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    Clinical Trial Results:
    A phase III, randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of atezolizumab or placebo in combination with neoadjuvant doxorubicin + cyclophosphamide followed by paclitaxel + trastuzumab + pertuzumab in early HER2-positive breast cancer.

    Summary
    EudraCT number
    2018-001881-40
    Trial protocol
    DE   CZ   ES   PL   IT  
    Global end of trial date

    Results information
    Results version number
    v2(current)
    This version publication date
    13 Mar 2022
    First version publication date
    06 Feb 2022
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    BO40747
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03726879
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    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
    05 Feb 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Feb 2021
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    This study (also known as IMpassion050) is evaluating the efficacy and safety of atezolizumab compared with placebo when given in combination with neoadjuvant dose-dense anthracycline (doxorubicin) + cyclophosphamide followed by paclitaxel + trastuzumab + pertuzumab (ddAC-PacHP) in patients with early HER2-positive breast cancer (T2-4, N1-3, M0).
    Protection of trial subjects
    All study subjects were required to read and sign and Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    11 Jan 2019
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy
    Long term follow-up duration
    36 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 75
    Country: Number of subjects enrolled
    Canada: 26
    Country: Number of subjects enrolled
    Germany: 33
    Country: Number of subjects enrolled
    Italy: 46
    Country: Number of subjects enrolled
    Japan: 39
    Country: Number of subjects enrolled
    Korea, Republic of: 33
    Country: Number of subjects enrolled
    Poland: 31
    Country: Number of subjects enrolled
    Russian Federation: 45
    Country: Number of subjects enrolled
    Spain: 59
    Country: Number of subjects enrolled
    Taiwan: 49
    Country: Number of subjects enrolled
    United States: 8
    Country: Number of subjects enrolled
    Czechia: 10
    Worldwide total number of subjects
    454
    EEA total number of subjects
    179
    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)
    411
    From 65 to 84 years
    43
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 74 centers in 12 countries.

    Pre-assignment
    Screening details
    A total of 669 participants were screened, of which a total of 454 participants were enrolled.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Atezolizumab +ddAC-PacHP
    Arm description
    Participants received atezolizumab (atezo) 840 mg IV Q2W for 4 cycles during neoadjuvant phase with ddAC (doxorubicin 60 mg/m2 & cyclophosphamide 600 mg/m2 IV), followed by atezo 1200 mg IV Q3W for 4 cycles with paclitaxel 80 mg/m2 IV weekly for 12 continuous weeks, trastuzumab 6 mg/kg IV (with initial 8mg/kg IV loading dose) Q3W for 4 cycles, & pertuzumab 420 mg IV (with initial 840-mg IV loading dose) Q3W for 4 cycles. During adjuvant phase, participants continued to receive following study treatments Q3W to complete up to 1 year HER2-target therapy inclusive of therapy given both in neoadjuvant and adjuvant setting: atezo 1200 mg IV Q3W, trastuzumab 6 mg/kg IV (with initial 8-mg/kg IV loading dose) Q3W, & pertuzumab 420 mg IV (with initial 840-mg IV loading dose) Q3W. Participants who did not achieve pCR had option of receiving blinded atezo+trastuzumab emtansine post surgery for 14 cycles. In response to USM DIL dated 3 Feb 2021 treatment with atezo was discontinued.
    Arm type
    Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab was administered by intravenous infusion at a dose of 840 milligrams (mg) every 2 weeks (Q2W) for 4 cycles during neoadjuvant phase followed by atezolizumab 1200 mg IV every 3 weeks (Q3W) for 4 cycles. During the adjuvant phase, participants continued to receive atezolizumab 1200 mg IV Q3W. In response to USM DIL dated 3 Feb 2021 treatment with atezolizumab must be discontinued.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Doxorubicin was administered by IV infusion in the neoadjuvant setting at a dosage of 60 mg/m^2 on Day 2 of a 14 day cycle for cylces 1-4.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide was administered by IV infusion in the neoadjuvant setting at a dosage of 600 mg/m^2 on Day 2 of a 14 day cycle for cylces 1-4.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel was administered by IV infusion in the neoadjuvant setting at a dosage of 80 mg/m^2 for 12 continuous weeks (cycles 5-8).

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Herceptin
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab was administered on Day 1 of a 21-day cycle as an 8-mg/kilogram(kg) loading dose and then a 6 mg/kg IV Q3W up to 52 weeks.

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    Other name
    Perjeta
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pertuzumab was administered on Day 1 of a 21-day cycle as a fixed non-weight-based dose of 840-mg IV loading dose and then 420 mg IV Q3W up to 52 weeks.

    Investigational medicinal product name
    Trastuzumab Emtansine
    Investigational medicinal product code
    Other name
    Kadcyla
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab emtansine was administered at a dose of 3.6 mg/kg IV infusion Q3W.

    Arm title
    Placebo + ddAC-PacHP
    Arm description
    Participants received placebo 840 mg IV Q2W for 4 cycles during neoadjuvant phase with ddAC (doxorubicin 60 mg/m2 & cyclophosphamide 600 mg/m2 IV), followed by placebo 1200 mg IV Q3W for 4 cycles with paclitaxel 80 mg/m2 IV weekly for 12 continuous weeks, trastuzumab 6 mg/kg IV (with initial 8-mg/kg IV loading dose) Q3W for 4 cycles & pertuzumab 420 mg IV (with initial 840-mg IV loading dose) Q3W for 4 cycles. During adjuvant phase, participants continued to receive following study treatments Q3W to complete up to 1 year HER2-target therapy inclusive of therapy given both in neoadjuvant & adjuvant setting: placebo 1200 mg IV Q3W, trastuzumab 6 mg/kg IV (with initial 8-mg/kg IV loading dose) Q3W, & pertuzumab 420 mg IV (with initial 840-mg IV loading dose) Q3W. Participants who did not achieve pCR had option of receiving blinded atezolizumab + trastuzumab emtansine post surgery for 14 cycles. In response to USM DIL, dated 3 Feb 2021 treatment with placebo was discontinued.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo was administered by intravenous infusion at a dose of 840 mg Q2W for 4 cycles during neoadjuvant phase followed by placebo 1200 mg IV Q3W for 4 cycles. During the adjuvant phase, participants continued to receive placebo 1200 mg IV Q3W. In response to USM DIL dated 3 Feb 2021 treatment with placebo must be discontinued.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide was administered by IV infusion in the neoadjuvant setting at a dosage of 600 mg/m^2 on Day 2 of a 14 day cycle for cylces 1-4.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Doxorubicin was administered by IV infusion in the neoadjuvant setting at a dosage of 60 mg/m^2 on Day 2 of a 14 day cycle for cylces 1-4.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel was administered by IV infusion in the neoadjuvant setting at a dosage of 80 mg/m^2 for 12 continuous weeks (cycles 5-8).

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Herceptin
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab was administered on Day 1 of a 21-day cycle as an 8-mg/kg loading dose and then a 6 mg/kg IV Q3W up to 52 weeks.

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    Other name
    Perjeta
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pertuzumab was administered on Day 1 of a 21-day cycle as a fixed non-weight-based dose of 840-mg IV loading dose and then 420 mg IV Q3W up to 52 weeks.

    Investigational medicinal product name
    Trastuzumab Emtansine
    Investigational medicinal product code
    Other name
    Kadcyla
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab emtansine was administered at a dose of 3.6 mg/kg IV infusion Q3W.

    Notes
    [1] - The roles blinded appear to be inconsistent with a double blind trial.
    Justification: The roles blinded are correct
    Number of subjects in period 1
    Atezolizumab +ddAC-PacHP Placebo + ddAC-PacHP
    Started
    226
    228
    Completed
    0
    0
    Not completed
    226
    228
         Consent withdrawn by subject
    5
    5
         Physician decision
    -
    2
         Continuing on Study
    215
    215
         Death
    6
    4
         TSH result is unstable
    -
    1
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Atezolizumab +ddAC-PacHP
    Reporting group description
    Participants received atezolizumab (atezo) 840 mg IV Q2W for 4 cycles during neoadjuvant phase with ddAC (doxorubicin 60 mg/m2 & cyclophosphamide 600 mg/m2 IV), followed by atezo 1200 mg IV Q3W for 4 cycles with paclitaxel 80 mg/m2 IV weekly for 12 continuous weeks, trastuzumab 6 mg/kg IV (with initial 8mg/kg IV loading dose) Q3W for 4 cycles, & pertuzumab 420 mg IV (with initial 840-mg IV loading dose) Q3W for 4 cycles. During adjuvant phase, participants continued to receive following study treatments Q3W to complete up to 1 year HER2-target therapy inclusive of therapy given both in neoadjuvant and adjuvant setting: atezo 1200 mg IV Q3W, trastuzumab 6 mg/kg IV (with initial 8-mg/kg IV loading dose) Q3W, & pertuzumab 420 mg IV (with initial 840-mg IV loading dose) Q3W. Participants who did not achieve pCR had option of receiving blinded atezo+trastuzumab emtansine post surgery for 14 cycles. In response to USM DIL dated 3 Feb 2021 treatment with atezo was discontinued.

