurrences all number
    13
    6
    Pruritus
         subjects affected / exposed
    66 / 239 (27.62%)
    29 / 246 (11.79%)
         occurrences all number
    76
    34
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    16 / 239 (6.69%)
    17 / 246 (6.91%)
         occurrences all number
    16
    19
    Hypothyroidism
         subjects affected / exposed
    26 / 239 (10.88%)
    21 / 246 (8.54%)
         occurrences all number
    26
    27
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    20 / 239 (8.37%)
    25 / 246 (10.16%)
         occurrences all number
    25
    27
    Back pain
         subjects affected / exposed
    17 / 239 (7.11%)
    19 / 246 (7.72%)
         occurrences all number
    17
    19
    Pain in extremity
         subjects affected / exposed
    14 / 239 (5.86%)
    9 / 246 (3.66%)
         occurrences all number
    17
    9
    Infections and infestations
    COVID-19
         subjects affected / exposed
    13 / 239 (5.44%)
    17 / 246 (6.91%)
         occurrences all number
    13
    17
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    58 / 239 (24.27%)
    38 / 246 (15.45%)
         occurrences all number
    62
    50
    Hypokalaemia
         subjects affected / exposed
    11 / 239 (4.60%)
    20 / 246 (8.13%)
         occurrences all number
    14
    24
    Hypomagnesaemia
         subjects affected / exposed
    14 / 239 (5.86%)
    14 / 246 (5.69%)
         occurrences all number
    20
    24
    Hyponatraemia
         subjects affected / exposed
    20 / 239 (8.37%)
    14 / 246 (5.69%)
         occurrences all number
    24
    17

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 May 2020
    The secondary efficacy objective endpoints were revised to clarify the definition of confirmed objective response and DOR and to measure TTCD in the participant’s physical functioning and global health status. In addition to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0, the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading scale will be used for reporting the severity of cytokine release syndrome (CRS). The study design was amended to include the requirement for participants to provide written informed consent at the time of initial radiographic disease progression per RECIST v1.1 if they met the criteria for treatment beyond radiographic disease progression and wished to continue study treatment. The protocol-specified adverse events of special interest (AESI) and serious adverse event (SAE) reporting period was extended until 90 days after the final dose of study treatment. Crossover will not be allowed from the control arm to the experimental arm. Exclusion criteria related to Epstein-Barr virus (EBV) infection and tests required at screening were clarified. Inclusion criteria were updated to clarify the coagulation criterion and include recommendations for oocyte cryopreservation and sperm conservation. Contraceptive language was added for female partners of childbearing potential. Tumor and response evaluation requirements were clarified: computerized tomography (CT) scans of the chest and abdomen with IV and oral contrast are required at screening and at subsequent tumor assessments; CT scan with contrast of the pelvis is required at screening; irradiated brain metastases do not need to be categorized and followed as target or nontarget lesions at baseline or at subsequent tumor assessments, untreated central nervous system (CNS) disease must be recorded as a non-target lesion per RECIST 1.1 at screening as well as at subsequent scheduled follow-up tumor assessments.
    22 Oct 2020
    The efficacy objectives were updated to reflect a focus on the primary population (PP) of participants without the presence or history of brain metastases at baseline. The study schema was updated to include the new study size of 470 participants and PP sample size of 400 participants, as well as a change in the approximate number of participants in each arm. The independent data monitoring committee (iDMC) review frequency was updated from approximately every 6 months to approximately every 4 to 6 months at the request of the iDMC. The end of the study was updated to indicate that it will occur when approximately 288 deaths have been observed in the PP. Also, the total length of study was updated to 50 months due to the updated statistical testing hierarchy and increased sample size. Exclusion criteria related to EBV infection and EBV tests required at screening were amended in alignment with other tiragolumab protocols. Patients positive for EBV VCA IgM or EBV PCR were not eligible. EBV VCA IgG or EBNA IgG test was required at screening to understand the infection history, but the results will not determine eligibility. The statistical analysis plan was updated to reflect the updated statistical testing hierarchy and sample size change. The primary analysis of PFS and the final analysis of OS was updated to occur approximately 24 months and 38 months after the first participant was randomized, respectively.
    09 Jun 2021
    The timing of the OS interim analysis and PFS primary analysis was updated to occur when approximately 202 OS events (51% of 400 patients) are observed in the PP. Immunosuppressive medications were removed from the prohibited therapy section and added to the cautionary therapy section to align with management guidelines that permit the use of immunosuppressive medications for the treatment of corticosteroid-refractory immune-mediated adverse events. The treatment interruption period for atezolizumab and tiragolumab/placebo was updated to 12 weeks after event onset instead of from last dose of study drug to align with all sections of the protocol.
    15 Nov 2021
    The term "intent-to-treat (ITT) population" was changed to "full analysis set" (FAS) and the term "primary population" (PP) was changed to "primary analysis set" (PAS). The method for computing the 95% CI of confirmed ORR was updated to the Wilson score method and the method for computing the 95% CI of the difference of confirmed ORR between treatment arms was updated to the Newcombe method to align with the calculation method specified in the study's Statistical Analysis Plan (SAP) version 1. It was clarified that the same information fraction in the PAS will be applied to calculate the statistical boundary in the FAS for the overall survival analyses.
    20 Dec 2022
    The adverse event management guidelines have been updated to align with the the Atezolizumab Investigator's Brochure. Immune-mediated hepatitis has been updated from a potential risk to an identified risk associated with tiragolumab. Lymphopenia has been updated to an identified risk associated with the combination of tiragolumab, atezolizumab, and chemotherapies. Embryofetal toxicity has been added as a potential risk associated with tiragolumab. The list of identified risks for atezolizumab has been revised to include myelitis, facial paresis and pericardial disorders. Hemophagocytic lymphohistiocytosis has been updated from a potential risk to an identified risk associated with atezolizumab. The list of adverse events of special interest has been revised to include myelitis and facial paresis. Text has been revised to indicate that caution should be used when considering atezolizumab for participants who have previously experienced a pericardial disorder while receiving another immunostimulatory anti-cancer agent. The association between anti-drug antibodies (ADAs) and infusion-related reactions (IRRs) to tiragolumab has been removed as a low incidence of ADAs against tiragolumab and no association between ADAs and IRRs have been observed to date. Language on study blinding has been amended to account for change in study treatment blinding status after the final overall survival analysis. Patient Reported Outcomes (PRO) assessments have been modified to remove the requirement for PRO Questionnaires for participants on active study treatment at the time of final OS analysis in order to reduce administrative burden to participants.
    11 Dec 2023
    The total duration of study participation for each individual was updated to approximately 72 months taking into account updated event projections. The survival follow-up duration was updated from 3 months to 6 months in response to continuing to follow ongoing patients in the study for limited information. The pharmacokinetic, immunogenicity, and biomarker sample collection schedule were changed so that samples are no longer collected at treatment discontinuation visit because the Sponsor has decided no additional sample collection was needed. At the time of Protocol Amendment version 7, all biomarker sample requirements were removed for remaining participants on study in order to reduce burden to participants.

    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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