    Reporting group title
    Placebo + ddAC-PacHP
    Reporting group description
    Participants received placebo 840 mg IV Q2W for 4 cycles during neoadjuvant phase with ddAC (doxorubicin 60 mg/m2 & cyclophosphamide 600 mg/m2 IV), followed by placebo 1200 mg IV Q3W for 4 cycles with paclitaxel 80 mg/m2 IV weekly for 12 continuous weeks, trastuzumab 6 mg/kg IV (with initial 8-mg/kg IV loading dose) Q3W for 4 cycles & pertuzumab 420 mg IV (with initial 840-mg IV loading dose) Q3W for 4 cycles. During adjuvant phase, participants continued to receive following study treatments Q3W to complete up to 1 year HER2-target therapy inclusive of therapy given both in neoadjuvant & adjuvant setting: placebo 1200 mg IV Q3W, trastuzumab 6 mg/kg IV (with initial 8-mg/kg IV loading dose) Q3W, & pertuzumab 420 mg IV (with initial 840-mg IV loading dose) Q3W. Participants who did not achieve pCR had option of receiving blinded atezolizumab + trastuzumab emtansine post surgery for 14 cycles. In response to USM DIL, dated 3 Feb 2021 treatment with placebo was discontinued.

    Reporting group values
    Atezolizumab +ddAC-PacHP Placebo + ddAC-PacHP Total
    Number of subjects
    226 228 454
    Age Categorical
    Units: Participants
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    204 207 411
        From 65-84 years
    22 21 43
        85 years and over
    0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    50.3 ( 10.7 ) 50.8 ( 10.4 ) -
    Sex: Female, Male
    Units: Participants
        Male
    1 1 2
        Female
    225 227 452
    Race
    Units: Subjects
        American Indian or Alaska Native
    1 1 2
        Asian
    62 66 128
        Black or African American
    8 13 21
        White
    149 142 291
        Multiple
    2 3 5
        Unknown
    4 3 7
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    26 33 59
        Not Hispanic or Latino
    195 191 386
        Not Reported
    5 4 9

    End points

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    End points reporting groups
    Reporting group title
    Atezolizumab +ddAC-PacHP
    Reporting group description
    Participants received atezolizumab (atezo) 840 mg IV Q2W for 4 cycles during neoadjuvant phase with ddAC (doxorubicin 60 mg/m2 & cyclophosphamide 600 mg/m2 IV), followed by atezo 1200 mg IV Q3W for 4 cycles with paclitaxel 80 mg/m2 IV weekly for 12 continuous weeks, trastuzumab 6 mg/kg IV (with initial 8mg/kg IV loading dose) Q3W for 4 cycles, & pertuzumab 420 mg IV (with initial 840-mg IV loading dose) Q3W for 4 cycles. During adjuvant phase, participants continued to receive following study treatments Q3W to complete up to 1 year HER2-target therapy inclusive of therapy given both in neoadjuvant and adjuvant setting: atezo 1200 mg IV Q3W, trastuzumab 6 mg/kg IV (with initial 8-mg/kg IV loading dose) Q3W, & pertuzumab 420 mg IV (with initial 840-mg IV loading dose) Q3W. Participants who did not achieve pCR had option of receiving blinded atezo+trastuzumab emtansine post surgery for 14 cycles. In response to USM DIL dated 3 Feb 2021 treatment with atezo was discontinued.

    Reporting group title
    Placebo + ddAC-PacHP
    Reporting group description
    Participants received placebo 840 mg IV Q2W for 4 cycles during neoadjuvant phase with ddAC (doxorubicin 60 mg/m2 & cyclophosphamide 600 mg/m2 IV), followed by placebo 1200 mg IV Q3W for 4 cycles with paclitaxel 80 mg/m2 IV weekly for 12 continuous weeks, trastuzumab 6 mg/kg IV (with initial 8-mg/kg IV loading dose) Q3W for 4 cycles & pertuzumab 420 mg IV (with initial 840-mg IV loading dose) Q3W for 4 cycles. During adjuvant phase, participants continued to receive following study treatments Q3W to complete up to 1 year HER2-target therapy inclusive of therapy given both in neoadjuvant & adjuvant setting: placebo 1200 mg IV Q3W, trastuzumab 6 mg/kg IV (with initial 8-mg/kg IV loading dose) Q3W, & pertuzumab 420 mg IV (with initial 840-mg IV loading dose) Q3W. Participants who did not achieve pCR had option of receiving blinded atezolizumab + trastuzumab emtansine post surgery for 14 cycles. In response to USM DIL, dated 3 Feb 2021 treatment with placebo was discontinued.

    Primary: Percentage of Participants with Pathological Complete Response (pCR) in the PD-L1-Positive Population (IC 1/2/3)

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    End point title
    Percentage of Participants with Pathological Complete Response (pCR) in the PD-L1-Positive Population (IC 1/2/3)
    End point description
    pCR is defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (NAST) (i.e., ypT0/is ypN0 in the current American Joint Committee on Cancer [AJCC] staging system, 8th edition). The PD-L1-positive population is defined as participants in the Intent-to-Treat (ITT) population whose PD-L1 status is IC1/2/3 at the time of randomization.
    End point type
    Primary
    End point timeframe
    From randomization to approximately 6 months
    End point values
    Atezolizumab +ddAC-PacHP Placebo + ddAC-PacHP
    Number of subjects analysed
    109
    109
    Units: Percentage of Particpants
        number (not applicable)
    64.2
    72.5
    Statistical analysis title
    Atezolizumab +ddAC-PacHP vs. Placebo + ddAC-PacHP
    Statistical analysis description
    Treatment comparison was made using Cochran-Mantel-Haenszel test stratified by disease stage (T2 vs. T3-4) and hormone receptor status (estrogen receptor (ER) positive and/or progesterone receptor (PgR) positive vs. ER negative and PgR negative).
    Comparison groups
    Atezolizumab +ddAC-PacHP v Placebo + ddAC-PacHP
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1846 [1]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.37
         upper limit
    1.21
    Notes
    [1] - The threshold for statistical significance was a p-value =0.048

    Primary: pCR in the ITT Population

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    End point title
    pCR in the ITT Population
    End point description
    pCR is defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (NAST) (i.e., ypT0/is ypN0 in the current American Joint Committee on Cancer [AJCC] staging system, 8th edition). The ITT population is defined as all randomized participants, regardless of whether the assigned study treatment was received.
    End point type
    Primary
    End point timeframe
    From randomization to approximately 6 months
    End point values
    Atezolizumab +ddAC-PacHP Placebo + ddAC-PacHP
    Number of subjects analysed
    226
    228
    Units: Percentage of Participants
        number (not applicable)
    62.4
    62.7
    Statistical analysis title
    Atezolizumab +ddAC-PacHP vs. Placebo + ddAC-PacHP
    Statistical analysis description
    Treatment comparison was made using Cochran-Mantel-Haenszel test stratified by disease stage (T2 vs. T3-4) and hormone receptor status (ER positive and/or PgR positive vs. ER negative and PgR negative).
    Comparison groups
    Atezolizumab +ddAC-PacHP v Placebo + ddAC-PacHP
    Number of subjects included in analysis
    454
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9551 [2]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.67
         upper limit
    1.46
    Notes
    [2] - The threshold for statistical significance was a p-value =0.002

    Secondary: Percentage of Participants with pCR Based on Hormone Receptor Status

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    End point title
    Percentage of Participants with pCR Based on Hormone Receptor Status
    End point description
    pCR (ypT0/is ypN0) based upon hormone receptor status (estrogen receptor [ER]/progesterone receptor [PgR] positive or ER/PgR negative). The ITT population is defined as all randomized participants, regardless of whether the assigned study treatment was received.
    End point type
    Secondary
    End point timeframe
    From randomization to approximately 24 months.
    End point values
    Atezolizumab +ddAC-PacHP Placebo + ddAC-PacHP
    Number of subjects analysed
    226
    228
    Units: Percentage of Participants
    number (not applicable)
        ER+ and/or PgR+ (n= 116, 117)
    50.9
    54.7
        ER- and/or PgR- (n= 110, 111)
    74.5
    71.2
    No statistical analyses for this end point

    Secondary: Percentage of Participants with pCR in the PD-L1-Negative Population

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    End point title
    Percentage of Participants with pCR in the PD-L1-Negative Population
    End point description
    pCR (ypT0/is ypN0) in the IC 0 Population. The PD-L1-negative population is defined as participants in the ITT population whose PD-L1 status is IC 0 at the time of randomization.
    End point type
    Secondary
    End point timeframe
    From randomization to approximately 24 months
    End point values
    Atezolizumab +ddAC-PacHP Placebo + ddAC-PacHP
    Number of subjects analysed
    117
    119
    Units: Percentage of Participants
        number (not applicable)
    60.7
    53.8
    No statistical analyses for this end point

    Secondary: Event-Free Survival (EFS)

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    End point title
    Event-Free Survival (EFS)
    End point description
    EFS defined as the time from randomization to the first documented disease recurrence, unequivocal tumor progression determined by the treating investigator, or death from any cause, whichever occurs first, in all patients and based upon hormone receptor status (ER/PgR positive or ER/PgR negative) and PD-L1 status (IC 0; IC 1/2/3). The ITT population is defined as all randomized participants, regardless of whether the assigned study treatment was received. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.
    End point type
    Secondary
    End point timeframe
    From randomization to first documented disease recurrence, unequivocal tumor progression determined by the treating investigator, or death from any cause (up to approximately 54 months)
    End point values
    Atezolizumab +ddAC-PacHP Placebo + ddAC-PacHP
    Number of subjects analysed
    0 [3]
    0 [4]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [3] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion
    [4] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    OS defined as the time from randomization to death from any cause in all patients and based upon hormone receptor status (ER/PgR positive or ER/PgR negative) and PD-L1 status (IC 0; IC 1/2/3). The ITT population is defined as all randomized participants, regardless of whether the assigned study treatment was received. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.
    End point type
    Secondary
    End point timeframe
    From randomization to date of death from any cause (up to approximately 54 months)
    End point values
    Atezolizumab +ddAC-PacHP Placebo + ddAC-PacHP
    Number of subjects analysed
    0 [5]
    0 [6]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [5] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion
    [6] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion
    No statistical analyses for this end point

    Secondary: Disease-Free Survival (DFS)

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    End point title
    Disease-Free Survival (DFS)
    End point description
    DFS defined as the time from surgery to the first documented disease recurrence or death from any cause, whichever occurs first, in all patients who undergo surgery and based upon hormone receptor status (ER/PgR positive or ER/PgR negative) and PD-L1 status (IC 0; IC 1/2/3). The ITT population is defined as all randomized participants, regardless of whether the assigned study treatment was received. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.
    End point type
    Secondary
    End point timeframe
    Time from surgery to first documented disease recurrence or death from any cause (up to approximately 54 months)
    End point values
    Atezolizumab +ddAC-PacHP Placebo + ddAC-PacHP
    Number of subjects analysed
    0 [7]
    0 [8]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [7] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion
    [8] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion
    No statistical analyses for this end point

    Secondary: Mean Changes From Baseline in Function (Role, Physical)

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    End point title
    Mean Changes From Baseline in Function (Role, Physical)
    End point description
    EORTC QLQ-C30 is a self-reported questionnaire that included functional scales (physical, role, cognitive, emotional, social), symptom scales (fatigue, pain, nausea/vomiting), global health scale/quality of life (GHS/QOL) and single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, financial difficulties). Questions 1-28 on the QLQ-C30 were on a 4-point scale (1=Not at All to 4=Very Much). Questions 29-30 (GHS scale) were on a 7-point scale (1=Very Poor to 7=Excellent). For this instrument, GHS/QOL and functional scales were linearly transformed so each score ranged 0-100, where lower scores indicate poorer functioning (e.g., worsening) and higher scores indicate better functioning (e.g., improvement). The patient-reported outcomes (PRO)-evaluable population is defined as participants in the ITT population with a baseline and at least 1 post-baseline PRO assessment. 9999999 = SD was non-estimable as only 1 participant was evaluated for this category.
    End point type
    Secondary
    End point timeframe
    Baseline; Day 1 of Cycle 1-9, on Day 1 of every other cycle thereafter until Cycle 22; at the treatment discontinuation or early termination visit and follow up visit. Cycle 1-4, each cycle is 14 days. Cycle 5-22, each cycle is 21 days.
    End point values
    Atezolizumab +ddAC-PacHP Placebo + ddAC-PacHP
    Number of subjects analysed
    223
    224
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Role: Baseline (n=223, 224)
    91.70 ( 16.28 )
    90.85 ( 20.26 )
        Role: Cycle (C) 2 Day (D) 1 (n=222, 222)
    -13.06 ( 23.02 )
    -9.83 ( 23.08 )
        Role: C3D1 (n=219, 220)
    -17.88 ( 26.20 )
    -15.15 ( 22.64 )
        Role: C4D1 (n=217, 216)
    -22.27 ( 27.04 )
    -17.98 ( 25.10 )
        Role: C5D1 (n=218, 219)
    -24.08 ( 28.21 )
    -19.79 ( 26.36 )
        Role: C6D1 (n=215, 216)
    -20.70 ( 25.46 )
    -18.60 ( 25.01 )
        Role: C7D1 (n=210, 210)
    -19.21 ( 25.50 )
    -16.67 ( 26.34 )
        Role: C8D1 (n=211, 208)
    -21.25 ( 26.48 )
    -17.79 ( 26.39 )
        Role: Adjuvant Week 1 D1 (n=206, 202)
    -22.82 ( 26.70 )
    -26.24 ( 31.27 )
        Role: Adjuvant Week 7 D43 (n=183, 176)
    -15.48 ( 22.31 )
    -15.15 ( 26.50 )
        Role: Adjuvant Week 13 D85 (n=171, 163)
    -14.42 ( 23.77 )
    -15.24 ( 26.99 )
        Role: Adjuvant Week 19 D127 (n=155, 147)
    -14.30 ( 24.26 )
    -15.42 ( 25.74 )
        Role: Adjuvant Week 25 D169 (n=134, 127)
    -13.68 ( 24.00 )
    -15.88 ( 22.99 )
        Role: Adjuvant Week 31 D211 (n=112, 110)
    -13.24 ( 23.69 )
    -14.55 ( 24.43 )
        Role: Adjuvant Week 37 D253 (n=91, 94)
    -9.34 ( 21.11 )
    -15.43 ( 27.35 )
        Role: End of Treatment (EOT) (n=108, 116)
    -14.04 ( 25.18 )
    -18.10 ( 29.04 )
        Role: Follow-Up (FU) 1 D1 (n=62, 68)
    -11.02 ( 25.06 )
    -17.16 ( 23.21 )
        Role: FU2D92 (n=20, 33)
    -9.17 ( 23.24 )
    -14.65 ( 25.94 )
        Role: FU3D183 (n=3, 8)
    -16.67 ( 16.67 )
    -10.42 ( 21.71 )
        Role: FU4D274 (n=3, 6)
    -27.78 ( 25.46 )
    -25.00 ( 9.13 )
        Role: FU5D457 (n=0, 1)
    0.0 ( 0.0 )
    -33.33 ( 9999999 )
        Physical: Baseline (n=223, 224)
    92.74 ( 11.60 )
    92.20 ( 12.92 )
        Physical: C2D1 (n=222, 221)
    -4.32 ( 9.75 )
    -3.88 ( 13.44 )
        Physical: C3D1 (n=219, 220)
    -6.82 ( 13.39 )
    -7.18 ( 12.91 )
        Physical: C4D1 (n=217, 216)
    -11.98 ( 17.67 )
    -9.48 ( 14.65 )
        Physical: C5D1 (n=218, 219)
    -12.84 ( 18.19 )
    -10.67 ( 15.91 )
        Physical: C6D1 (n=215, 216)
    -12.25 ( 15.97 )
    -11.40 ( 17.05 )
        Physical: C7D1 (n=210, 210)
    -11.33 ( 14.86 )
    -11.45 ( 17.43 )
        Physical: C8D1 (n=211, 208)
    -13.30 ( 17.11 )
    -11.56 ( 17.54 )
        Physical: Adjuvant Week 1 D1 (n=206, 202)
    -12.27 ( 18.26 )
    -12.19 ( 19.27 )
        Physical: Adjuvant Week 7 D43 (n=183, 176)
    -8.96 ( 14.74 )
    -8.60 ( 16.33 )
        Physical: Adjuvant Week 13 D85 (n=171, 163)
    -8.38 ( 14.97 )
    -8.88 ( 15.04 )
        Physical: Adjuvant Week 19 D127 (n=154, 147)
    -9.22 ( 15.17 )
    -10.03 ( 15.52 )
        Physical: Adjuvant Week 25 D169 (n=134, 127)
    -9.35 ( 16.19 )
    -8.45 ( 14.34 )
        Physical: Adjuvant Week 31 D211 (n=112, 110)
    -7.80 ( 13.69 )
    -9.88 ( 15.84 )
        Physical: Adjuvant Week 37 D253 (n=91, 94)
    -7.77 ( 13.67 )
    -10.78 ( 16.82 )
        EOT (n=109, 116)
    -8.20 ( 15.78 )
    -13.05 ( 19.17 )
        Physical: FU1D1 (n=62, 68)
    -8.06 ( 18.11 )
    -11.57 ( 19.29 )
        Physical: FU2D92 (n=20, 33)
    -3.33 ( 12.52 )
    -9.90 ( 15.73 )
        Physical: FU3D183 (n=3, 8)
    2.22 ( 16.78 )
    -14.17 ( 7.51 )
        Physical: FU4D274 (n=3, 6)
    0.00 ( 20.00 )
    -6.67 ( 11.93 )
        Physical: FU5D457 (n=0, 1)
    0.0 ( 0.0 )
    60.00 ( 9999999 )
    No statistical analyses for this end point

    Secondary: Mean Changes From Baseline in Global Health Status

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    End point title
    Mean Changes From Baseline in Global Health Status
    End point description
    EORTC QLQ-C30 is a self-reported questionnaire that included functional scales (physical, role, cognitive, emotional, social), symptom scales (fatigue, pain, nausea/vomiting), GHS/QOL and single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, financial difficulties). Questions 1-28 on the QLQ-C30 were on a 4-point scale (1=Not at All to 4=Very Much). Questions 29-30 (GHS scale) were on a 7-point scale (1=Very Poor to 7=Excellent). For this instrument, GHS/QOL and functional scales were linearly transformed so each score ranged 0-100, where lower scores indicate poorer functioning (e.g., worsening) and higher scores indicate better functioning (e.g., improvement). The PRO-evaluable population is defined as participants in the ITT population with a baseline and at least 1 post-baseline PRO assessment. 9999999 = SD was non-estimable as only 1 participant was evaluated for this category.
    End point type
    Secondary
    End point timeframe
    Baseline; Day 1 of Cycle 1-9, on Day 1 of every other cycle thereafter until Cycle 22; at the treatment discontinuation or early termination visit and follow up visit. Cycle 1-4, each cycle is 14 days. Cycle 5-22, each cycle is 21 days.
    End point values
    Atezolizumab +ddAC-PacHP Placebo + ddAC-PacHP
    Number of subjects analysed
    223
    224
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=223, 224)
    76.49 ( 19.33 )
    76.79 ( 19.05 )
        C2D1 (n=222, 222)
    -7.28 ( 19.70 )
    -6.31 ( 19.54 )
        C3D1 (n=219, 220)
    -10.96 ( 22.16 )
    -8.33 ( 20.93 )
        C4D1 (n=217, 216)
    -13.67 ( 22.47 )
    -10.88 ( 21.51 )
        C5D1 (n=218, 219)
    -14.14 ( 23.76 )
    -12.63 ( 23.66 )
        C6D1 (n=215, 216)
    -12.33 ( 22.10 )
    -9.99 ( 20.96 )
        C7D1 (n=210, 210)
    -11.47 ( 19.81 )
    -10.52 ( 21.59 )
        C8D1 (n=211, 208)
    -12.72 ( 22.45 )
    -10.86 ( 22.66 )
        Adjuvant Week 1 D1 (n=206, 202)
    -7.89 ( 21.89 )
    -7.14 ( 23.68 )
        Adjuvant Week 7 D43 (n=183, 176)
    -7.51 ( 22.97 )
    -5.21 ( 21.96 )
        Adjuvant Week 13 D85 (n=171, 163)
    -7.07 ( 22.31 )
    -6.75 ( 21.13 )
        Adjuvant Week 19 D127 (n=155, 147)
    -7.20 ( 21.47 )
    -6.01 ( 20.52 )
        Adjuvant Week 25 D169 (n=134, 127)
    -8.02 ( 21.10 )
    -5.05 ( 20.39 )
        Adjuvant Week 31 D211 (n=112, 110)
    -7.29 ( 21.75 )
    -7.80 ( 22.56 )
        Adjuvant Week 37 D253 (n=91, 94)
    -5.95 ( 21.71 )
    -6.03 ( 20.72 )
        EOT (n=109, 116)
    -5.96 ( 22.08 )
    -9.41 ( 24.29 )
        FU1D1 (n=62, 68)
    -3.90 ( 21.64 )
    -5.15 ( 21.01 )
        FU2D92 (n=20, 33)
    -1.25 ( 19.55 )
    -3.03 ( 16.11 )
        FU3D183 (n=3, 8)
    -8.33 ( 8.33 )
    -7.29 ( 15.06 )
        FU4D274 (n=3, 6)
    -13.89 ( 12.73 )
    -31.94 ( 37.42 )
        FU5D457 (n=0, 1)
    0.0 ( 0.0 )
    -16.67 ( 9999999 )
    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
    The safety-evaluable population is defined as participants who received at least one dose of any study drug.
    End point type
    Secondary
    End point timeframe
    From randomization up until clinical cut-off date (approximately 24 months)
    End point values
    Atezolizumab +ddAC-PacHP Placebo + ddAC-PacHP
    Number of subjects analysed
    226
    225
    Units: Percentage of Participants
        number (not applicable)
    100
    100
    No statistical analyses for this end point

    Secondary: Maximum Serum Concentration (Cmax) of Atezolizumab

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    End point title
    Maximum Serum Concentration (Cmax) of Atezolizumab [9]
    End point description
    Cmax is the maximum (or peak) concentration that a study drug achieves in the body. The pharmacokinetic (PK)-evaluable population is defined as all participants who received any dose of study medication and who have at least one post-baseline PK sample available.
    End point type
    Secondary
    End point timeframe
    30 minutes post infusion on Day 1 Cycle (C) 1.
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analyses for this end point. Atezolizumab was not administered in the placebo arm.
    End point values
    Atezolizumab +ddAC-PacHP
    Number of subjects analysed
    219
    Units: micrograms/milliliters (ug/mL)
        arithmetic mean (standard deviation)
    348 ( 122 )
    No statistical analyses for this end point

    Secondary: Minimum Serum Concentration (Cmin) of Atezolizumab

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    End point title
    Minimum Serum Concentration (Cmin) of Atezolizumab [10]
    End point description
    Cmin is the minimum (or trough) concentration that a study drug achieves in the body. The PK-evaluable population is defined as all participants who received any dose of study medication and who have at least one post-baseline PK sample available.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1 Cycle (C) 2, 3, 4, 8, 12, 16, ATDV (an average of 1 year). C 2-4, each C is 14 days. C 8-16, each C is 21 days. With protocol version 5, collection is only required ATDV/completion (an average of 1 year).
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analyses for this end point. Atezolizumab was not administered in the placebo arm.
    End point values
    Atezolizumab +ddAC-PacHP
    Number of subjects analysed
    226
    Units: ug/mL
    arithmetic mean (standard deviation)
        C2D1/predose (n=222)
    103 ( 40.3 )
        C3D1/predose (n=214)
    163 ( 44.4 )
        C4D1/predose (n=212)
    204 ( 51.9 )
        C8D1/predose (n=203)
    225 ( 97.1 )
        C12D1/predose (n=166)
    217 ( 101 )
        C16D1/predose (n=133)
    226 ( 114 )
    No statistical analyses for this end point

    Secondary: Trough Concentration (Ctrough) for Pertuzumab and Trastuzumab in Serum

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    End point title
    Trough Concentration (Ctrough) for Pertuzumab and Trastuzumab in Serum
    End point description
    The PK-evaluable population is defined as all participants who received any dose of study medication and who have at least one post-baseline PK sample available.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1 Cycle (C) 8, 12, and at treatment discontinuation visit (ATDV) (an average of 1 year). C 1-4, each C is 14 days. C 8-12, each C is 21 days. With protocol version 5, collection is only required ATDV/completion (an average of 1 year).
    End point values
    Atezolizumab +ddAC-PacHP Placebo + ddAC-PacHP
    Number of subjects analysed
    226
    225
    Units: ug/mL
    arithmetic mean (standard deviation)
        Pertuzumab: C8D1/predose (n=205, 201)
    93.2 ( 40.7 )
    94.8 ( 39.8 )
        Pertuzumab: C12D1/predose (n=150, 147)
    87.7 ( 58.4 )
    91.6 ( 59.7 )
        Trastuzumab: C8D1/predose (n=205, 201)
    58.5 ( 29.1 )
    56.5 ( 23.9 )
        Trastuzumab: C12D1/predose (n=150, 147)
    62.4 ( 32.7 )
    60.4 ( 30.9 )
    No statistical analyses for this end point

    Secondary: Cmax of Trastuzumab Emtansine in Serum

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    End point title
    Cmax of Trastuzumab Emtansine in Serum
    End point description
    Cmax is the maximum (or peak) concentration that a study drug achieves in the body. The PK-evaluable population is defined as all participants who received any dose of study medication and who have at least one post-baseline PK sample available. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycle 9 and Cycle 12, at treatment disontinuation visit (an average of 1 year). Cycle 9 and 12 are each 21 days. With protocol version 5, collection is only required at the time of treatment discontinuation/completion (an average of 1 year).
    End point values
    Atezolizumab +ddAC-PacHP Placebo + ddAC-PacHP
    Number of subjects analysed
    0 [11]
    0 [12]
    Units: ug/mL
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [11] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion
    [12] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion
    No statistical analyses for this end point

    Secondary: Cmin of Trastuzumab Emtansine in Serum

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    End point title
    Cmin of Trastuzumab Emtansine in Serum
    End point description
    Cmin is the minimum (or trough) concentration that a study drug achieves in the body. The PK-evaluable population is defined as all participants who received any dose of study medication and who have at least one post-baseline PK sample available. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.
    End point type
    Secondary
    End point timeframe
    Pre-dosDay 1 of Cycle 9 and Cycle 12, at treatment disontinuation visit (an average of 1 year). Cycle 9 and 12 are each 21 days. With protocol version 5, collection is only required at the time of treatment discontinuation/completion (an average of 1 year
    End point values
    Atezolizumab +ddAC-PacHP Placebo + ddAC-PacHP
    Number of subjects analysed
    0 [13]
    0 [14]
    Units: ug/mL
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [13] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion
    [14] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion
    No statistical analyses for this end point

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

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    End point title
    Number of Participants with Treatment-Emergent Anti-Drug Antibodies (ADAs) to Atezolizumab [15]
    End point description
    Participants were considered to be treatment-emergent ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following study drug exposure (treatment-induced ADA response), or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 0.60 titer units greater than the titer of the baseline sample (treatment-enhanced ADA response). Participants were considered to be treatment-emergent ADA-negative if they were ADA-negative or were missing data at baseline and all post-baseline samples were negative, or if they were ADA-positive at baseline but did not have any post-baseline samples with a titer that was at least 0.60 titer units greater than the titer of the baseline sample (treatment unaffected). The immunogenicity analysis included all safety evealuable participants who had at least one baseline or post-baseline ADA result from at least one sample.
    End point type
    Secondary
    End point timeframe
    Day 1 Cycle (C) 1, 2, 3, 4, 8, 12, 16, at treatment discontinuation visit (ATDV) (an average of 1 year). C 1-4, each C is 14 days. C 8-16, each C is 21 days. With protocol version 5, collection is only required ATDV/completion (an average of 1 year).
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analyses for this end point. Atezolizumab was not administered in the placebo arm.
    End point values
    Atezolizumab +ddAC-PacHP
    Number of subjects analysed
    225
    Units: Participants
    number (not applicable)
        Baseline (BL): ADA Positive
    1
        BL: ADA Negative
    224
        Post-BL: Treatment-Emergent ADA Positive
    7
        Post-BL: Treatment-Emergent ADA Negative
    218
    No statistical analyses for this end point

    Secondary: Number of Participants with Treatment-Emergent ADAs to Trastuzumab

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    End point title
    Number of Participants with Treatment-Emergent ADAs to Trastuzumab
    End point description
    Participants were considered to be treatment-emergent ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following study drug exposure (treatment-induced ADA response), or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 0.60 titer units greater than the titer of the baseline sample (treatment-enhanced ADA response). Participants were considered to be treatment-emergent ADA-negative if they were ADA-negative or were missing data at baseline and all post-baseline samples were negative, or if they were ADA-positive at baseline but did not have any post-baseline samples with a titer that was at least 0.60 titer units greater than the titer of the baseline sample (treatment unaffected). The immunogenicity analysis included all safety evealuable participants who had at least one baseline or post-baseline ADA result from at least one sample.
    End point type
    Secondary
    End point timeframe
    Day 1 Cycle (C) 1, 8, 12 and at treatment discontinuation visit (ATDV) (an average of 1 year). C 1-4, each C is 14 days. C 8-12, each C is 21 days. With protocol version 5, collection is only required ATDV/completion (an average of 1 year).
    End point values
    Atezolizumab +ddAC-PacHP Placebo + ddAC-PacHP
    Number of subjects analysed
    225
    225
    Units: Participants
    number (not applicable)
        BL: ADA Positive (n=220, 211)
    2
    1
        BL: ADA Negative (220, 211)
    218
    210
        Post-BL: Trt.-Emergent ADA Positive (n=216, 214)
    1
    0
        Post-BL: Trt.-Emergent ADA Negative (n=216, 214)
    215
    214
    No statistical analyses for this end point

    Secondary: Number of Participants with Treatment-Emergent ADAs to Pertuzumab

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    End point title
    Number of Participants with Treatment-Emergent ADAs to Pertuzumab
    End point description
    Participants were considered to be treatment-emergent ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following study drug exposure (treatment-induced ADA response), or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 0.60 titer units greater than the titer of the baseline sample (treatment-enhanced ADA response). Participants were considered to be treatment-emergent ADA-negative if they were ADA-negative or were missing data at baseline and all post-baseline samples were negative, or if they were ADA-positive at baseline but did not have any post-baseline samples with a titer that was at least 0.60 titer units greater than the titer of the baseline sample (treatment unaffected). The immunogenicity analysis included all safety evealuable participants who had at least one baseline or post-baseline ADA result from at least one sample.
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycle (C) 1, 8, 12, and at treatment discontinuation visit (ATDV) (an average of 1 year). C 1-4, each C is 14 days. C 8-12, each C is 21 days. With protocol version 5, collection is only required ATDV/completion (an average of 1 year).
    End point values
    Atezolizumab +ddAC-PacHP Placebo + ddAC-PacHP
    Number of subjects analysed
    225
    225
    Units: Participants
    number (not applicable)
        BL: ADA Positive (n=221, 211)
    6
    3
        BL: ADA Negative (n=221, 211)
    215
    208
        Post-BL: Trt-Emergent ADA Positive (n=216, 214)
    13
    12
        Post-BL: Trt-Emergent ADA Negative (n=216, 214)
    203
    202
    No statistical analyses for this end point

    Secondary: Number of Participants with Treatment-Emergent ADAs to Trastuzumab Emtansine

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    End point title
    Number of Participants with Treatment-Emergent ADAs to Trastuzumab Emtansine
    End point description
    Participants were considered to be treatment-emergent ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following study drug exposure (treatment-induced ADA response), or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 0.60 titer units greater than the titer of the baseline sample (treatment-enhanced ADA response). Participants were considered to be treatment-emergent ADA-negative if they were ADA-negative or were missing data at baseline and all post-baseline samples were negative, or if they were ADA-positive at baseline but did not have any post-baseline samples with a titer that was at least 0.60 titer units greater than the titer of the baseline sample (treatment unaffected). Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycle 9 and Cycle 12, at treatment disontinuation visit (an average of 1 year). Cycle 9 and 12 are each 21 days. With protocol version 5, collection is only required at the time of treatment discontinuation/completion (an average of 1 year).
    End point values
    Atezolizumab +ddAC-PacHP Placebo + ddAC-PacHP
    Number of subjects analysed
    0 [16]
    0 [17]
    Units: Participants
        number (not applicable)
    Notes
    [16] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion
    [17] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion
    No statistical analyses for this end point

    Secondary: Percentage of Particpants with pCR Based on PIK3CA Mutation Status

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    End point title
    Percentage of Particpants with pCR Based on PIK3CA Mutation Status
    End point description
    pCR is defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (NAST) (i.e., ypT0/is ypN0 in the current American Joint Committee on Cancer [AJCC] staging system, 8th edition). The ITT population is defined as all randomized participants, regardless of whether the assigned study treatment was received.
    End point type
    Secondary
    End point timeframe
    From randomization to approximately 24 months
    End point values
    Atezolizumab +ddAC-PacHP Placebo + ddAC-PacHP
    Number of subjects analysed
    226
    228
    Units: Percentage of participants with pCR
    number (not applicable)
        Mutated (n pCR=40, 34)
    59.7
    55.7
        Wildtype (n pCR=98, 101)
    65.3
    65.2
        Missing (n pCR=3, 8)
    33.3
    66.7
    No statistical analyses for this end point

    Secondary: EFS Based on PIK3CA Mutation Status

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    End point title
    EFS Based on PIK3CA Mutation Status
    End point description
    Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.
    End point type
    Secondary
    End point timeframe
    From randomization to first documented disease recurrence, unequivocal tumor progression determined by the treating investigator, or death from any cause (up to approximately 54 months)
    End point values
    Atezolizumab +ddAC-PacHP Placebo + ddAC-PacHP
    Number of subjects analysed
    0 [18]
    0 [19]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [18] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion
    [19] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion
    No statistical analyses for this end point

    Secondary: DFS Based on PIK3CA Mutation Status

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    End point title
    DFS Based on PIK3CA Mutation Status
    End point description
    Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.
    End point type
    Secondary
    End point timeframe
    Time from surgery to first documented disease recurrence or death from any cause (up to approximately 54 months)
    End point values
    Atezolizumab +ddAC-PacHP Placebo + ddAC-PacHP
    Number of subjects analysed
    0 [20]
    0 [21]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [20] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion
    [21] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion
    No statistical analyses for this end point

    Secondary: OS Based on PIK3CA Mutation Status

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    End point title
    OS Based on PIK3CA Mutation Status
    End point description
    Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.
    End point type
    Secondary
    End point timeframe
    From randomization to date of death from any cause (up to approximately 54 months)
    End point values
    Atezolizumab +ddAC-PacHP Placebo + ddAC-PacHP
    Number of subjects analysed
    0 [22]
    0 [23]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [22] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion
    [23] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up until clinical cut off date (approximately 24 months)
    Adverse event reporting additional description
    AEs were recorded for the safety-evaluable population which included all randomized participants who received any dose of study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Placebo + ddAC-PacHP
    Reporting group description
    Participants received placebo 840 mg IV Q2W for 4 cycles during neoadjuvant phase with ddAC (doxorubicin 60 mg/m2 & cyclophosphamide 600 mg/m2 IV), followed by placebo 1200 mg IV Q3W for 4 cycles with paclitaxel 80 mg/m2 IV weekly for 12 continuous weeks, trastuzumab 6 mg/kg IV (with initial 8-mg/kg IV loading dose) Q3W for 4 cycles & pertuzumab 420 mg IV (with initial 840-mg IV loading dose) Q3W for 4 cycles. During adjuvant phase, participants continued to receive following study treatments Q3W to complete up to 1 year HER2-target therapy inclusive of therapy given both in neoadjuvant & adjuvant setting: placebo 1200 mg IV Q3W, trastuzumab 6 mg/kg IV (with initial 8-mg/kg IV loading dose) Q3W, & pertuzumab 420 mg IV (with initial 840-mg IV loading dose) Q3W. Participants who did not achieve pCR had option of receiving blinded atezolizumab + trastuzumab emtansine post surgery for 14 cycles. In response to USM DIL, dated 3 Feb 2021 treatment with placebo was discontinued.

    Reporting group title
    Atezolizumab +ddAC-PacHP
    Reporting group description
    Participants received atezolizumab (atezo) 840 mg IV Q2W for 4 cycles during neoadjuvant phase with ddAC (doxorubicin 60 mg/m2 & cyclophosphamide 600 mg/m2 IV), followed by atezo 1200 mg IV Q3W for 4 cycles with paclitaxel 80 mg/m2 IV weekly for 12 continuous weeks, trastuzumab 6 mg/kg IV (with initial 8mg/kg IV loading dose) Q3W for 4 cycles, & pertuzumab 420 mg IV (with initial 840-mg IV loading dose) Q3W for 4 cycles. During adjuvant phase, participants continued to receive following study treatments Q3W to complete up to 1 year HER2-target therapy inclusive of therapy given both in neoadjuvant and adjuvant setting: atezo 1200 mg IV Q3W, trastuzumab 6 mg/kg IV (with initial 8-mg/kg IV loading dose) Q3W, & pertuzumab 420 mg IV (with initial 840-mg IV loading dose) Q3W. Participants who did not achieve pCR had option of receiving blinded atezo+trastuzumab emtansine post surgery for 14 cycles. In response to USM DIL dated 3 Feb 2021 treatment with atezo was discontinued.

    Serious adverse events
    Placebo + ddAC-PacHP Atezolizumab +ddAC-PacHP
    Total subjects affected by serious adverse events
         subjects affected / exposed
    44 / 225 (19.56%)
    62 / 226 (27.43%)
         number of deaths (all causes)
    4
    6
         number of deaths resulting from adverse events
    0
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    MENINGIOMA
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NERVOUS SYSTEM NEOPLASM BENIGN
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    SUBCLAVIAN VEIN THROMBOSIS
         subjects affected / exposed
    0 / 225 (0.00%)
    2 / 226 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THROMBOSIS
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VASCULAR PAIN
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    JUGULAR VEIN THROMBOSIS
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         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
    PYREXIA
         subjects affected / exposed
    3 / 225 (1.33%)
    3 / 226 (1.33%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FATIGUE
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASTHENIA
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CAPSULAR CONTRACTURE ASSOCIATED WITH BREAST IMPLANT
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    ADNEXAL TORSION
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    DYSPNOEA EXERTIONAL
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         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
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ALVEOLITIS
         subjects affected / exposed
    1 / 225 (0.44%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    IMMUNE-MEDIATED PNEUMONITIS
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         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
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONITIS
         subjects affected / exposed
    2 / 225 (0.89%)
    9 / 226 (3.98%)
         occurrences causally related to treatment / all
    2 / 2
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ACUTE RESPIRATORY DISTRESS SYNDROME
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         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
    3 / 225 (1.33%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    DEPRESSION
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    DEVICE EXTRUSION
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    GAMMA-GLUTAMYLTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GLYCOSYLATED HAEMOGLOBIN INCREASED
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLATELET COUNT DECREASED
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LIPASE INCREASED
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRANSAMINASES INCREASED
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EJECTION FRACTION DECREASED
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OXYGEN SATURATION DECREASED
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    IMPLANTATION COMPLICATION
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WOUND COMPLICATION
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEROMA
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUMBAR VERTEBRAL FRACTURE
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RADIATION PNEUMONITIS
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFUSION RELATED REACTION
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ATRIAL TACHYCARDIA
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC FAILURE CHRONIC
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MITRAL VALVE INCOMPETENCE
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC FAILURE ACUTE
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC FAILURE CONGESTIVE
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUPRAVENTRICULAR TACHYCARDIA
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         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
    5 / 225 (2.22%)
    3 / 226 (1.33%)
         occurrences causally related to treatment / all
    6 / 6
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    MENINGITIS NONINFECTIVE
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (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
    NEUTROPENIA
         subjects affected / exposed
    2 / 225 (0.89%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANAEMIA
         subjects affected / exposed
    1 / 225 (0.44%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    3 / 225 (1.33%)
    10 / 226 (4.42%)
         occurrences causally related to treatment / all
    3 / 3
    11 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LEUKOPENIA
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    APLASTIC ANAEMIA
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    MEIBOMIANITIS
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EYE DISCHARGE
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    COLITIS
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    1 / 225 (0.44%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IMMUNE-MEDIATED PANCREATITIS
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    1 / 225 (0.44%)
    2 / 226 (0.88%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STOMATITIS
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCREATITIS
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    HEPATIC HAEMORRHAGE
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STEATOHEPATITIS
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERTRANSAMINASAEMIA
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BILIARY COLIC
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    1 / 225 (0.44%)
    2 / 226 (0.88%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    SECONDARY ADRENOCORTICAL INSUFFICIENCY
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ADRENAL INSUFFICIENCY
         subjects affected / exposed
    0 / 225 (0.00%)
    4 / 226 (1.77%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOPHYSITIS
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOTHYROIDISM
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    POST PROCEDURAL INFECTION
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOCYSTIS JIROVECII PNEUMONIA
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VULVAL CELLULITIS
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VASCULAR ACCESS SITE INFECTION
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 225 (0.44%)
    2 / 226 (0.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    ABSCESS
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BACTERAEMIA
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEBRILE INFECTION
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    APPENDICITIS
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MASTITIS
         subjects affected / exposed
    0 / 225 (0.00%)
    2 / 226 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 225 (0.00%)
    2 / 226 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA BACTERIAL
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HERPES ZOSTER
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANAL ABSCESS
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    2 / 225 (0.89%)
    2 / 226 (0.88%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    2 / 225 (0.89%)
    4 / 226 (1.77%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STAPHYLOCOCCAL BACTERAEMIA
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POSTOPERATIVE WOUND INFECTION
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEVICE RELATED INFECTION
         subjects affected / exposed
    0 / 225 (0.00%)
    2 / 226 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CYSTITIS
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPTIC SHOCK
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    STAPHYLOCOCCAL INFECTION
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRITIS BACTERIAL
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TOOTH ABSCESS
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WOUND INFECTION
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    METABOLIC ACIDOSIS
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERGLYCAEMIA
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIABETES MELLITUS
         subjects affected / exposed
    1 / 225 (0.44%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo + ddAC-PacHP Atezolizumab +ddAC-PacHP
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    225 / 225 (100.00%)
    226 / 226 (100.00%)
    Vascular disorders
    HOT FLUSH
         subjects affected / exposed
    25 / 225 (11.11%)
    23 / 226 (10.18%)
         occurrences all number
    28
    27
    HYPERTENSION
         subjects affected / exposed
    13 / 225 (5.78%)
    14 / 226 (6.19%)
         occurrences all number
    21
    23
    General disorders and administration site conditions
    CHILLS
         subjects affected / exposed
    13 / 225 (5.78%)
    8 / 226 (3.54%)
         occurrences all number
    14
    8
    PYREXIA
         subjects affected / exposed
    42 / 225 (18.67%)
    44 / 226 (19.47%)
         occurrences all number
    66
    60
    PAIN
         subjects affected / exposed
    15 / 225 (6.67%)
    15 / 226 (6.64%)
         occurrences all number
    21
    20
    FATIGUE
         subjects affected / exposed
    38 / 225 (16.89%)
    61 / 226 (26.99%)
         occurrences all number
    49
    104
    ASTHENIA
         subjects affected / exposed
    85 / 225 (37.78%)
    96 / 226 (42.48%)
         occurrences all number
    189
    197
    MUCOSAL INFLAMMATION
         subjects affected / exposed
    29 / 225 (12.89%)
    33 / 226 (14.60%)
         occurrences all number
    43
    41
    MALAISE
         subjects affected / exposed
    16 / 225 (7.11%)
    11 / 226 (4.87%)
         occurrences all number
    21
    20
    OEDEMA PERIPHERAL
         subjects affected / exposed
    16 / 225 (7.11%)
    14 / 226 (6.19%)
         occurrences all number
    17
    19
    Reproductive system and breast disorders
    BREAST PAIN
         subjects affected / exposed
    15 / 225 (6.67%)
    8 / 226 (3.54%)
         occurrences all number
    16
    8
    Respiratory, thoracic and mediastinal disorders
    RHINORRHOEA
         subjects affected / exposed
    13 / 225 (5.78%)
    24 / 226 (10.62%)
         occurrences all number
    17
    28
    DYSPNOEA
         subjects affected / exposed
    22 / 225 (9.78%)
    18 / 226 (7.96%)
         occurrences all number
    30
    21
    EPISTAXIS
         subjects affected / exposed
    28 / 225 (12.44%)
    28 / 226 (12.39%)
         occurrences all number
    37
    30
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    13 / 225 (5.78%)
    12 / 226 (5.31%)
         occurrences all number
    14
    13
    COUGH
         subjects affected / exposed
    46 / 225 (20.44%)
    37 / 226 (16.37%)
         occurrences all number
    62
    47
    Psychiatric disorders
    INSOMNIA
         subjects affected / exposed
    29 / 225 (12.89%)
    38 / 226 (16.81%)
         occurrences all number
    34
    46
    ANXIETY
         subjects affected / exposed
    15 / 225 (6.67%)
    8 / 226 (3.54%)
         occurrences all number
    17
    8
    Investigations
    BLOOD LACTATE DEHYDROGENASE INCREASED
         subjects affected / exposed
    9 / 225 (4.00%)
    12 / 226 (5.31%)
         occurrences all number
    9
    13
    LYMPHOCYTE COUNT DECREASED
         subjects affected / exposed
    12 / 225 (5.33%)
    13 / 226 (5.75%)
         occurrences all number
    19
    21
    PLATELET COUNT DECREASED
         subjects affected / exposed
    12 / 225 (5.33%)
    15 / 226 (6.64%)
         occurrences all number
    16
    19
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    29 / 225 (12.89%)
    33 / 226 (14.60%)
         occurrences all number
    47
    69
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    49 / 225 (21.78%)
    65 / 226 (28.76%)
         occurrences all number
    77
    99
    BLOOD ALKALINE PHOSPHATASE INCREASED
         subjects affected / exposed
    12 / 225 (5.33%)
    10 / 226 (4.42%)
         occurrences all number
    12
    12
    EJECTION FRACTION DECREASED
         subjects affected / exposed
    19 / 225 (8.44%)
    14 / 226 (6.19%)
         occurrences all number
    25
    14
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    10 / 225 (4.44%)
    13 / 226 (5.75%)
         occurrences all number
    16
    25
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    63 / 225 (28.00%)
    77 / 226 (34.07%)
         occurrences all number
    93
    126
    WEIGHT DECREASED
         subjects affected / exposed
    14 / 225 (6.22%)
    24 / 226 (10.62%)
         occurrences all number
    14
    25
    Injury, poisoning and procedural complications
    WOUND COMPLICATION
         subjects affected / exposed
    16 / 225 (7.11%)
    13 / 226 (5.75%)
         occurrences all number
    16
    14
    RADIATION SKIN INJURY
         subjects affected / exposed
    40 / 225 (17.78%)
    51 / 226 (22.57%)
         occurrences all number
    41
    53
    INFUSION RELATED REACTION
         subjects affected / exposed
    33 / 225 (14.67%)
    39 / 226 (17.26%)
         occurrences all number
    41
    58
    PROCEDURAL PAIN
         subjects affected / exposed
    18 / 225 (8.00%)
    15 / 226 (6.64%)
         occurrences all number
    18
    15
    Nervous system disorders
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    38 / 225 (16.89%)
    46 / 226 (20.35%)
         occurrences all number
    43
    55
    POLYNEUROPATHY
         subjects affected / exposed
    13 / 225 (5.78%)
    13 / 226 (5.75%)
         occurrences all number
    15
    17
    DYSGEUSIA
         subjects affected / exposed
    35 / 225 (15.56%)
    32 / 226 (14.16%)
         occurrences all number
    40
    36
    HEADACHE
         subjects affected / exposed
    48 / 225 (21.33%)
    52 / 226 (23.01%)
         occurrences all number
    67
    81
    PARAESTHESIA
         subjects affected / exposed
    20 / 225 (8.89%)
    15 / 226 (6.64%)
         occurrences all number
    24
    16
    DIZZINESS
         subjects affected / exposed
    22 / 225 (9.78%)
    23 / 226 (10.18%)
         occurrences all number
    29
    29
    HYPOAESTHESIA
         subjects affected / exposed
    9 / 225 (4.00%)
    14 / 226 (6.19%)
         occurrences all number
    11
    15
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    43 / 225 (19.11%)
    43 / 226 (19.03%)
         occurrences all number
    58
    49
    Blood and lymphatic system disorders
    LYMPHOPENIA
         subjects affected / exposed
    13 / 225 (5.78%)
    11 / 226 (4.87%)
         occurrences all number
    28
    21
    NEUTROPENIA
         subjects affected / exposed
    76 / 225 (33.78%)
    66 / 226 (29.20%)
         occurrences all number
    188
    168
    ANAEMIA
         subjects affected / exposed
    114 / 225 (50.67%)
    114 / 226 (50.44%)
         occurrences all number
    217
    173
    THROMBOCYTOPENIA
         subjects affected / exposed
    20 / 225 (8.89%)
    22 / 226 (9.73%)
         occurrences all number
    40
    31
    LEUKOPENIA
         subjects affected / exposed
    50 / 225 (22.22%)
    37 / 226 (16.37%)
         occurrences all number
    122
    105
    Eye disorders
    DRY EYE
         subjects affected / exposed
    8 / 225 (3.56%)
    15 / 226 (6.64%)
         occurrences all number
    8
    15
    Gastrointestinal disorders
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    14 / 225 (6.22%)
    12 / 226 (5.31%)
         occurrences all number
    16
    19
    CONSTIPATION
         subjects affected / exposed
    59 / 225 (26.22%)
    67 / 226 (29.65%)
         occurrences all number
    78
    92
    VOMITING
         subjects affected / exposed
    53 / 225 (23.56%)
    77 / 226 (34.07%)
         occurrences all number
    86
    116
    DRY MOUTH
         subjects affected / exposed
    14 / 225 (6.22%)
    13 / 226 (5.75%)
         occurrences all number
    15
    13
    DIARRHOEA
         subjects affected / exposed
    137 / 225 (60.89%)
    145 / 226 (64.16%)
         occurrences all number
    271
    333
    NAUSEA
         subjects affected / exposed
    138 / 225 (61.33%)
    145 / 226 (64.16%)
         occurrences all number
    281
    313
    STOMATITIS
         subjects affected / exposed
    44 / 225 (19.56%)
    49 / 226 (21.68%)
         occurrences all number
    54
    66
    ABDOMINAL PAIN
         subjects affected / exposed
    21 / 225 (9.33%)
    15 / 226 (6.64%)
         occurrences all number
    23
    16
    DYSPEPSIA
         subjects affected / exposed
    27 / 225 (12.00%)
    25 / 226 (11.06%)
         occurrences all number
    41
    27
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    29 / 225 (12.89%)
    25 / 226 (11.06%)
         occurrences all number
    36
    29
    HAEMORRHOIDS
         subjects affected / exposed
    14 / 225 (6.22%)
    16 / 226 (7.08%)
         occurrences all number
    15
    16
    Skin and subcutaneous tissue disorders
    RASH
         subjects affected / exposed
    46 / 225 (20.44%)
    65 / 226 (28.76%)
         occurrences all number
    58
    96
    ONYCHOLYSIS
         subjects affected / exposed
    6 / 225 (2.67%)
    13 / 226 (5.75%)
         occurrences all number
    9
    15
    DERMATITIS
         subjects affected / exposed
    13 / 225 (5.78%)
    20 / 226 (8.85%)
         occurrences all number
    14
    22
    PRURITUS
         subjects affected / exposed
    23 / 225 (10.22%)
    33 / 226 (14.60%)
         occurrences all number
    33
    38
    ERYTHEMA
         subjects affected / exposed
    17 / 225 (7.56%)
    12 / 226 (5.31%)
         occurrences all number
    23
    19
    NAIL DISORDER
         subjects affected / exposed
    21 / 225 (9.33%)
    17 / 226 (7.52%)
         occurrences all number
    21
    19
    ALOPECIA
         subjects affected / exposed
    141 / 225 (62.67%)
    145 / 226 (64.16%)
         occurrences all number
    150
    149
    DRY SKIN
         subjects affected / exposed
    20 / 225 (8.89%)
    21 / 226 (9.29%)
         occurrences all number
    21
    23
    NAIL DISCOLOURATION
         subjects affected / exposed
    24 / 225 (10.67%)
    17 / 226 (7.52%)
         occurrences all number
    24
    17
    Renal and urinary disorders
    DYSURIA
         subjects affected / exposed
    16 / 225 (7.11%)
    19 / 226 (8.41%)
         occurrences all number
    20
    23
    Endocrine disorders
    HYPERTHYROIDISM
         subjects affected / exposed
    6 / 225 (2.67%)
    22 / 226 (9.73%)
         occurrences all number
    7
    25
    HYPOTHYROIDISM
         subjects affected / exposed
    21 / 225 (9.33%)
    48 / 226 (21.24%)
         occurrences all number
    23
    59
    Musculoskeletal and connective tissue disorders
    BACK PAIN
         subjects affected / exposed
    18 / 225 (8.00%)
    22 / 226 (9.73%)
         occurrences all number
    20
    27
    BONE PAIN
         subjects affected / exposed
    16 / 225 (7.11%)
    14 / 226 (6.19%)
         occurrences all number
    19
    15
    ARTHRALGIA
         subjects affected / exposed
    51 / 225 (22.67%)
    51 / 226 (22.57%)
         occurrences all number
    78
    75
    MYALGIA
         subjects affected / exposed
    41 / 225 (18.22%)
    45 / 226 (19.91%)
         occurrences all number
    65
    61
    PAIN IN EXTREMITY
         subjects affected / exposed
    23 / 225 (10.22%)
    25 / 226 (11.06%)
         occurrences all number
    31
    38
    Infections and infestations
    NASOPHARYNGITIS
         subjects affected / exposed
    15 / 225 (6.67%)
    17 / 226 (7.52%)
         occurrences all number
    17
    20
    CONJUNCTIVITIS
         subjects affected / exposed
    17 / 225 (7.56%)
    14 / 226 (6.19%)
         occurrences all number
    17
    16
    PARONYCHIA
         subjects affected / exposed
    13 / 225 (5.78%)
    13 / 226 (5.75%)
         occurrences all number
    16
    13
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    19 / 225 (8.44%)
    19 / 226 (8.41%)
         occurrences all number
    20
    23
    URINARY TRACT INFECTION
         subjects affected / exposed
    24 / 225 (10.67%)
    23 / 226 (10.18%)
         occurrences all number
    29
    33
    Metabolism and nutrition disorders
    HYPERGLYCAEMIA
         subjects affected / exposed
    4 / 225 (1.78%)
    13 / 226 (5.75%)
         occurrences all number
    5
    15
    HYPOKALAEMIA
         subjects affected / exposed
    10 / 225 (4.44%)
    12 / 226 (5.31%)
         occurrences all number
    12
    15
    HYPOMAGNESAEMIA
         subjects affected / exposed
    14 / 225 (6.22%)
    12 / 226 (5.31%)
         occurrences all number
    22
    20
    DECREASED APPETITE
         subjects affected / exposed
    34 / 225 (15.11%)
    45 / 226 (19.91%)
         occurrences all number
    43
    61

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Mar 2019
    The following updates were made: [1] Trastuzumab emtansine was added as a therapeutic optional therapy in combination with atezolizumab/placebo in the adjuvant setting for participants who did not achieve pathological complete response (pCR); [2] Secondary efficacy endpoints were added; [3] Tissue requirements at screening were clarified; [4] Participants with synchronous bilateral invasive breast cancer, ulcerating and inflammatory breast cancer were excluded; [5] Trastuzumab emtansine, doxorubicin, cyclophosphamide, and paclitaxel were included as investigational medicinal products; [6] Screening mammograms were performed prior to the start of the study; [7] Updated information regarding immune-related nephritis and immune-related myositis risks associated with the administration of atezolizumab; [8] Reference to the continuation and discontinuation of study treatment on the basis of left ventricular ejection fraction (LVEF) measurements.
    04 Jun 2019
    The following updates were made: [1] To provide statistical power to test the primary endpoint of pathological complete response (pCR); [2] An extended China enrollment was added; [3] Participant population and the study rationale was updated; [4] Clarifications were added in regards to the full axillary lymph node dissection; [5] The approved dosage and administration for atezolizumab was added; [6] Clarification of the requirements for performing breast imaging and the performance and intent of tumor assessments; [7] The prescribing information was specified; [8] There was an increase in sites and sample size; [9] Revisions were made to align with the Atezolizumab Investigator's Brochure.
    14 Feb 2020
    The following updates were made: [1] Protocol aligns with atezolizumab Investigator’s Brochure, Version 15; [2] Updates to management guidelines for infusion-related reactions; [3] “Immune-related” was changed to “immune-mediated;” [4] The atezolizumab AE management guidelines for immune mediated myocarditis was revised; [5] The list of potential risks for atezolizumab was revised; [6] Exclusion criteria was updated; [7] Investigational therapy was no longer prohibited during the duration of the study; [8] Clarification that data on breast cancer surgery and pathological assessment was collected from participants who discontinued study treatment during the neoadjuvant phase; [9] Certain participants in the adjuvant phase were not required to provide PK and ADA samples; [10] Participants who discontinued treatment with trastuzumab emtansine for pneumonitis had to discontinue all study treatment.
    12 Feb 2021
    The following updates were made: [1] The independent Data Monitoring Committee (iDMC) recommended to stop treatment with atezolizumab/placebo; [2] China extension phase was cancelled; [3] PK and ADA samples for atezolizumab, trastuzumab and pertuzumab was discontinued during the study treatment phase; [4] Participants would enter the follow-up phase and undergo follow up assessments regardless of reason for discontinuing; [5] Extension of the LVEF assessments; [6] Clarification of continuation of HER2-targeted therapy following Medical Monitor approval; [7] Updates to appendices 9 and 12; [8] Alignment with Investigator's Brochure v17.

    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.
    On February 5, 2021, the experimental treatment was discontinued and unblinded following the recommendation of the independent Data Monitoring Committee (iDMC) to stop treatment with atezolizumab/placebo.
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